Chronic Headache 2019 PDF

Chronic
Headache
A Comprehensive Guide to
Evaluation and Management
Mark W. Green
Robert Cowan
Frederick G. Freitag
Editors
123
Chronic Headache
Mark W. Green • Robert Cowan
Frederick G. Freitag
Editors
Chronic Headache
A Comprehensive Guide
to Evaluation and Management
Editors
Mark W. Green, MD Robert Cowan, MD
Department of Headache and Pain Neurology & Neurological Sciences
Medicine Stanford School of Medicine Neurology
Icahn School of Medicine at Mt. Sinai & Neurological Sciences
Department of Headache and Pain Stanford
Medicine CA, USA
New York
NY, USA
Frederick G. Freitag, DO
Department of Neurology
Medical College of Wisconsin
Department of Neurology
Milwaukee
WI, USA
ISBN 978-3-319-91490-9 ISBN 978-3-319-91491-6 (eBook)

https://doi.org/10.1007/978-3-319-91491-6
© Springer International Publishing AG, part of Springer Nature 2019

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Dedicated to many giants in the field of headache medicine:
Donald Dalessio
John Edmeads
Steven Graff-Radford
John Graham
Robert Kunkel
Marcia Wilkinson
Preface
Chronic daily headache occurs in 3 and 5% of the population worldwide.

While not as common as many other primary headache disorders, the various
chronic daily headaches are associated with greater healthcare utilization,
loss of productivity, and relatively poor quality of life. In many forms of
chronic daily headache, they represent the end stage of headache.
Chronic daily headache is not a diagnosis but a constellation of symptoms.
The headache needs to be evaluated with a thorough understanding of the
history, careful examination of the patient, appropriate diagnostic studies,
consultation with colleagues, and ongoing assessment of the patient leading
to the appropriate diagnosis and treatment.
This book hopes to clarify the diagnosis of chronic daily headache disor-
ders, provide an understanding of the underlying biological substrates, pro-
vide guidance on the use of diagnostic testing and additional consultations,
and develop treatment strategies with the greatest potential to alleviate the
burden of these patients through the highest quality of care.
The book includes an examination of chronic daily headache, the role of
behavioral medicine, and the important elements of the history. Following are
the major forms of these disorders, the role of diagnostic testing and treat-
ment. The underlying biology of these disorders is reviewed and the impact
of these headaches in society is examined. The risk factors that lead patients
to transform episodic primary headache disorders into the chronic form are
examined. Invasive and neuromodulatory techniques are discussed. Somewhat
by way of review and summary we close with a section on the classification
of these disorders.
It is the belief of the authors that this logical approach to chronic daily
headache will provide a greater understanding of these disorders leading to
effective quality care for patients and reduces the burden they experience.
New York, NY Mark W. Green

Stanford, CA Robert Cowan
Milwaukee, WI Frederick G. Freitag
vii
Contents
1 Chronic Daily Headache: Do We Know

It When We See It?�� 1
Shweta Teckchandani and Robert Cowan
2 Refractory Headache or Refractory Patient? Issues
of Locus of Control in Chronic Daily Headache (CDH)�� 11
Sarah E. Trost, Matthew T. Seipel, Emily J. Kalscheur,
and Rebecca C. Anderson
3 Collecting the History in the CDH Patients�� 25
Marius Birlea and Mark W. Green
4 Chronic Migraine: Epidemiology, Mechanisms,
and Treatment�� 37
Teshamae S. Monteith
5 Yogi’s Headache: Chronic Tension-Type Headache �� 63
Duren Michel Ready, Weiwei Dai, Linda Kirby Keyser,
and Cristina Cabret-Aymat
6 Chronic Cluster Headaches�� 77
Soma Sahai-Srivastava
7 New Daily Persistent Headache�� 97
Lauren R. Natbony, Huma U. Sheikh, and Mark W. Green
8 Chronic Secondary Headaches �� 113
Robert Kaniecki
9 Chronic Facial Pain and Other Chronic Neuralgias�� 125
Salman Farooq and Fallon C. Schloemer
10 CDH in Pediatric and Adolescent Patients�� 147
Andrew D. Hershey and Shannon Babineau
11 Imaging in CDH �� 157
Danielle D. DeSouza and Anton Rogachov
12 Laboratory Investigation in CDH�� 169
Benjamin J. Saunders, Iryna S. Aberkorn, and Barbara L. Nye
13 Monitoring of Chronic Daily Headaches �� 185
Sam Hooshmand and Fallon C. Schloemer
ix
x Contents
14 Medication Overuse in Chronic Daily Headache�� 195

Hans-Christoph Diener, Dagny Holle-Lee, and Frederick G.
Freitag
15 Optimizing Acute Headache Treatment
in the Setting of Chronic Migraine�� 207
Amanda Tinsley and John Farr Rothrock
16 Pharmacologic Approaches to CDH:
Evidence and Outcomes�� 217
Miguel J. A. Láinez and Ane Mínguez-Olaondo
17 Behavioral Approaches to CDH: Evidence and Outcomes�� 231
Shalonda S. Slater and Hope L. O’Brien
18 Complementary and Alternative Approaches to Chronic
Daily Headache: Part I—Mind/Body�� 239
Rebecca Erwin Wells, Laura Granetzke, and Brielle Paolini
19 Complementary and Alternative Approaches to Chronic
Daily Headache: Part II—Manipulation-Based Therapies
and Other CAM Therapies �� 253
Brielle Paolini, Laura Granetzke, and Rebecca Erwin Wells
20 Complementary and Alternative Approaches
to Chronic Daily Headache: Part III—Nutraceuticals�� 273
Laura Granetzke, Brielle Paolini, and Rebecca Erwin Wells
21 Animal Models in Chronic Daily Headache (CDH)
and Pathophysiology of CDH�� 289
Xianghong Arakaki, Noah B. Gross, Alfred N. Fonteh,
and Michael G. Harrington
22 Economic Impact of Chronic Headaches�� 309
Anna Pace
23 From Episodic to Chronic: A Discussion on Headache
Transformation�� 313
Anna Pace and Bridget Mueller
24 Chronic Daily Headache and Comorbid Disorders�� 321
Sara Siavoshi, Carrie Dougherty, and Jessica Ailani
25 Neurostimulation in the Management
of Chronic Migraine�� 335
Derrick Alan Shumate and Frederick G. Freitag
26 Postsurgical Headaches and Their Management�� 345
Michael Doerrler and José Biller
27 Chronic Daily Headache Classification�� 357
Maggie W. Waung and Morris Levin
Index�� 383
Contributors
Iryna S. Aberkorn, MD Dartmouth-Hitchcock Medical Center, Lebanon,

NH, USA
Jessica Ailani, MD, FAHS Department of Neurology, Medstar Georgetown
Headache Center, Medstar Georgetown University Hospital, Washington,
DC, USA
Rebecca C. Anderson, BS, MSE, PhD Department of Anesthesiology,
Medical College of Wisconsin, Milwaukee, WI, USA
Xianghong Arakaki, MD, PhD Neurosciences, Huntington Medical
Research Institutes (HMRI), Pasadena, CA, USA
Shannon Babineau, MD
Pediatrics, Goryeb Children’s Hospital,
Morristown, NJ, USA
José Biller, MD, FACP, FAAN, FANA, FAHA Department of Neurology,
Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Marius Birlea, MD, FAHS Neurology, University of Colorado Denver
School of Medicine, Aurora, CO, USA
Cristina Cabret-Aymat, MD Central Texas Headache Fellowship,
Headache Medicine, Baylor Scott and White, Temple, TX, USA
Robert Cowan, MD Department of Neurology and Neurological Sciences,
Stanford Headache and Facial Pain Clinic, Stanford School of Medicine,
Stanford, CA, USA
Weiwei Dai, DO Neurology, Presbyterian Hospital, Rio Rancho, NM, USA
Danielle D. DeSouza, MSc, PhD Neurology and Neurological Sciences,
Stanford University, Palo Alto, CA, USA
Hans-Christoph Diener, MD, PhD Clinical Neurosciences, Department of
Neurology, University Duisburg-Essen, Essen, Germany
Michael Doerrler, DO Department of Neurology, Loyola University
Chicago Stritch School of Medicine, Maywood, IL, USA
Carrie Dougherty, MD, FAHS Department of Neurology, Medstar
Georgetown Headache Center, MedStar Georgetown University Hospital,
Washington, DC, USA
xi
xii Contributors
Salman Farooq, MD Neurology, Medical College of Wisconsin,

Wauwatosa, WI, USA
Alfred N. Fonteh, PhD Neurosciences, Huntington Medical Research
Institutes (HMRI), Pasadena, CA, USA
Frederick G. Freitag, DO Department of Neurology, Medical College of
Wisconsin, Milwaukee, WI, USA
Laura Granetzke, MSN, FNP-C, NCHP Neurology, Wake Forest School
of Medicine, Winston-Salem, NC, USA
Mark W. Green, MD Neurology, Icahn School of Medicine at Mt. Sinai,
New York, NY, USA
Anesthesiology, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
Rehabilitation Medicine, Icahn School of Medicine at Mt. Sinai, New York,
NY, USA
Noah B. Gross, PhD Neurosciences, Huntington Medical Research
Michael G. Harrington, MB, ChB, FRCP Neurosciences, Huntington
Medical Research Institutes (HMRI), Pasadena, CA, USA
Andrew D. Hershey, MD, PhD, FAHS Department of Pediatrics, Division
of Neurology, Cincinnati Children’s Hospital Medical Center, University of
Cincinnati College of Medicine, Cincinnati, OH, USA
Dagny Holle-Lee, MD, PhD Department of Neurology and Headache
Center, University Hospital Essen, Essen, Germany
Sam Hooshmand, DO Department of Neurology, Froedtert and the Medical
College of Wisconsin, Milwaukee, WI, USA
Emily J. Kalscheur, MS (Clinical Psychology) Department of Psychology,
Rosalind Franklin University of Medicine and Science, North Chicago, IL,
USA
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee,
WI, USA
Robert Kaniecki, MD Headache Division, Department of Neurology,
UPMC Headache Center, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA
Linda Kirby Keyser, MD Central Texas Headache Fellowship, Headache
Medicine, Baylor Scott and White, Temple, TX, USA
Miguel J. A. Láinez, MD, PhD, FAAN, FANA, FAHS Department of
Neurology, Neurology Service, University Clinical Hospital, Catholic
University of Valencia, Valencia, Spain
Morris Levin, MD Department of Neurology, UCSF Headache Center,
University of California San Francisco, San Francisco, CA, USA
Ane Mínguez-Olaondo, MD Neurology Service, University Clinical
Hospital, Catholic University of Valencia, Valencia, Spain
Contributors xiii
Teshamae S. Monteith, MD Department of Neurology, Miller School of

Medicine, University of Miami, Miami, FL, USA
Bridget Mueller, MD, PhD Department of Neurology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
Lauren R. Natbony, MD Neurology, Center for Headache and Facial Pain,
Icahn School of Medicine at Mount Sinai, New York, NY, USA
Barbara L. Nye, MD Dartmouth-Hitchcock Medical Center, Lebanon, NH,
USA
Hope L. O’Brien, MD Division of Neurology, Department of Pediatrics,
Cincinnati Children’s Hospital Medical Center, University of Cincinnati
College of Medicine, Cincinnati, OH, USA
Anna Pace, MD Department of Neurology, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
Brielle Paolini, MD, PhD Wake Forest School of Medicine, Winston-Salem,
NC, USA
Duren Michel Ready, MD, FAHS Central Texas Headache Fellowship,
Headache Medicine, Baylor Scott and White, Temple, TX, USA
Anton Rogachov, BSc (PhD Candidate) Institute of Medical Science,
Krembil Research Institute, Toronto Western Hospital, Toronto, ON, Canada
John Farr Rothrock, MD Department of Neurology, GW-MFA Headache
Center, George Washington University School of Medicine and Health
Sciences, Washington, DC, USA
Soma Sahai-Srivastava, MD Clinical Professor of Neurology, Keck school
of Medicine, Los Angeles, CA, USA
Benjamin J. Saunders, MD Commonwealth of Massachusetts, Boston,
MA, USA
Fallon C. Schloemer, DO Department of Neurology, Froedtert and the
Medical College of Wisconsin, Milwaukee, WI, USA
Matthew T. Seipel, MS Department of Psychology, Iowa State University,
Ames, IA, USA
Huma U. Sheikh, MD Neurology, Mount Sinai, New York, NY, USA
Derrick Alan Shumate, DO Neurology, Medical College of Wisconsin,
Milwaukee, WI, USA
Sara Siavoshi, MD Department of Neurosciences, University of California
San Diego, San Diego, CA, USA
Shalonda S. Slater, PhD Division of Behavioral Medicine and Clinical
Psychology, Department of Pediatrics, Cincinnati Children’s Hospital
Medical Center, University of Cincinnati College of Medicine, Cincinnati,
OH, USA
xiv Contributors
Shweta Teckchandani, DO Department of Neurology, Stanford Headache

and Facial Pain Clinic, Stanford Hospital and Clinics, Palo Alto, CA, USA
Amanda Tinsley, MD, MS Department of Neurology, GW-MFA Headache
Center, George Washington University School of Medicine and Health
Sciences, Washington, DC, USA
Sarah E. Trost, PhD Department of Anesthesiology, Medical College of
Wisconsin, Milwaukee, WI, USA
Maggie W. Waung, MD, PhD Department of Neurology, University of
California San Francisco, San Francisco, CA, USA
Rebecca Erwin Wells, MD, MPH Neurology, Wake Forest School of
Medicine, Winston-Salem, NC, USA
Chronic Daily Headache: Do
We Know It When We See It? 1
Shweta Teckchandani and Robert Cowan
Definition stand to be embraced within that shorthand

description and perhaps I could never succeed in
According to Silberstein et al., Chronic daily intelligibly doing so. But I know it when I see
headache (CDH) is a primary headache disorder, it…” Most doctors would agree that this state-
in which headaches occur at least 15 days out of ment is equally applicable to the topic of Chronic
the month for 3 months or more. This is further Daily Headache (CDH). However, in the
subdivided into short-duration (<4 h) headaches International Headache Society’s International
and long-duration (>4 h) headaches. The cate- Classification of Headache Disorders, CDH does
gory includes chronic tension-type headache, not appear as a discrete primary or secondary
chronic migraine, new daily persistent headache, headache disorder. Rather, for chronic migraine
chronic cluster headaches, and hemicrania conti- and tension-type headaches there exists an epi-
nua. The vast majority of patients with CDH sodic presentation. This presumes that the epi-
meet criteria for chronic migraine or chronic sodic headaches precede their chronic
tension-type headache. More than half of these presentation and that they share a common
patients have associated medication overuse pathophysiology.
headache (MOH), which is a separate entity clas- This chapter will explore the roles of treat-
sified as a secondary headache, but commonly ment response, pathophysiology, epidemiology,
seen in patients with CDH [1]. comorbidity, and other factors in chronic daily
headaches. This chapter is not intended to answer
these questions. Other chapters in this book will
Introduction look, in detail, at various aspects of CDH in head-
ache practice. Here we will create a framework, a
Supreme Court Justice Potter Stewart famously context, for this important discussion.
said (in another context) “I shall not today attempt
further to define the kinds of material I under-
Epidemiology
S. Teckchandani (*)
Department of Neurology, Stanford Headache and The prevalence of CDH worldwide is approxi-
Facial Pain Clinic, Stanford Hospital and Clinics, mately 3%, with a range in between 1 and 4% [2,
Palo Alto, CA, USA
3]. In the United States, CDH is 33% more com-
R. Cowan mon in caucasions and in women [4]. CDH is
Department of Neurology and Neurological Sciences,
Stanford Headache and Facial Pain Clinic, Stanford more commonly found in patients with lower
School of Medicine, Stanford, CA, USA socioeconomic status, individuals with comorbid
© Springer International Publishing AG, part of Springer Nature 2019 1

M. W. Green et al. (eds.), Chronic Headache, https://doi.org/10.1007/978-3-319-91491-6_1
2 S. Teckchandani and R. Cowan
pain disorders, and patients who tend to overuse secondary cause. Diagnostic workup may
acute medications for headache management. include brain imaging and a laboratory evalua-
According to Yancey et al., among patients with tion, lumbar puncture, if indicated, physical
CDH, 63% use rescue medications for 14 days or examination to assess for postural dysfunction
more to treat headaches [5]. Patients with CDH are and muscle spasms, and a thorough psychiatric
also more likely to have psychiatric comorbidities evaluation to discover underlying psychiatric
including depression, anxiety, and post-traumatic comorbidities. In a study by Mercante et al.,
stress disorder (PTSD) [1, 6]. CDH is associated major depression was present in 58.7% of the
with poor quality of life and impaired functioning, patients with chronic migraine [8]. The preva-
as well as a decrease in work productivity. This lence of “some depression” was 85.8% in
results in an increased economic burden on society patients with CM, whereas it was only 28.1% in
[6]. In the United States, direct and indirect costs patients with episodic migraine [10]. It is also
from migraines are estimated to be $20 billion important to identify any underlying medication
annually, most of which is due to chronic migraine overuse, specifically if the patient takes barbitu-
[7]. As compared to an individual with episodic rates or opioid medications. The National
migraine, the yearly average cost per person with Association of State Controlled Substances
chronic migraine is more than four times greater Authorities is working to provide a forum for
[7]. the discussion and exchange of information and
ideas to develop, implement, and monitor ongo-
ing strategies to curtail the abuse, misuse, and
Pathophysiology diversion of controlled substances. The avail-
ability of such a report may help with the type of
The pathophysiology of CDH remains largely medication use, dosing, and timing of pharma-
unknown but is likely multifactorial. The pro- cotherapy. Once a secondary cause is ruled out,
posed mechanism involves genetic factors, in treatment includes appropriate management
association with maladaptive neural plasticity of therapy of the underlying primary headache
the nervous system that includes peripheral and with a multidisciplinary approach.
central sensitization, defective pain modulation,
and lack of habituation [1]. In addition, abuse of
analgesics, significant comorbidity with psychi- Chronic Migraine
atric disorders (anxiety, depression, and panic),
and sleep disorders may all be involved [8]. As defined by the ICHD-3 criteria, chronic
Epidemiological studies have identified several migraine is a headache occurring on 15 or more
risk factors associated with chronification of days per month for more than 3 months, with on
headaches. These include medication overuse, at least 8 days per month, with features of epi-
obesity, female gender, caffeine overuse, psychi- sodic migraine with or without aura.
atric comorbidities (depression, anxiety, and
somatization disorders), allodynia, high baseline
headache frequency, old age and low socioeco- iagnostic Criteria for Chronic
D
nomic status [9]. Migraine
A. Headache (tension-type-like and/or migraine-

Diagnosis and Classification like) on ≥15 days per month for >3 months
of Chronic Daily Headache [6] and fulfilling criteria B and C.
B. Occurring in a patient who has had at least
The first step in the evaluation of patients with five attacks fulfilling criteria B-D for 1.1
chronic daily headache is to obtain a thorough Migraine without aura and/or criteria B and C
history and physical examination to exclude a for 1.2 Migraine with aura.
1 Chronic Daily Headache: Do We Know It When We See It? 3
C. On ≥8 days per month for >3 months, fulfill- combination of pharmacologic and non-
ing any of the following [2]: pharmacologic therapies. Pharmacologic treat-
1. Criteria C and D for 1.1 Migraine without ment typically involves daily preventative
aura. medication. It should be noted that only two
2. Criteria B and C for 1.2 Migraine with agents (OnabotulinumtoxinA and topiramate)
aura. have strong evidence in chronic migraine [11],
3. Believed by the patient to be migraine at while a wide variety, with evidence only for epi-
onset and relieved by a triptan or ergot sodic migraine, is commonly used.
derivative. First-line agents that have evidence of efficacy
D. Not better accounted for by another ICHD-3 include medications from three broad classes:
diagnosis. anti-epileptics, anti-depressants, and anti-
hypertensives [12]. Medications that are com-
monly used in treating chronic migraine are listed
Treatment in Table 1.1. In the United States only a few have
FDA approval for migraine prophylaxis (propran-
There is an attractive misconception in medicine olol, timolol, divalproex sodium, and topiramate)
that if treatment A is recommended for diagnosis [13]. However, calcium-channel blockers includ-
X, then it follows that if the treatment is unsuc- ing verapamil, flunarizine (not available in the
cessful, the diagnosis is incorrect. Nowhere in United States), and some antidepressants (tricy-
medicine is treatment response less reliable as a clic antidepressants, serotonin reuptake inhibi-
diagnostic tool than in chronic daily headache tors, serotonin norepinephrine reuptake inhibitors)
diagnosed as Chronic Migraine. The best are frequently used off-label [13]. Dosages should
approach to treatment of chronic migraine is a be increased gradually to avoid adverse effects
Table 1.1 Medications for the Treatment of Chronic Migraine

Drug Daily dose range Possible adverse effects
Beta blockers
Propranolol 80–240 mg divided bid or tid Hypotension, fatigue, asthma/COPD
exacerbations
Timolol 10–50 mg bid or 20 mg daily
Anti-epileptic drugs
Valproate 250–500 mg bid Alopecia, drowsiness, weight gain, tremors,
Valproate extended release 500–1000 mg daily liver abnormalities, fetal abnormalities
Topiramate 50 mg bid Paresthesias, word-finding difficulty,
cognitive slowing, nephrolithiasis, acute
angle-closure glaucoma
Gabapentin 300–3600 mg divided bid or tid Edema, sedation, fatigue
Tricyclic antidepressants
Nortriptyline 10–150 mg daily Weight gain, dry mouth, drowsiness
Amitriptyline 30–150 mg daily
Venlafaxine 75–150 mg daily Nausea, vomiting
Calcium Channel blockers
Verapamil 80–480 mg divided tid Constipation, atrioventricular conduction
disturbances
Extended-release-generic 240 mg daily
Angiotensin–converting enzyme indicator
Lisinopril, generic 5–40 mg daily Hypotension
Angiotensin–Receptor blocker
Candesartan 8–21 mg daily Hypotension
Data from [58, 59]
and treated for an adequate period of time. Once Diagnostic Criteria

an effective treatment is found, it should typically
be continued for at least 3–12 months. An effec- A. Headache occurring on ≥15 days per month
tive treatment is one without significant adverse on average for >3 months (≥180 days per
effects and improvement in headache frequency year), fulfilling criteria B-D.
by at least 50% [12]. Increasingly, improvement B. Lasting hours to days, or unremitting.
in disability measures is considered an important C. At least two of the following four
measure of overall improvement. characteristics:
OnabotulinumtoxinA: Botox is FDA-approved 1. Bilateral location.
for chronic migraine, rather than high frequency 2. Pressing or tightening (non-pulsating)

episodic migraine. It was approved in 2010 by quality.
the Food and Drug Administration (FDA) based 3. Mild or moderate intensity.
on phase III research studies evaluating migraine 4. Not aggravated by routine physical activ-
prophylactic therapy (PREEMPT protocol). At a ity such as walking or climbing stairs.
24-week follow-up, researchers assessed whether D. Both of the following:
patients had at least 50% reduction in their head- 1. No more than one of photophobia, phono-
ache frequency. According to the study, at least phobia, or mild nausea.
47.1% of the patients treated with onabotulinum- 2. Neither moderate or severe nausea nor

toxinA had achieved this degree of improvement vomiting
as compared to 37.1% of the placebo group [14, E. Not better accounted for by another ICHD-3
15]. diagnosis.
Patients should also be cautioned regarding
medication overuse headaches and advised to
limit the use of acute medications. Non- Treatment of Chronic Tension-Type
pharmacologic strategies involve behavioral ther- Headache
apies and life-style changes, primarily and are
discussed later [16]. Anxiety and depression are common in patients
experiencing CTTH. Therefore, management of
CTTH may properly include pharmacotherapy,
Chronic Tension-Type Headache psychotherapy including cognitive behavioral
therapy, biofeedback, and physical therapy to
Tension-type headache is the most prevalent type include trigger point focused massage. Evidence
of headache, and affects 78% of people at some for pharmacologic therapies is limited and incon-
point in their life. Chronic tension-type headache sistent, but strongest for tricyclic anti-depressants
(CTTH) affects 3% of the population in the [18]. In a study by Jackson et al., it was noted that
United States and is more prevalent in women TCAs significantly reduced the number of days
[17]. Those with TTH are less likely to come to with tension-type headache and number of head-
medical attention compared to migraineurs. ache attacks compared to placebo. The effect of
According to ICHD-3 beta classification, TCAs increased with longer duration of treatment
chronic tension-type headache (CTTH) evolves and TCAs were also more likely to reduce the
from frequent episodic tension-type headache, intensity of headaches by at least 50% compared
with daily or very frequent episodes of headache. to placebo or SSRIs [19]. Tricyclic antidepres-
They are typically bilateral, pressing, or tighten- sants (TCAs) that are commonly used for prophy-
ing in quality, and of mild to moderate intensity, laxis include amitriptyline and nortriptyline.
lasting hours to days, or unremitting. The pain According to Cohen, protriptyline may be compa-
does not worsen with routine physical activity, rable in effectiveness to amitriptyline in CTTH
but may be associated with mild nausea, photo- without causing drowsiness and weight gain [20].
phobia, or phonophobia, but not more than one of In a double-blind placebo-controlled trial con-
these. ducted by Saper et al. of fluoxetine in patients
with chronic daily headache and migraine, it was 1. At least one of the following symptoms or
reported to be helpful, but in general the use of signs, ipsilateral to the headache:
SSRIs in chronic tension-type headache has little a) Conjunctival injection and/or
evidence [21]. Small studies using venlafaxine lacrimation.
and mirtazapine have been positive. There is little b) Nasal congestion and/or rhinorrhea.
support for the use of muscle relaxants in c) Eyelid edema.
CTTH. In a randomized controlled trial by d) Forehead and facial sweating.
Holroyd et al., combination therapy of antidepres- e) Forehead and facial flushing.
sants and stress management therapy had better f) Sensation of fullness in the ear.
outcomes than either treatment individually [22]. g) Miosis and/or ptosis.
In addition to medications, individualized psy- 2. A sense of restlessness or agitation, or

chotherapy targeting stress and anxiety manage- aggravation of the pain by movement.
ment, developing relaxation techniques, and D. Responds absolutely to therapeutic doses of
biofeedback training play an important role in the indomethacin.
management of CTTH. Other treatment modali- E. Not better accounted for by another ICHD-3
ties that are useful as adjunct therapies include diagnosis.
physical therapy with heat, massages, transcuta-
neous electric nerve stimulation (TENS), and
stretching exercises [23, 24]. Additionally, mini- Treatment of Hemicrania Continua
mally invasive procedures such as trigger point
injections, greater and occipital nerve blocks, and As indicated in the diagnostic criteria, indometha-
acupuncture can be helpful [25, 26]. cin is the first-line treatment for treating HC [2, 27].
It is recommended to start at 25 mg three times
daily, with a gradual titration in dose until complete
Hemicrania Continua pain relief. Typically, therapeutic doses range from
150 mg to 225 mg daily [2]. Treatment failure is
Hemicrania continua (HC) is one of the trigemi- considered if the patient does not respond to a dose
nal autonomic cephalalgias (TACs), and is an of 300 mg daily or develops significant adverse
extremely disabling disorder. Exact prevalence of effects. Given the significant gastrointestinal
HC is unknown. The incidence is higher among adverse effects of Indomethacin, periodic attempts
females, with a ratio of approximately 2:1 and to decrease the dose should be made. Concurrent
can occur at any age [27]. It commonly occurs in use of proton pump inhibitors is indicated to protect
the third decade of life, but with a range from first from gastrointestinal side effects of indomethacin
to seventh decades [28]. As defined by the [28]. It remains controversial whether alternative
ICHD-3 beta, HC is a persistent, strictly unilat- delivery (such as suppository) can circumvent the
eral side-locked headache, associated with ipsi- GI side effects. Although not commonly used, there
lateral conjunctival injection, lacrimation, nasal have been case reports of other alternative therapies
congestion, rhinorrhea, forehead and facial including melatonin, Boswellia, topiramate, vera-
sweating, miosis, ptosis and/or eyelid edema, pamil, COX-2 inhibitors, gabapentin, and occipital
and/or restlessness or agitation. The headache is nerve stimulation [27, 29–34].
absolutely responsive to indomethacin.
Chronic Cluster Headache

Diagnostic Criteria
Cluster headache belongs to a group of idiopathic
. Unilateral headache fulfilling criteria B-D.
A headache entities, the trigeminal autonomic
B. Present for >3 months, with exacerbations of cephalalgias (TACs), all of which involve unilat-
moderate or greater intensity. eral, often severe headache attacks and typical
C. Either or both of the following: accompanying autonomic symptoms [2, 35].
About 10–15% of cluster headache patients have headache attacks and prophylactic therapy aimed
chronic cluster headache (CCH) [36]. to prevent future attacks [37]. Cluster headache
ICHD 3-beta defines cluster headaches as pain is intense and builds up rapidly. Therefore,
attacks of severe, strictly unilateral pain which is for acute therapy, medications with a rapid onset
orbital, supraorbital, temporal, or in any combi- are needed [38]. The most effective treatments
nation of these sites, lasting 15–180 min and for acute therapy include 100% oxygen or a
occurring from once every other day to eight rapidly-acting triptan [38]. A double-blind ran-
times a day. The pain is associated with ipsilat- domized trial evaluated 76 patients, each treating
eral conjunctival injection, lacrimation, nasal four cluster headache attacks, and compared 100
congestion, rhinorrhea, forehead and facial percent oxygen therapy (at 12 L/min for 15 min)
sweating, miosis, ptosis and/or eyelid edema, with air placebo. By intention-to-treat analysis,
and/or with restlessness or agitation. pain-free status or adequate relief of attacks at
15 minutes was significantly more frequent with
oxygen (78 percent of attacks, versus 20 percent
Diagnostic Criteria with placebo) [39]. Randomized, double-blind,
placebo- controlled trials have established that
. At least five attacks fulfilling criteria B-D.
A triptans, particularly sumatriptan (subcutaneous
B. Severe or very severe unilateral orbital, supra- and intranasal) and zolmitriptan (intranasal), are
orbital and/or temporal pain lasting effective for the acute treatment of cluster head-
15–180 min (when untreated). ache [40]. Another important consideration is the
C. Either or both of the following: use of transitional medications while prophylac-
1. At least one of the following symptoms or tic medications are being increased to therapeutic
signs, ipsilateral to the headache: levels. A tapering schedule of oral corticosteroids
a) Conjunctival injection and/or is frequently used to rapidly stop cluster attacks,
lacrimation. usually within days [38]. However, in rare cases,
b) Nasal congestion and/or rhinorrhea. corticosteroids may be used long-term if patients
c) Eyelid edema. fail to respond to other prophylactic therapies
d) Forehead and facial sweating. [41, 42]. Prolonged systemic steroid use can
e) Forehead and facial flushing. cause weight gain, Cushingoid facies, easy bruis-
f) Sensation of fullness in the ear. ing and skin fragility, cataracts, aseptic necrosis
g) Miosis and/or ptosis. of the femoral or humeral heads, hypertension,
2. A sense of restlessness or agitation. diabetes, infection, and osteoporosis all of which
D. Attacks have a frequency between one every need to be discussed with the patient prior to ini-
other day and 8 per day for more than half of tiating therapy.
the time when the disorder is active. With respect to prophylactic therapy, vera-
E. Not better accounted for by another ICHD-3 pamil has the best evidence in the treatment of
diagnosis. chronic cluster headaches [35, 38]. In a double-
blinded study by Leone et al., verapamil signifi-
Chronic cluster headache is defined as having cantly reduced attack frequency and analgesic
all the features mentioned above occurring with- consumption as compared to placebo [43].
out a remission period, or with remissions lasting Verapamil is usually initiated at a dose of 240 mg
<1 month, for at least 1 year. daily (divided into three doses) and an adequate
trial for most patients entails use of a total daily
dose of 480 mg to 960 mg daily or as tolerated
reatment of Chronic Cluster
T before the medication is regarded as a failure [35,
Headache 44]. At higher doses, verapamil can cause brady-
cardia and prolongation of PR interval. Therefore,
In general, treatment for cluster headache can be regular electrocardiographic (ECG) monitoring
divided into acute therapy to abort individual is recommended [37]. Lithium carbonate is
second-line therapy in cases where verapamil is Diagnostic Criteria

contraindicated or ineffective, or as an add-on to
verapamil. In a comparison study by Bussone A. Persistent headache fulfilling criteria B and
et al., verapamil and lithium appeared to have C.
similar efficacy but lithium was found to work B. Distinct and clearly-remembered onset, with
slowly and had more adverse effects [45]. The pain becoming continuous and unremitting
initial dose for adults is usually 300 mg two or within 24 h.
three times daily, with a gradual increase in dose C. Present for >3 months.
based upon lithium levels and the response; the D. Not better accounted for by another ICHD-3
typical maintenance dose is 900–1200 mg/day diagnosis.
given in three to four divided doses of the regular
formulation, or in two divided doses of the sus- NDPH can occur at any age, with an average
tained release formulation. The lithium plasma onset at about 35 years. Clinically, NDPH may
level should be monitored and should not exceed resemble migraine or tension-type headaches or
1.2 mEq/L [35]. No therapeutic lithium level in have no distinguishing features. However, the
cluster headache has been established. Major key difference is that patients with NDPH
adverse effects of lithium include renal dysfunc- remember the exact time of onset of headache
tion, tremor, and endocrinologic abnormalities [46]. The precise mechanism that underlies this
[38]. Other medications that have been used as condition is unknown. In a study by Rozen et al.
adjunctive therapies include topiramate, melato- it was noted that TNF-alpha levels were elevated
nin, and divalproex sodium [42]. in the CSF of 19 out 20 NDPH patients, but these
Although not yet approved, CGRP antibodies findings have not been replicated [49]. Post-
show promise in the treatment of cluster head- surgical events, stressful life events, and/or toxic
ache. External vagal nerve stimulation has been exposures are also thought to be triggers for the
approved in the United States for the treatment of development of NDPH. Patients who develop
cluster headache. NDPH after a viral illness or a stressful event
may develop glial activation and persistent cyto-
kine production that triggers a chronic inflamma-
New Daily Persistent Headache tory response [46]. When evaluating a patient
with a suspected diagnosis of NDPH, diagnostic
New daily persistent headache (NDPH) presents workup should exclude secondary causes of
as a prolonged, unremitting headache that is headache prior to establishing the diagnosis of
often refractory to treatment [3]. It starts out NDPH. Initial workup includes MRI of the brain
abruptly, sometimes following a particularly with and without contrast, and MRV and MRA of
stressful event or a viral illness, but often times, the head and neck. Laboratory testing includes
without any specific triggering event. Up to 30% complete blood count, serum chemistry and elec-
of individuals have had a viral illness prior to trolyte panel, thyroid studies, erythrocyte sedi-
onset of the headache [46]. In one study, more mentation rate, lupus antibody, and viral titers
than 50% of 186 NDPH patients tested positive [50]. Finally, a lumbar puncture should be con-
for Epstein-Barr virus (EBV) serology [47]. sidered if the above-mentioned studies are within
However, more than 50% of the patients do not normal limits.
recall any triggering event. Once the headache
starts, it is unremitting, persisting as a continuous
headache [48]. Often, there is no previous history Treatment of NDPH
of headaches. As defined by ICHD-3, it is a per-
sistent headache, daily from its onset, the time of The challenges with NDPH are establishing this
which is often remembered. The pain lacks char- diagnosis, and the lack of evidence-based treat-
acteristic features, and may be migraine-like, or ments [50]. A reasonable course of management
tension-type-like, or have elements of both. is to combine a healthy lifestyle with exercise, a
regular diet, and a regular sleep schedule in com- of CBT includes behavioral techniques that
bination with preventative medications used for include differential reinforcement, progressive
other headache disorders [50]. Given that there muscle relaxation, and pacing strategies [55].
is little evidence for effective treatments for Simultaneous use of different therapies may be
NDPH, a commonly used strategy by headache needed for maximum benefit. In a study by
specialists is to select treatments based on the Marcus et al., a combination of physical ther-
phenotype (migrainous vs tension-type). apy and biofeedback was shown to provide
Potential treatments that have been studied for greater relief than physical therapy alone [57].
NDPH include doxycycline, low dose naltrex-
one, topiramate, and prazosin [51]. Naltrexone is
commonly used for chronic pain disorders and is Discussion
shown to inhibit the production of TNF-α which
is a proposed mechanism for the development of There are many challenges in the diagnosis and
NDPH [51, 52]. In a small study by Rozen, four treatment of CDH. With respect to the diagnosis,
patients with NDPH were treated with doxycy- an important question remains: Is CDH simply
cline 100 mg twice daily [49]. These patients the chronic presentation of a primary episodic
had previously failed five other preventative headache? In other words, does a patient with
agents. All of the patients had a significant headache more days than not, of which 8 head-
improvement after 3 months. Two patients were ache days monthly have migrainous features,
pain-free, and the other two patients had more have the same headache as a patient without daily
than 50% reduction in frequency of the head- headaches who also has 8 headache days with
aches. These findings have not been replicated in migrainous features? Considerable evidence sug-
larger studies. gests that one with CM has a different medical
condition and pathophysiology compared to
someone with episodic migraine. Other questions
Non-Pharmacologic Treatment persist: Why is chronic migraine seen in only 4%
for Chronic Daily Headache of migraine sufferers while chronic cluster is
present in 10–15% of patients with cluster head-
CDH is a serious disease and results in a poor ache? Why are treatments for episodic primary
quality of life, impaired function, and disabil- headache disorders poorly effective in their epi-
ity. Pharmacologic therapies, both acute and sodic counterparts, even in the absence of medi-
preventative, are insufficient in the manage- cation overuse? And finally, is NDPH, in which
ment of these patients [53, 54]. Therefore, half of patients report some precipitating event,
CDH should be managed with an interdisci- truly a primary headache disorder or simply a
plinary approach. In conjunction with pharma- secondary headache disorder with a yet to be
cologic therapy, non-pharmacologic treatments unidentified etiology?
such as cognitive behavioral therapy, physical Challenging the assumptions behind these
therapy, biofeedback, and mindfulness training classification decisions remains equally impor-
as a form of relaxation therapy may be useful tant. The underlying genetic and epigenetic fea-
[54]. The Cochrane review from 2014 showed tures, comorbidities, and behavioral factors that
that psychological treatments in children and determine whether a given individual will prog-
adolescent patients are effective in reducing ress from either no headaches or episodic head-
pain intensity and maintenance of therapeutic aches to chronic headaches are yet to be identified.
gains [55]. Cognitive behavioral therapy (CBT) Future improved imaging, proteomic and
can have short-term and long-term benefits in genomic marker development, and novel thera-
patients with migraines [12, 56]. Patients are pies are likely to better elucidate the underlying
taught to use imagery and distraction tech- pathophysiology and risk factors for the chronifi-
niques as coping skills [55]. The other aspect cation of headache disorders [60].
Conclusion 12. Garza I, Schwedt TJ. Diagnosis and manage-

CDH is widely viewed as arising from its epi- ment of chronic daily headache. Semin Neurol.
2015;30(2):154–66.
sodic counterpart. It is clear from recent imag- 13. Bloudek LM. Cost of healthcare for patients with
ing and pathophysiologic studies that CDH migraine in five European countries: results from
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org/10.1007/s10194-012-0460-7. Published online
and investigative studies might help to predict 2012 May 29PMCID: PMC3381065
which patients with episodic headache syn- 14. Silberstein S, Mathew N, Saper J, for the Botox

dromes are at increased risk for developing Migraine Clinical Research Group. Botulinum toxin
CDH. Careful attention to the consensus- a as a migraine preventive treatment. Headache.
2000;40:445–50.
based diagnostic criteria presented here, in 15. Tepper D, Traduzido por Marcelo MV. Onabotulinum
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Trigeminal autonomic cephalalgias: diagnostic
Refractory Headache or Refractory
Patient? Issues of Locus of Control 2
in Chronic Daily Headache (CDH)
Sarah E. Trost, Matthew T. Seipel,
Emily J. Kalscheur, and Rebecca C. Anderson
Introduction between patient and provider and to help each

move toward a more positive treatment outcome.
The treatment of chronic daily headache (CDH) In this chapter, we present an overview of
can be a challenge for both patient and provider. locus of control and the related concept of self-
While many patients find relief with available efficacy and discuss findings from the empirical
treatment options, some patients continue to literature relevant to the treatment of CDH. Next,
experience intractable symptoms despite the best we provide a broad overview of two psychoso-
efforts of their treatment team. In this scenario, cial interventions, cognitive-behavioral therapy
it is not uncommon for patients to become frus- and motivational interviewing, both of which can
trated, expecting their provider to do more to be used to increase a patient’s sense of control
treat their pain. In the same way, providers may over the management of their headaches as well
become frustrated that a patient’s pain remains as the self-efficacy to make necessary behavioral
unchanged and speculate how the patient may changes. Common assessments and the use of
be contributing to the maintenance of the status biofeedback in the treatment plan are also dis-
quo. In short, treatment can become stuck. The cussed. We conclude by offering providers sug-
psychological construct of locus of control has gestions to increase both patient and provider
much to offer in understanding this dynamic locus of control and self-efficacy to optimize the
course of treatment. Concepts are illustrated in a
case study.
S. E. Trost (*) · R. C. Anderson Locus of Control

Department of Anesthesiology, Medical College of
Wisconsin, Milwaukee, WI, USA Locus of Control Defined
e-mail: strost@mcw.edu
M. T. Seipel The locus of control (LOC) construct was origi-
Department of Psychology, Iowa State University,
nally introduced in Rotter’s social learning the-
Ames, IA, USA
ory of personality [1] to characterize the extent
E. J. Kalscheur
to which people believe the outcomes of events
Department of Psychology, Rosalind Franklin
University of Medicine and Science, North Chicago, in their lives are controlled by themselves or by
IL, USA external factors (e.g., other people, chance). Rot-
Department of Anesthesiology, Medical College of ter emphasized that LOC is a continuum, rang-
Wisconsin, Milwaukee, WI, USA ing from internality to externality, rather than a

12 S. E. Trost et al.
dichotomous typology. For example, a person global health in a recent study: the relation-
with a more strongly internal LOC may attribute ship was positive for internal HLOC and nega-
their ability to fall asleep to their own capacity to tive for chance and powerful others HLOC [6].
relax their body, yet they may also acknowledge Another recent study found chance HLOC to
the contribution of external factors such as room be associated with deficits in health promotion
temperature and street noise. Additionally, each behaviors (e.g., physical activity, usage of pre-
person can be thought to exhibit a global LOC ori- ventative healthcare, health information-seeking)
entation, as well as varying LOC for specific life [7]. Higher levels of internal HLOC have also
domains (e.g., health, work, romantic relation- been associated with better treatment adherence
ships), with internal LOC generally associated in patients with type 2 diabetes [8], higher quality
with more positive outcomes [2]. The application of life and physical functioning in recently hospi-
of LOC theory and research has guided practice talized older adults [9], and adolescents’ engage-
in a variety of domains, including health psychol- ment in positive health behaviors [10]. Stronger
ogy, clinical psychology, and medicine. internal HLOC, in addition to lower powerful
others HLOC, was also associated with a greater
likelihood of patients with coronary heart dis-
Health LOC ease returning to work [11], as well as improved
physical functioning in patients with chronic pain
The concept of LOC has been applied to health [12]. Conversely, in a sample of cancer patients,
since Rotter introduced it, and a health-specific internal HLOC was associated with higher risk of
LOC construct emerged in the literature in the depression, whereas powerful others HLOC was
early 1970s. Wallston and Wallston provided a associated with lower risk of depression [13].
simple definition of health LOC (HLOC): “the Examining newer conceptualizations of HLOC,
degree to which individuals believe that their a stronger belief that a higher power determined
health is controlled by internal versus external health outcomes has also been associated with
factors” [3], p. 68. Initially HLOC was concep- lower treatment compliance (e.g., asthma medi-
tualized as a unidimensional construct, with its cation adherence) [14]. Attention is now turned
first formal measure classifying individuals as to a growing niche in this literature: headache-
either “health externals” or “health internals” specific locus of control.
[4]. Shortly thereafter, a new paradigm and asso-
ciated measure emerged that conceptualized
HLOC as multidimensional, involving internal Headache-Specific LOC
LOC and two forms of external LOC. Specifi-
cally, it divided external HLOC into two distinct General HLOC was naturally extended to
components: powerful others (e.g., physicians, research and treatment conceptualization in
family members) and chance [5]. Thus, an indi- the headache domain, but experts in this area
vidual with external HLOC could to varying quickly began to question if chronic headache
degrees believe their health is contingent upon patients attributed control of their headache
the acumen of their medical providers as well as symptoms to the same source(s) as their overall
fate. This multidimensional measure has since heath, as well as whether simply imputing the
been adapted to assess LOC relative to a specific word “headache” into existing HLOC measures
illness or disease (as opposed to overall health), would provide accurate and useful information.
as well as to include a higher power (i.e., God) as The construct of headache-specific LOC (HSLC)
a third type of external locus. first appeared in the literature in 1990, with the
HLOC has demonstrated significant relation- publication of the headache-specific locus of
ships with health behaviors and outcomes in vari- control scale (discussed further in Assessments
ous populations. The three predominant types below) [15]. This measure was developed from
of HLOC were significantly related to self-rated new, e xpert-generated items, as well as adapted
2 Refractory Headache or Refractory Patient? Issues of Locus of Control in Chronic Daily Headache (CDH) 13
items from the multidimensional HLOC scale. A patients who believe their headache pain is due
similar three-factor structure was upheld in the to chance or the skill of their doctor fare more
HSLC scale (i.e., internal LOC, chance LOC, poorly than those who do not have such external
and healthcare professionals LOC), and it dem- attributions.
onstrated incremental validity by explaining The direct relationship between internal
significant variance in outcomes (e.g., headache HSLC and headache-related outcomes has been
frequency and intensity) beyond that accounted less clear. On the one hand, some researchers
for by the general HLOC scale. have found internal HSLC was related to impair-
The initial validation of the HSLC scale ments in quality of life and emotional function-
yielded interesting results that illustrated the ing [17], as well as greater headache-related
practical impact of HSLC for chronic headache disability [18]. However, other researchers have
patients [15]. Chance HSLC was positively asso- found that internal HSLC was associated with
ciated with headache-related disability, physical lower levels of depression and that it moderated
complaints, depression, and maladaptive coping the relationship between headache pain severity
strategies. Healthcare professionals HSLC was and depression [23]. Additionally, some evidence
positively associated with level of medication use suggests that internal HSLC may have an indirect
and preference for medical treatment. Internal positive association with quality of life by way
HSLC was positively associated with preference of self-efficacy (discussed later in this chapter)
for self-regulation treatment. Additionally, all [18], and researchers have noted that behavioral
of these associations remained significant after treatments (e.g., behavioral migraine manage-
controlling for headache frequency and intensity, ment) that increase internal HSLC are effective
which suggests that HSLC is a salient treatment in decreasing migraine-related impairment [19].
consideration for chronic headache patients. The In a recent article, Grinberg and Seng offered
psychometric properties and predictive validity the following attempt to reconcile the discrepant
of the HSLC scale were independently validated findings regarding internal HSLC:
shortly thereafter, with scores on the three sub- It is possible that internal HSLC is multifac-
scales differentiating chronic headache patients torial; perhaps internal HSLC is adaptive in
from non-patients with less severe headache relation to headache-related phenomena that
symptoms [16]. are indeed controllable by the individual (e.g.,
These early findings have been largely sup- stress management, migraine medication-taking
ported by ensuing research, with many studies behaviors), whereas, internal HSLC is less adap-
highlighting additional nuances and complexity tive in relation to phenomena which the individ-
in the relationships between HSLC and head- ual may exert little influence (e.g., the presence
ache-related outcomes [17–19]. However, the of migraine), partly due to the relationship with
evidence has been particularly consistent that anxiety and emotional migraine-related quality
high chance and healthcare professionals HSLC of life impairments[…] Although effective behav-
are associated with poor headache-related out- ioral treatments increase internal HSLC, higher
comes. A recent study found both chance and internal HSLC in the absence of migraine man-
healthcare professionals HSLC were related to agement tools taught during behavioral treat-
lower quality of life [17]. Another recent study ment may be maladaptive [17] pp. 140–1.
found higher chance HSLC was associated with Thus, the relationship between internal HSLC
greater symptom chronicity [20]. Healthcare pro- and headache-related outcomes appears to be
fessionals HSLC previously demonstrated a posi- context-dependent and is likely affected by the
tive association with headache-related disability type of outcome measured, as well as the pres-
[21]. Another earlier study also found greater ence of symptom management tools and sup-
chance and healthcare professionals HSLC were ports.
predictive of greater pain intensity and subjective Overall, the dimensions of HSLC are clearly
impairment [22]. Thus, research suggests that salient in headache patient outcomes. This makes
HSLC an important consideration in and poten- Unlike LOC, standardized measures of

tial target of medical and psychosocial interven- health-related SE have been less prevalent. A
tions, with its utility optimized when regarded notable exception is the Arthritis Self-Efficacy
alongside other psychological constructs such as Scale, which has been widely used since 1989
self-efficacy. and has demonstrated good validity and reliabil-
ity [31]. The first headache-specific SE scale
appeared in the literature in 1993, and it focused
Self-Efficacy on SE regarding the prevention of headaches
[32]. The Headache Management Self-Efficacy
Self-efficacy (SE), introduced in 1977 as a key (HMSE) scale (discussed further in Assessments
construct in Bandura’s social cognitive theory, below) was published in 2000 and continues to
is defined as a person’s belief in his or her abil- be the most cited measure of headache-specific
ity to complete a specific task or be successful SE today [18]. It extended beyond beliefs about
in a specific situation [24]. Additionally, SE has preventing headaches to include beliefs about
also been regarded as a broader individual dif- managing headaches and headache-related dis-
ference construct in which a person possesses a ability, which is noteworthy given that for most
general belief regarding his or her ability to com- patients headaches are difficult to predict and
plete any task that they encounter. SE is typically prevent. Recently, a measure was also intro-
considered to be moderately to strongly related duced that targets SE specifically for acute
to LOC, and some scholars have even suggested headache medication adherence, an important
that the two may be markers of a higher-order component of treatment for most chronic head-
psychological construct [25]. However, the rela- ache patients [33].
tionship between these two constructs is not per- The initial validation of the HMSE scale
fect, as someone could believe that a behavioral illustrated the relationships of HMSE with
outcome is within their control (internal LOC), HSLC and headache-related outcomes. HMSE
but not think that they have the ability to achieve was positively associated with internal HSLC,
the desired outcome (low self-efficacy). Fur- negatively associated with chance HSLC, and
ther, Luszczynska and Schwarzer [26] noted an did not display a significant relationship with
important distinction in that LOC beliefs do not healthcare professionals HSLC. Patients’ coping
necessarily imply subsequent action, whereas SE strategies were able to be discriminated based
beliefs are by nature prospective and operative. on HMSE, such that patients who used positive
Like LOC, SE was quickly applied to medicine coping strategies (e.g., cognitive restructuring,
and behavioral health. An early review identified coping self-statements) had significantly higher
two pathways by which SE influenced health. First, HMSE scores. HMSE was also associated with
SE was directly related to the adoption of health lower levels of headache-related disability and
promotion behaviors (e.g., smoking cessation, con- less severe headache symptoms, and it explained
dom use). Second, SE impacted the physiological unique variance in headache-related disability
stress response in bodily regions such as the endog- beyond that accounted for by headache severity
enous opioid and immune systems, which in turn and HSLC. HMSE was not significantly related
exerted an influence on health and illness [27]. to level of depression [18].
Much research has applied SE to pain manage- The linkage between HMSE and headache-
ment, broadly defined. For example, in rheumatoid related disability was replicated in a recent study
arthritis patients, SE was positively associated with that found HMSE was negatively associated with
active efforts to prevent and manage pain [28]. In disability and also that HMSE significantly medi-
fibromyalgia patients, SE was negatively associated the relationship between pain severity and
ated with maladaptive pain behaviors [29]. SE has disability [34]. An earlier study also confirmed
also been associated with increased pain tolerance this linkage in primary care headache patients
in a non-clinical sample [30]. [35]. Additionally, a body of literature has also
found SE to mediate or moderate outcomes of (1) the understanding that certain behaviors may
several headache treatments (e.g., biofeedback, cause or at least influence their headaches and (2)
pharmacological, cognitive-behavioral) [36]. the confidence in their ability to modify behavior
Thus, while the direct relationships between in order to ameliorate or reduce the severity of
HMSE and HSLC and headache-related out- their headaches. Thus, enhancing internal LOC
comes are fairly clear, such that greater HMSE and increasing SE for modifiable health behav-
and internal HSLC are generally associated with iors are targets of psychosocial interventions for
positive functioning and treatment outcomes, the the CDH population, including cognitive-behav-
nature of indirect relations incorporating HMSE ioral therapy and motivational interviewing, dis-
and HSLC is less clear. For example, Seng and cussed next.
Holroyd [19] discussed how “clinical wisdom”
suggests that that HMSE moderates the relation-
ship between HSLC and treatment outcomes, Cognitive-Behavioral Therapy
yet the question has received minimal empirical
attention. Further, the directionality of a poten- Cognitive-behavioral therapy (CBT) is recog-
tial moderation effect remains disputed. That nized as the leading psychological treatment for
is, does higher baseline internal HSLC enable individuals with chronic pain, including CDH
patients to make greater HMSE gains during [39]. In short, CBT for chronic pain aims to
treatment, or do patients with lower baseline reduce pain and psychological distress, as well as
internal HSLC see more improvement in HMSE to increase functionality. Common goals include
because they simply have more room to change decreasing behaviors that adversely affect the
[19]? More research is needed to refine our pain condition (e.g., erratic sleep, medication
understanding of how HSLC and HMSE jointly overuse); increasing adaptive behaviors (e.g.,
impact headache symptoms, impairment, and regular exercise, implementation of stress man-
treatment outcomes. agement tools); identifying, challenging, and
replacing unhelpful thoughts and beliefs (e.g.,
“I can’t do anything with this headache”); and
sychosocial Interventions for CDH:
P increasing SE that one can manage or influence
Cognitive-Behavioral Therapy pain [40].
and Motivational Interviewing As many patients will attest, headache symp-
toms are often triggered and/or exacerbated
Illness, including chronic headache, can be con- by stress. CBT teaches patients to notice how
ceptualized not only as a biological phenomenon thoughts influence the stress response. In our
but also as a social phenomenon. An individual own practice, we often ask patients whether there
suffering from illness can take on sickness as are things they could think about that might make
their social function, thereby adopting a “sick their headaches worse. The answer is a resound-
role” [37]. The sick role script reads that the ing “yes” with work demands, financial strain,
patient is relieved of his or her usual responsi- deadlines of various sorts, and marital and par-
bilities in order to focus on regaining health. The enting difficulties as commonly identified stress-
assumption is that the patient wants to achieve ors that exacerbate headache pain. Through use
wellness as quickly as possible, condones the of a daily thought record, patients learn to notice
undesirability of their illness [38], and defers thoughts relating to stress, pain, and the impact of
responsibility to the medical professional. These pain on daily functioning. Often patients identify
expectations set the stage for an externally based thoughts that can be characterized as catastroph-
LOC and low SE in the management of the health izing: “I can’t deal with this pain. Nothing helps.
condition, a combination commonly encountered No one understands how I suffer.” A goal of CBT
clinically in chronic headache populations [19]. is to help patients recognize such thoughts, gently
Within this framework, the patient may lack both challenge them, and to replace with thoughts that
have less of a deleterious impact on a patient’s the body, and audial or visual feedback allows
mood, level of tension, and subsequent ability patients to know when sympathetic arousal is
to function (e.g., “I’ve functioned with this level reduced. Over time, patients learn to recognize
of pain before. I can do it again.”). Patients learn tension in the body and lower arousal before ten-
that they have the ability to modify their thoughts sion levels become high.
and to thereby exert influence on their pain expe- The effectiveness of biofeedback for head-
rience. aches has been documented for decades (see,
In addition to thought monitoring, relaxation e.g., [43, 44]), and two recent meta-analyses
training is an aspect of CBT that also teaches [45, 46] found sound evidence supporting the
patients how to influence their experience of pain. effectiveness of biofeedback training for the
Penzien et al. [41] identify progressive muscle treatment of headache pain. In addition, multi-
relaxation (PMR), autogenic training, and medi- ple studies demonstrate that when coupled with
tation/passive relaxation as forms of relaxation medical therapy, biofeedback enhances out-
training commonly used to treat chronic head- comes for headache patients [47–49]. A recent
aches. PMR has been used since the 1930s as a study in our own clinic found biofeedback to be
treatment to lower anxiety [42]. Patients practice an effective strategy to manage headache and
tensing and relaxing muscle groups through- other forms of pain [50]. Participants (N = 72)
out the body. With continued practice, patients reported a significant reduction in self-reported
become skilled at recognizing the first signs of pain and distress immediately following bio-
tension in the body and to effectively and quickly feedback sessions, with pain and distress ratings
relax. Autogenic training involves patients using decreasing more than a point on a 0–10 rating
the suggestions of heaviness, warmth, calmness, scale. While decreases in pain and distress were
and ease to promote a sense of deep relaxation in not maintained from session to session, patients’
the body. For example, a patient will subvocally scores on a measure of catastrophizing signifi-
or mentally repeat the suggestion, “My arms are cantly decreased across biofeedback sessions,
heavy and warm,” before moving to another part suggesting that beliefs in one’s ability to cope
of the body. Put simply, meditation and passive with pain can be enhanced over time through a
relaxation involve focusing on an anchor (e.g., biofeedback intervention.
breath, words) to calm both mind and body. Cognitive factors such as LOC and SE influ-
When thoughts wander, they are redirected to ence the patient’s participation in headache man-
the anchor. Relaxation training as a whole aims agement, including medical adherence and the
to enhance patients’ sense of control over physi- monitoring and management of triggers [51].
ological responses, in particular sympathetic The assessment of these cognitive constructs in
arousal [41]. In other words, patients learn they the context of CBT and other psychosocial inter-
are capable of exerting influence over the level of ventions serves a number of purposes: (1) to bet-
tension in the body and their subsequent experi- ter understand the patient’s beliefs about chronic
ence of pain. headache before beginning treatment, (2) to
inform the treatment plan by including targeted
Biofeedback and Assessments interventions aimed at such beliefs and bolstering
Biofeedback is used alongside CBT techniques to confidence in the patient’s skills to prevent and
teach headache patients how to reduce physiolog- manage headaches (i.e., increasing SE and inter-
ical arousal. For the treatment of chronic head- nal LOC), and (3) to examine changes throughout
aches, thermal biofeedback (measuring finger the treatment process. A number of standardized
temperature) and electromyographic (EMG) bio- assessments have been developed, three of which
feedback (measuring muscle tension) are often are described below. The first two directly assess
used [41]. Heart rate variability biofeedback can the concepts of LOC and SE, while the final
also be employed. Patients learn to use breath- assesses LOC indirectly through the construct of
ing and cognitive strategies in real time to calm catastrophizing.
eadache-Specific Locus of Control (HSLC)

H (4 items), magnification (3 items), and helpless-
Scale ness (6 items) [53]. Participants respond to each
The HSLC scale is a 33-item measure consisting item using a 5-point Likert scale (where 0 = not at
of three subscales: (1) healthcare professionals all and 4 = all the time) in reference to the degree
LOC (e.g., “Following my doctor’s medication to which they have specific thoughts and feelings
regimen is the best way for me not to be laid- when experiencing pain (e.g., “There’s nothing
up with a headache”), (2) internal LOC (e.g., I can do to reduce the intensity of the pain”; “I
“My actions influence whether or not I have can’t seem to keep it out of my mind”). Total
headaches”), and (3) chance LOC (e.g., “My PCS scores are calculated by summing the scores
headaches are beyond all control”). Participants of all items, with higher scores representing a
respond to each item using a 5-point Likert scale higher tendency to catastrophize pain. The items
where 1 = strongly disagree and 5 = strongly included in each subcategory are also summed
agree. For each subscale, higher values indicate to provide subscale scores. Scores ≥30 indicate
greater LOC ascribed [15, 16]. clinically significant levels of catastrophizing
As discussed earlier in the chapter, the sub- [53].
scales have demonstrated good internal con- The PCS has been validated for a many dif-
sistency (α’s ranging from 0.80 to 0.89) and ferent languages, including Arabic [54], Korean
adequate 3-week test-retest reliability (rs ranging [55], Hindi [56], Turkish [57], Brazilian [58],
from 0.72 to 0.78) [15]. Additionally, expected Sinhala [59], and Italian [60]. The scale has also
relationships have been demonstrated with other been validated for use in children, including Ger-
related measures: the chance LOC subscale is man- [61] and Catalan-speaking [62] children.
associated with catastrophizing (r = 0.44), the Additionally, a short form of the PCS has been
internal LOC subscale is associated with pref- validated for English-[63] and Japanese-speaking
erence for self-regulation treatments (r = 0.21), populations [64].
and the healthcare professionals LOC subscale is In sum, assessments can be an effective tool to
associated with preference for medical treatment measure client LOC and SE, providing objective
(r = 0.45) [15]. Versions of the HSLC have been data to observe the process of change. Addition-
validated for Spanish-speaking populations [52]. ally, they can serve as a useful springboard for
conversation about the patient’s capacity to influ-
eadache Management Self-Efficacy
H ence headache pain, one that may increase moti-
(HMSE) Scale vation to make necessary behavioral changes.
The HMSE scale consists of 25 items measur-
ing the patient’s confidence in his or her ability
to apply behavioral skills to prevent or manage Motivational Interviewing
recurrent headaches [18]. Participants respond to
items (e.g., “I can reduce the intensity of a head- Motivational interviewing (MI), a therapeu-
ache by relaxing”) on a 7-point Likert scale where tic intervention that specifically explores and
1 = strongly disagree and 7 = strongly agree with addresses the difficulties inherent in trying to
higher scores indicating greater headache man- modify behavior, has powerful potential to move
agement SE. The HMSE has shown good internal CDH patients toward lasting behavioral change.
consistency (α = 0.90)18 and predictive validity A growing body of literature demonstrates
(described previously in this chapter). that MI can be effectively delivered in medical
settings by a range of providers with minimal
ain Catastrophizing Scale (PCS)
P investment of time [65]. Reviewed in a recent
The PCS is a 13-item scale assessing thoughts meta-analysis, MI was successfully employed
and feelings associated with pain. Three dimen- to address a variety of diverse health concerns
sions of pain catastrophizing are measured and including body weight, alcohol and tobacco use,
constitute subcategories of the scale: rumination dental outcomes, sedentary behavior, HIV viral
load, and optimal utilization of physical therapy When a person is leaning toward making a
[65]. Few empirical studies exist that examine MI behavior change, he or she is said to be in prepa-
exclusively with the CDH population (although ration. Here is where the provider works with the
see [66] for a study on telephone-based MI for patient to explore and identify change strategies
adolescent chronic headache). However, the by offering a menu of options. In the action stage
behavioral changes often needed by individu- of change, a person chooses a strategy and makes
als with CDH (e.g., prioritizing sleep, exercise, a clear commitment to behavior change. Main-
nutrition, and daily relaxation) – and the associ- tenance follows, whereby the provider checks in
ated ambivalence in making such changes—lend to see if what the patient is doing is still work-
themselves well to modification via MI. While a ing, in order to maintain gains and continue skill
thorough review of MI is beyond the scope of this building. Lastly, an integral component of the
chapter, Rollnick et al. [67] provide an excellent model is relapse, when a person stops a healthy
resource on MI in healthcare settings. behavior and/or resumes an unhealthy behavior.
In short, MI is “a client-centered, directive Relapse is reframed as a more forgiving “slip,”
method for enhancing intrinsic motivation to and the patient and provider evaluate what went
change by exploring and resolving ambivalence” wrong, with the patient ultimately recommitting
[68], p. 25. It is client-centered in the sense that it to change.
is an open, respectful, and nonjudgmental way of The underlying philosophy of MI is to meet
being with clients. It is directive in that the pro- patients where they are in the Stage of Change
vider chooses what to attend to and therefore is model and to work with them to increase their
gently guiding the session to elicit from patients motivation for change. The question is “for what
their own motivations for behavior change. is this person motivated?” (e.g., to contemplate,
MI is based in part on the Stages of Change to take action). MI understands that pushing a
model developed by Prochaska and DiClemente person toward change when they are not commit-
[69]. According to this model, change happens ted will result in resistance [67, 70].
gradually, in stages. In the first stage of change, A core clinical principle in MI is that of devel-
precontemplation, a client does not acknowledge oping discrepancy [70]. The provider works with
that they have a problem with a given behavior. the patient to develop the discrepancy between
The task of the provider is to raise awareness their current behavior and current values. Put
through education and feedback. In the realm another way, the patient is prodded to discuss the
of CDH, education can be on the contributory difference between what they say they want and
roles of medication overuse, missed meals, poor what they are actually doing. The goal of devel-
hydration, or inadequate sleep to headache risk, oping discrepancy is to maximize opportunities
for example. Feedback can be given in the form for the patient to present reasons for change (also
of assessment results (discussed above), which called “change talk”; see [67, 70]). In other words,
allows the patient to see how their pain behaviors the aim is for the patient to engage in problem
and beliefs compare to others as well as to them- recognition (e.g., “I guess my stress level makes
selves across time. In the second stage of change, my headaches worse”), express concern about
contemplation, a person experiences ambivalence problem (“I can see that staying up late to work is
about changing a given behavior. A patient may literally hurting me”), state advantages of change
want to make time to exercise most days, and she (“My children would like it if I exercised with
may know it will help her headaches, but she also them”), express SE (“I think I could make self-
does not believe she has enough time to exercise care a priority if I decided to”), and/or verbalize
and views exercise as taking away from other intention to change (“I’ve got to do something”).
work and home responsibilities. The provider’s While it is the patient that presents reasons to
role is to help the patient explore her ambivalence change, the provider can help to evoke change
and ultimately to resolve it such that she is ready talk via simple questions such as, “What is
to make the first steps toward behavior change. truly important to you? How does this fit with
behaviors that contribute to CDH?” For example, been trialed, and providers may feel helpless in
a client might state that being a good parent is the face of dwindling options to offer. Refractory
of primary importance. The provider can [gently] patients are often high utilizers of services. Some
wonder how a lack of self-care—that ultimately are seeking answers, treatments, and cures, while
leads to lost time with family—fits with such a others may experience anxiety, mood disorders,
value. Ultimately, the goal is for the patient to substance abuse issues, and personality disor-
see that self-care supports the priority of being ders. Provider workload may increase the percep-
a good parent. Other useful questions include, tion of a patient being difficult, with healthcare
“What worries you about your behavior? What system pressures such as reduction of costs and
do you think will happen if you don’t change increased productivity playing a role [71].
your behavior? What encourages you that you Just as patient SE is important for the effec-
can change if you want to?” Discussing the positive treatment of CDH, so is provider SE. Under-
tive as well as the negative aspects of change is standing the needs of headache patients can
also an important conversation to have, so that bolster a provider’s SE to effectively treat this
the patient makes a choice to engage in behav- population. Cottrell and associates [72] con-
ior change having thought about all sides of the ducted a focus group to identify the perceptions
issue. and needs of migraine patients. The results sug-
Other core clinical principles include provid- gested that patients seek better understanding of
ing empathy for the patient’s situation, treading their migraines and information as well as pain
carefully when clients show resistance to change relief. They would like a collaborative relation-
(e.g., by responding “the choice is up to you. You ship with their physicians combined with a team
can decide to do what you like”), and supporting approach to treatment. Participants identified
a patient’s SE to make changes by asking them areas of concern, which included the impact of
to reflect on other times in their lives where they their headaches on family, relationships/social
made a difficult change and followed through functioning, and employment, as well as issues
with it. related to physician care. Physician care factors
In MI, motivation for change comes from involved the provider’s willingness to consider
within and is not imposed from without. Through alternative treatments, the ability of the provider
meaningful conversation, MI cultivates internal to listen, and a sense of feeling dismissed by pro-
resources for change, leaving the client with the viders who failed to take them seriously. Ability
sense that change is within his or her own control to obtain insurance coverage of prescribed medi-
and not something the provider can make happen cations was also a concern. Patients in the focus
for him or her. In this way, MI is a tool to support group recognized that tools related to technology
SE and increase internal HSLC. may be available to them and appreciated phy-
sicians who understood this fact. Providers who
acknowledge such patient concerns are in a bet-
OC and SE: Suggestions
L ter position to more effectively meet the needs of
for the Provider their patients.
There appear to be specific patient and physi-
Healthcare providers treating headache patients cian characteristics that contribute to the percep-
may face frustrations of their own. The provider tion that a given headache patient is difficult to
may be caught between wanting to help the manage [72, 73]. Challenging patients include
patient find a means to manage headaches and those with refractory headaches, psychiatric
struggling when nothing appears to be work- pathology, multiple unexplained symptoms, and
ing. Sometimes the refractory headache patient substance abuse difficulties. Interestingly, there
is considered by the provider to be difficult. are physician characteristics associated with the
Indeed, they may be difficult to manage medi- provider perception that a patient is difficult.
cally, especially if all reasonable options have Those physicians who are younger, under greater
stress, and who do not utilize collaborative treat- Rains and colleagues [76] identify four
ment models are more likely to perceive a patient important dimensions of care in the manage-
as challenging. General principles that might ment of the migraine patient, which include
prove helpful in the management of the refractory administration, psychoeducation, behavioral
patient include evaluating for possible mental factors, and social support. In the area of admin-
health or substance abuse problems followed by istration, they suggest scheduling regular con-
specific treatment if identified as useful. A shift tact and rapport building, providing verbal and
from the treatment philosophy of searching for a written recommendations, screening for psy-
cure in favor of the goal of management and the chiatric comorbidities, tracking compliance,
use of written agreements that outline conditions encouraging participation of significant others,
of treatment can prove valuable in the approach and assessing and treating psychiatric comor-
to refractory patients. Lastly and importantly, use bidities. Psychoeducation encompasses provid-
of an integrated, multimodal treatment approach ing patient education about migraines, use of
that includes behavioral and nonpharmacological printed materials, patient involvement in plan-
treatment options is suggested. ning, and education related to adherence and
In the treatment of headaches, there are modi- health-related behavior change. The behavioral
fiable risks and those over which the patient has piece includes providing a simple daily health
less capability to change [74]. Those risks over regimen, training the patient in self-monitoring
which the patient has the ability to exercise of compliance, understanding and managing
some element of control or may modify include stimulus control (such as known headache trig-
such factors as sleep-related difficulties, obe- gers), using medication contracts, enhancing
sity, medication overuse, allodynia or increased SE, and reinforcing successes. Lastly, social
pain sensitivity, and nausea or prolonged head- support factors such as provider communica-
ache duration. Non-modifiable risks include tion and support, a collaborative therapeutic
age, sex, genetic background, head and/or neck alliance, and spouse and family support offer
injury, socioeconomic status, and uncontrollable potential benefit for headache management.
major life events (e.g., job loss). Headache pro- With these factors in mind, take the illustrative
viders should encourage patients to gain a sense case of Dr. Nikou and Ms. Connelly to see how
of SE for modifiable risks. As discussed above, each might alter their approach or belief systems
CBT or MI can prove useful in reframing the to effect a better patient outcome.
patient’s sense of control over modifiable risks
and increasing efficacy to make positive changes.
Once headaches have transitioned from epi- Case Study
sodic to chronic and daily, they become more dif-
ficult to manage. Management of the risk factors Ms. Connelly, a 40-year-old female, presents to
prior to that happening is very important. Risk the clinic complaining of sharp pain at the base
factors for transition from episodic to chronic of her neck that radiates behind and over her
daily headaches include obesity, headache fre- head. She meets with Dr. Nikou, a young physi-
quency, medication overuse, and psychiatric cian who just began his practice at the clinic less
comorbidity [75]. Often these patients are diffi- than a year ago. Besides having a heavy clinical
cult to treat due to multiple factors, not the least load each week, Dr. Nikou is also developing a
of which is nonadherence. They should be seen research program within the clinic and is find-
frequently and educated about the mechanisms of ing the day he sees Ms. Connelly to be an espe-
headache. Treatment favors a collaborative rela- cially busy day. Dr. Nikou introduced himself to
tionship between patient and provider and the use the patient and began taking her medical history.
of behavioral strategies to help the patient take an Ms. Connelly rated her pain today as 8/10 (with
active role in managing their headache disorder 10 being the worst). She reported a 3-year his-
and the therapeutic program [75]. tory of severe daily headaches and has found
little to no relief with previous prescription tri- and expectations. First, Dr. Nikou might do well
als. Ms. Connelly is a mother of three elementary to adjust the location of his computer so that he
school-aged children who are involved in many can make eye contact with the patient and enter
after-school activities. She previously worked as data into the medical record at the same time. He
a real estate agent but is currently unemployed could use reflective listening strategies such as
due to her daily headaches. While she has a his- “I hear you saying that …” or “I understand that
tory of anxiety dating back to high school, for when … you….” Summarizing what the patient
which she took a short-term anxiolytic, her anxi- says will help them to feel heard, and ending the
ety has recently increased due to changes in her visit by asking if there are any remaining ques-
husband’s work schedule. She shared this with tions gives the patient a last opportunity to get
Dr. Nikou, but she did not feel that he was lis- clarification. Additionally, Dr. Nikou might ask
tening because he was typing on the computer. a nurse or medical assistant to come back in to
Ms. Connelly reported drinking three to four offer patient education. He might want to talk to
cups of coffee daily and is a regular Diet Coke the patient about her expectations and explore
drinker. She does not sleep well: she averages what realistic outcomes for treatment might look
4–5 h per night and reports difficulty with early like. In addition, he might identify if there is a
morning awakenings. She also regularly skips psychologist, therapist, or social worker serving
meals because she “forgets” which has resulted the clinic who could work with Ms. Connelly to
in a loss of 10 lbs. unintentionally over the past manage her pain nonpharmacologically, given
several months. Dr. Nikou inquired about head- that the patient is open to doing so.
ache triggers, but Ms. Connelly was unable to Ms. Connelly appears to expect Dr. Nikou to
identify any: “They just happen. I can’t predict have the answers to her headaches, and she has
it.” She feels helpless, as no medications have not taken an active role in her treatment such as
helped and no one has been able to identify the keeping a headache diary (i.e., external LOC).
cause of her headaches. This has become very Additionally, she appears to want a cure, which
unsettling to her, leading her to seek out medical might not be a realistic expectation for her. Uti-
advice from a number of specialists who have lizing strategies such as guided imagery, biofeed-
helped to reduce her pain to a 5/10 temporarily back, breathing approaches, avoiding headache
(via injections, physical therapy, and chiroprac- triggers, and trying yoga or Tai Chi might build
tic care), but have not been able to cure her from a sense of internal LOC in the management of
her headache pain. She has begun to identify as her pain. For example, in the biofeedback study
a sick person, and she spends much of her day presented earlier, Wilson, Melchert, and Ander-
lying on the couch or looking up her symptoms son [77] discovered that when patients noted a
online to try to find a cause and possible cure for reduction in pain and distress during biofeed-
her pain. She reported she has failed to keep a back, they reported a sense of gaining greater
headache diary because she does not have time. control of their pain. Successfully employing
She also has little energy to engage in relaxation stress management strategies and verbalizing the
strategies. Dr. Nikou, with little time left before importance of self-care will help her to build a
needing to meet the next patient, said he would greater sense of SE.
change the dose of an existing medication and Generally speaking, a team approach where
told her to make a follow-up visit for 6 weeks the provider listens and works together with the
later. Ms. Connelly left the clinic to get her pre- patient to establish reasonable and attainable
scription, but found herself feeling dejected and expectations leads to a better outcome. When
wanting a plan to address her headaches so that patients accept that there may be no magic bullet
she can return to work. for their headaches and recognize they can actu-
There may be ways for Dr. Nikou to better ally influence their headaches through the use of
meet the needs of this patient and the patient self-care strategies, they tend to report greater
may benefit from an adjustment in both behavior satisfaction with their care.
Acknowledgments The authors wish to thank Annette

Conclusion
Wilson, Ph.D., for her contributions to the chapter, in par-
When patients continue to struggle with CDH ticular the results of her biofeedback study.
despite multiple interventions, treatment can Correspondence regarding this chapter should be
become stuck, with both patient and provider addressed to Sarah E. Trost, Pain Management Center,
Department of Anesthesiology, Medical College of
wondering what the other is doing (or not
Wisconsin, 959 N. Mayfair Rd., Wauwatosa, WI 53226.
doing) to fix the problem. The construct of
LOC, and its application to the treatment and
management of CDH, offers fruitful avenues
to explore to help both patient and provider References
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Collecting the History in the CDH
Patients 3
Marius Birlea and Mark W. Green
Chronic daily headache (CDH), while being of the evaluation and provides the diagnosis in
a great public health challenge and the “bread the vast majority of cases [3]. It is possible to
and butter” of specialized headache clinics, classify virtually all chronic headache patients
represents a symptom rather than a diagnosis. using the International Headache Society
Although the classification remains intensely Classification of Headache Disorders (ICHD),
debated, the consensus is that the term CDH currently third edition, with the final version in
refers to headache disorders which are expe- development, not available at the time of current
rienced 15 or more days a month [1]. Correct publication [4]. Chapter 27 undertakes to review
identification of the underlying headache eti- and summarize the classification of the chronic
ology is necessary for treatment planning. The daily headache disorder. Patients with chronic
vast majority of CDH is attributable to “benign” headache may have multiple headache diagno-
primary headache disorders, not related to a ses, and correct application of the IHS classi-
structural or systemic illness. Nonetheless, fication implies that every type of headache in
practitioners need to be vigilant for secondary each patient should be classified. When retro-
causes of headaches, and elimination of those spectively answering questions about their vari-
causes is always the first step when a patient ous headaches, patients often cannot distinguish
with CDH presents in the office of the physician between the types of headaches, and structured
[2]. A thorough history is the most critical aspect questionnaires, i.e., Bon Triage questionnaire,
may be useful before the first clinic appointment
[5]. The distinction between headache types is
possible only through a carefully performed
clinical interview, supplemented, when needed,
M. Birlea (*) by a headache diary [6]. The question “How
Neurology, University of Colorado Denver School of
Medicine, Aurora, CO, USA long do the patient’s individual headaches last if
e-mail: Marius.Birlea@ucdenver.edu left untreated?” narrows the main primary CDH
M. W. Green subtypes into two categories: (1) headaches that
Neurology, Icahn School of Medicine at Mt. Sinai, are short lasting (<4 h if untreated) and (2) those
New York, NY, USA that are long lasting (>4 h if left untreated) [3].
Anesthesiology, Icahn School of Medicine at Mt. Targeted questions to establish an anchor in
Sinai, New York, NY, USA time and subsequent temporal profile may help
Rehabilitation Medicine, Icahn School of Medicine at diagnose secondary headaches.
Mt. Sinai, New York, NY, USA

26 M. Birlea and M. W. Green
lassification of Chronic Daily

C Chronic Primary Headaches
Headache (CDH)
Primary CDH of Long Duration
1. Primary Chronic Daily Headaches.
• Primary CDH of long duration: Chronic hronic Migraine (CM)
C
migraine, chronic tension-type headache, The most common primary (or secondary) chronic
new daily persistent headache, hemicrania daily headache encountered in the practitioner’s
continua, and nummular headache. office or in emergency rooms is chronic migraine
• Primary CDH of short duration: Chronic (CM). This is a headache occurring on ≥15 days
cluster headache, chronic paroxysmal per month for >3 months, which has the features
hemicrania, chronic short-lasting unilateral of migraine headache for at least 8 days per month
neuralgiform headache attacks (chronic and there is no other explanation for it [4]. It is still
SUNCT/SUNA), hypnic headache, and underdiagnosed and undertreated [7]. In a recent
primary stabbing headache. representative study [8], the diagnosis of CM
2. Secondary Chronic Daily Headaches. among those consulting was most likely to obtain
• CDH attributed to trauma: Persistent head- be the correct diagnosis if symptoms were severe.
ache attributed to traumatic injury to the Rates of diagnosis among consulters were far
head. lower for CM (25%) than for episodic migraine,
• CDH attributed to cervical or cranial vas- EM (87%). This difference suggests an unmet
cular disorders. need for better CM diagnosis, particularly in pri-
• CDH attributed to nonvascular intracranial mary care settings. Barriers associated with diag-
disorder. nosis may be addressed by encouraging HCPs to
• CDH attributed to high cerebrospinal fluid use screening tools for migraine and CM, such as
pressure. the Identify (ID)-Migraine and ID-Chronic
• CDH attributed to low cerebrospinal fluid Migraine (ID-CM) [7, 8]. Patients with CM usu-
pressure. ally have a history of episodic migraine that began
• CDH attributed to intracranial neoplasia in their teens or 20s and has lasted for 10–20 years.
and other intracranial disorders. In the majority, the “transformation” from epi-
• CDH attributed to a substance or its with- sodic to CM is gradual, although the transition can
drawal. Medication-overuse headache. be abrupt in ~ 30% of cases [3]. It is important to
• CDH attributed to infection: Intracranial mention that, with treatment or spontaneously,
and systemic infection. patients with chronic migraine often reverts back
• CDH attributed to disorders of to episodic migraine. Two forms of CM can be
homeostasis. encountered in clinical practice: CM with continu-
• CDH attributed to disorders of the cra- ous headache and CM with pain-free periods
nium, neck, eyes, ears, nose, sinuses, teeth, (near-daily headache); these two forms are not
mouth, or other facial or cervical separately classified but are proposed in the
structures. Appendix of the ICHD-3 beta classification. There
• CDH attributed to psychiatric disorders. may also be constant fluctuating subtypes [9].
• CDH attributed to painful cranial neuropa-
thies and other facial pains. hronic Tension-Type Headache (CTTH)
C
• CDH not elsewhere classified and chronic This is a disorder that usually, but not always,
headache unspecified. evolves from frequent episodic tension-type
3 Collecting the History in the CDH Patients 27
headache, gradually developing daily or almost ummular Headache (NH)

N
daily episodes of headache, typically bilateral, This is a head pain of highly variable duration but
pressing or tightening in quality and of mild to is chronic (more than 3 months) in up to 75% of
moderate intensity, lasting hours to days or unre- published cases, continuous or intermittent, pres-
mitting. The pain does not worsen with routine ent in a small circumscribed area of the scalp
physical activity, but may be associated with (1–6 cm diameter), and fixed in size and shape.
mild nausea, photophobia, or phonophobia [4]. The painful area can be localized in any part of
A diagnosis of CM excludes the diagnosis of the scalp but is most common in the parietal
chronic tension-type headache (CTTH, “feature- region. Rarely, nummular headache is bi- or mul-
less headache”) although there can be signifi- tifocal, each symptomatic area retaining all the
cant overlap and controversies regarding proper characteristics of nummular headache. The pain
separation of these two conditions exist. CTTH intensity is generally mild to moderate but occa-
can be associated or unassociated with pericra- sionally severe. Superimposed on the background
nial tenderness, classified separately based on pain, spontaneous or triggered exacerbations
this criterion. may occur. Other causes, in particular meningeal,
bone, scalp, and skin lesions, must be excluded
emicrania Continua (HC)
H by history, physical examination, and appropriate
This is one of the trigeminal autonomic cephalal- investigations [4].
gias and is discussed with other conditions in the
same group below.
Primary CDHs of Short Duration
ew Daily Persistent Headache (NDPH)
N
This is a persistent headache for more than Chronic trigeminal autonomic cephalalgias
3 months that became continuous and unremit- (TACs) share historical and other diagnostic fea-
ting within 24 h from its onset, which is distinct tures that also includes with several additional
and clearly recalled, and if the patient cannot do entities of like hypnic headache and primary stab-
so, another diagnosis should be considered. The bing headache. Primary cranial neuralgias that
pain lacks pathognomonic features and may be consist of short-lasting recurrent attacks of head/
migraine-like or tension-type-like or have ele- face pain without autonomic symptoms are
ments of both. It typically occurs in individuals described at the end of the chapter. Chronic tri-
without a prior headache history. Nevertheless, geminal autonomic cephalalgias (TACs) represent
patients with prior headache (episodic migraine a group of unilateral headache disorders, associ-
or tension-type headache) are not excluded from ated with autonomic symptoms, separated from
this diagnosis, but they should not describe each other by criteria of frequency and duration
increasing headache frequency prior to onset. with the exception of hemicrania continua; they
New daily persistent headache (NDPH) has two generally consist of attacks of severe strictly uni-
subforms: a self-limiting subform that typically lateral pain which is orbital, supraorbital, tempo-
resolves within several months without therapy ral, or any combination of these sites. The pain is
and a refractory form that is resistant to aggres- associated with at least one of the following: ipsi-
sive treatment regimens. The diagnosis of new lateral conjunctival injection, lacrimation, nasal
daily persistent headache is one of exclusion congestion, rhinorrhea, forehead and facial sweat-
[10]. Secondary headaches such as headache ing, miosis, ptosis and/or eyelid edema, and/or
attributed to infection, headache attributed to restlessness or agitation (cluster headache).
increased cerebrospinal fluid pressure, headache Episodic forms of TACs exist and may be more
attributed to low cerebrospinal fluid pressure, and frequent than the chronic ones. The TACs are suf-
headache attributed to traumatic injury to the ficiently rare that any time a TAC is encountered
head and medication-overuse headache should be clinically, secondary causes need to be considered
excluded by appropriate investigations. and appropriately investigated [11].
hronic Cluster Headache (CCH)

C chronic short-lasting unilateral neuralgiform
Patients with chronic cluster headache present headache with conjunctival injection and tearing
with head pain attacks that last 15–180 min and (SUNCT) and chronic short-lasting unilateral
occur from once every other day to eight times a neuralgiform headache with cranial autonomic
day. The pain, which is strictly unilateral, is asso- symptoms (SUNA).
ciated, ipsilaterally, with at least one of the auto- SUNCT is characterized by pain attacks lasting
nomic symptoms described above. Chronic between 1 and 600 s, at least once a day for at least
cluster headache attacks occur for more than half the time, and at least 20 such attacks have
1 year without remission or with remission occurred. Attacks of chronic SUNCT occur for
periods lasting less than 1 month. Chronic cluster more than 1 year without remission or with remis-
headache may arise de novo (previously referred sion periods lasting less than 1 month. Often such
to as “primary chronic cluster headache”) or attacks occur tens to hundreds per day, as single
evolve from episodic cluster headache (previ- stabs, series of stabs, or in a saw-tooth pattern.
ously “secondary chronic cluster headache”) [4]. SUNA resembles SUNCT except either con-
In some patients, chronic cluster headache can junctival injection or lacrimation (tearing) or
revert to episodic cluster headache, with remis- both are absent.
sions longer than 1 month.
emicrania Continua (HC)
H
hronic Paroxysmal Hemicranias (CPH)
C This is a trigeminal autonomic cephalalgia pre-
The CPH attacks last 2–30 min, occur several or senting with a persistent, strictly unilateral head-
many times a day, and are associated with at least ache for at least 1 year, rather than separate attacks.
one of the autonomic symptoms described for The headache, like in chronic cluster headache or
chronic cluster headache above. They occur with- chronic paroxysmal hemicrania with which HC
out a remission period, or with remissions lasting can overlap, is associated with at least one of the
<1 month, for at least 1 year. Characteristically, following ipsilateral autonomic symptoms: con-
indomethacin prevents the attacks. There are rare junctival injection, lacrimation, nasal congestion,
patients who present with both CPH and trigemi- rhinorrhea, forehead and facial sweating, miosis,
nal neuralgia (sometimes referred to as CPH-tic ptosis and/or eyelid edema, and/or restlessness or
syndrome). This recognition is important since agitation. HC can have pain that is not continuous
both disorders may require treatment [4]. but is interrupted by remission periods of at least
1 day, or it can be daily and continuous [4]. The
hronic Short-Lasting Unilateral
C headache in HC is highly sensitive to indometha-
Neuralgiform Headache Attacks cin, which should be initiated anytime when the
There are two chronic trigeminal autonomic diagnosis of HC is suspected; the response to indo-
cephalalgias characterized by high frequency, methacin should be absolute, 100% [2].
short duration, and not more than two autonomic The differentiating clinical characteristics of
symptoms – conjunctival injection and tearing – the TACs are presented in Table 3.1.
Table 3.1 Chronic trigeminal autonomic cephalalgias: clinical characteristics

Disorder Duration Frequency Location Character
Chronic cluster headache 15–180 min Every other day Orbital, frontal, temporal, Very severe, boring
(CCH) to 8/day extracephalic
Chronic paroxysmal 2–30 min 1–40/day Orbital, frontal, temporal Very severe, boring,
hemicrania (CPH) throbbing
Chronic SUNCT SUNA 1–600 s Dozens to Orbital, frontal Very severe, burning,
hundreds per day stabbing
Hemicrania continua (HC) Continuous Continuous Orbital, frontal Moderate, with
spikes in severity
ypnic Headache (HH)

H cause headache. This remains true even when the
HH presents with recurring headache attacks, headache has the characteristics of a primary
occurring on at least 10 days/month for more headache and has a chronic course (migraine,
than 3 months, developing only during sleep, tension-type headache, trigeminal autonomic
causing wakening. Attacks usually last from 15 cephalalgias, or another primary headache).
to 180 min, although longer than 4 h duration has When a preexisting primary headache becomes
also been described. Most cases are persistent, chronic in close temporal relation to such a caus-
with daily or near-daily headaches, but an epi- ative disorder, both the primary and the second-
sodic subform (less than 15 days per month) may ary diagnoses should be given, provided that
occur. HH usually begins after age 50 years but there is good evidence that the disorder can cause
may be encountered in younger people. The pain headache. This evidence of causation can be clin-
is usually mild to moderate, although severe pain ical (i.e., orthostatic headache in patients with
is reported by one-fifth of patients and some low cerebrospinal fluid pressure/volume) or
patients experienced nausea during attacks. Pain based on investigations (i.e., imaging in patients
is bilateral in about two-thirds of cases. Other with brain tumors or elevated erythrocyte sedi-
possible causes of headache developing during mentation rate in patients with giant-cell arteritis)
and causing wakening from sleep should be [4]. Below are the most frequent known second-
excluded, in particular sleep apnea, nocturnal ary chronic daily headaches.
hypertension, hypoglycemia, and medication
overuse; intracranial disorders must also be
excluded. However, the presence of sleep apnea CDH Attributed to Trauma
syndrome does not necessarily exclude the diag-
nosis of hypnic headache [4]. ersistent Headache Attributed
P
to Traumatic Injury to the Head
rimary Stabbing Headache (PSH)
P This is a headache that began within 7 days of a
PSH is characterized by transient and localized head trauma (or within 7 days after discontinua-
stabs of pain in the head, lasting seconds and tion of medication (s) that impaired ability to
occurring spontaneously in the absence of sense or report headache following the injury to
organic cranial disease. Stabs recur with irregular the head) and lasted more than 3 months. The
frequency, generally low, one or a few per day. trauma can be a direct blow to the head, whiplash
No cranial autonomic symptoms occur, which injury, or craniotomy (about a quarter of patients
aids in differentiating PSH from chronic develop persistent headache after craniotomy).
SUNA. It may move from one area to another, in Interestingly, the persistence of headache is
either the same or the opposite hemicranium. inversely correlated with the severity of head
When stabs are strictly localized to one area, trauma [10]. When headache following head
structural changes at this site and in the distribu- injury becomes persistent, the possibility of
tion of the affected cranial nerve must be another secondary headache should be consid-
excluded. Primary stabbing headache is more ered, including medication-overuse headache.
commonly experienced by people with migraine,
in which case stabs tend to be localized to the site
habitually affected by migraine headaches [4]. DH Attributed to Cranial Vascular
C
Disorders
Secondary Chronic Daily Headaches DH Attributed to Giant-Cell Arteritis

C
(GCA)
Typically, a secondary headache is diagnosed Headache may be the sole symptom of GCA, but
when a headache occurs de novo in close tempo- other symptoms (i.e., polymyalgia rheumatica,
ral relationship with another disorder able to jaw claudication) usually accompany it. The vari-
ability in the features of the headache attributed brospinal fluid (CSF) pressure, usually accom-
to GCA and in other symptoms of GCA is such panied by other symptoms and/or clinical signs
that any recent persistent headache in a patient of increased intracranial pressure, especially
over 60 years of age should raise concern for papilledema. Idiopathic intracranial hyper-
GCA and lead to appropriate investigations [4] tension may or may not have an identifiable
and treatment rapidly administered. Duration of cause. Elevated CSF pressure can also occur
headache and the need for corticosteroid treat- as a result of cerebral venous sinus thrombosis,
ment often extend for months to years. Headache various medications, or other medical condi-
of giant-cell arteritis is due to inflammation of the tions such as renal disease or endocrinopathies.
cranial arteries, especially branches of the exter- The cerebrospinal fluid opening pressure is
nal carotid artery. Recent repeated attacks of more than 250 mm CSF, carefully measured
amaurosis fugax associated with headache are in lateral decubitus. Although more common
suggestive of GCA and should prompt urgent in obese females, IIH can also occur in non-
investigations, due to risk of severe complica- obese males. The presence of transient visual
tions, especially the major risk of blindness. The obscurations and intracranial noises may pro-
main risk after vision loss in one eye, usually vide clues [3]. The headache often remits after
irreversible, is vision loss in the other eye. normalization of CSF pressure but may require
Patients with GCA are also at risk of cerebral prolonged and comprehensive chronic daily
ischemic events and of dementia. Since this con- headache management based on the phenotype
dition can affect arteries that are peridural, other of the headache.
organ systems can suffer infarctions.
hronic Headache Attributed to Low
C
hronic Headache Attributed
C Cerebrospinal Fluid Pressure/Volume
to Reversible Cerebral Vasoconstriction Spontaneous intracranial hypotension: This
Syndrome (RCVS) headache occurs due to low cerebrospinal fluid
Headache caused by reversible cerebral vasocon- (CSF) pressure/volume or CSF leakage, usually
striction syndrome can be the sole symptom of accompanied by neck pain/stiffness, tinnitus,
RCVS and typically manifest with recurring thun- changes in hearing, photophobia, and nausea.
derclap headache up to 12 weeks, often triggered Headache that significantly worsens soon after
by sexual activity, exertion, certain medications, sitting upright or standing and/or improves after
Valsalva maneuvers, or emotion [4]. Recent stud- lying horizontally is likely to be caused by low
ies indicate that, in a significant proportion of CSF pressure, but this cannot be relied upon as a
cases, patients go on to develop chronic daily diagnostic criterion [4]. Typically, the cerebro-
headache, without the thunderclap appearance but spinal fluid pressure is lower than 60 mm CSF
with features that are similar to chronic migraine, and successful sealing of the CSF leak usually
chronic tension-type, or other primary headaches, resolves the headache. This headache diagnosis
including medication-overuse headache [12]. is usually delayed and follows a chronic course.
The orthostatic nature of the headache can be
prominent initially but may become less obvious
DH Attributed to Intracranial
C over time. Occasionally, orthostatic headache is
Nonvascular Disorders never present, and patients may notice that their
headaches begin and increase gradually after ris-
C ing in the morning [3] or the positional compo-
to Increased Cerebrospinal Fluid nent is even paradoxical. In that case it is
Pressure necessary to go back and review the history and
Idiopathic intracranial hypertension (IIH) or early imaging to ensure that a cause for a pre-
“pseudotumor cerebri” is the headache type sumable spontaneous intracranial hypotension
that is caused by spontaneously increased cere- was not missed [13].

C other than the treatment of headache and is not
to Intracranial Neoplasia necessarily reversible. Evidence of causation is
This type of headache is caused by an intracranial required as follows: headache has developed in
neoplasm, in the absence of a primary chronic temporal relation to the commencement of medi-
headache disorder or making a preexistent pri- cation intake and one or more of the following:
mary disorder chronic. A pattern of a progressive headache has significantly worsened after an
headache, often worse in the morning, is usually increase in dosage of the medication, or headache
elicited. Not uncommonly, the headache caused has significantly improved or resolved after a
by intracranial tumors mimics a primary head- reduction in dosage or cessation of the medication,
ache clinically [14]. and the medication is recognized to cause head-
ache [4]. Some common medications causing
hronic Headache Attributed to Chiari
C headache include monoamine oxidase inhibitors,
Malformation Type I (CM1) calcium channel blockers, nonsteroidal anti-
Headache caused by Chiari type I malformation inflammatory agents, caffeine, ranitidine, estrogen
is usually occipital or suboccipital, of short dura- compounds, and vasopressor agents [15].
tion (less than 5 min), and provoked by cough or
other Valsalva-like maneuvers. Almost all (95%) edication-Overuse Headache (MOH)
M
patients with CM1 report a constellation of five This is a headache occurring in 15 or more days
or more distinct symptoms. If headache is due to per month, developing as a consequence of regu-
Chiari malformation, it remits after the success- lar overuse of acute or symptomatic headache
ful treatment of this congenital condition [4]. medication (on 10 or more or 15 or more days per
Evidence of headache causation, based on spe- month, depending on the overused medication)
cific ICHD-3 beta criteria, are required as CM1 is for more than 3 months. By current definition, it
often asymptomatic and decompressive surgery has to occur in a patient with a preexisting head-
is not indicated and has significant potential for ache disorder. Among those with a previous pri-
morbidity. Cerebrospinal fluid leak, which can mary headache diagnosis, most have migraine or
mimic CM1, needs to be excluded. tension-type headache (or both); only a small
minority has other primary headache diagnoses
C such as chronic cluster headache or new daily
to Noninfectious Inflammatory Disease persistent headache.
This type of headache occurs in the presence of a It usually, but not invariably, resolves after the
noninfectious inflammatory intracranial disease, overuse is stopped but may take time. In almost all
usually with lymphocytic pleocytosis in the cere- cases, this necessitates diary follow-up [4]. The
brospinal fluid. It remits after resolution of the diagnosis of medication-overuse headache is
inflammatory disorder. Examples of conditions that extremely important. Approximately half of people
can be suspected include chronic inflammatory with headache on 15 or more days per month for
conditions like neurosarcoidosis, lupus, Behcet’s more than 3 months have MOH, and they consti-
syndrome, autoimmune encephalitis, and others [4]. tute a large proportion of the patients presenting to
headache clinics. Prevention of MOH is especially
important in patients prone to frequent headaches
DH Attributed to Long-Term Use
C that are likely to consume frequent medications.
of Medications Medication overuse may be responsible, in part for
the transformation of episodic migraine into
hronic Headache Attributed to Long-
C chronic migraine and for the perpetuation of the
Term Use of Non-Headache Medication syndrome [9]. However, medication-overuse head-
This headache type is present on more than 15 days ache is an interaction between a therapeutic agent
per month and develops as an adverse event during used excessively and a susceptible patient. There is
long-term use of a medication taken for purposes growing interest and research in this area, and this
is reflected in the ongoing scholarly controversy apnea, and resolving with successful treatment of
about whether symptomatic overuse is a cause or a sleep apnea. A definitive diagnosis requires over-
consequence of CDH [3]. night polysomnography. Obstructive sleep apnea
frequently leads to daily headaches upon awak-
ening and should be considered in patients with a
CDH Attributed to Infections snoring history, large neck size, or obesity.
Although morning headache is significantly more
DH Attributed to Intracranial
C common in patients with sleep apnea than in the
Infections general population, headache present upon awak-
Chronic headache attributed to bacterial menin- ening is a nonspecific symptom which occurs in a
gitis or meningoencephalitis: This is a headache variety of primary and secondary headache disor-
that has been present for >3 months and fulfills ders, in sleep-related respiratory disorders other
criteria for headache attributed to bacterial menin- than sleep apnea (e.g., Pickwickian syndrome,
gitis or meningoencephalitis and in which bacte- chronic obstructive pulmonary disorder), and in
rial meningitis or meningoencephalitis remains other primary sleep disorders such as periodic leg
active or has resolved within the last 3 months [4]. movements of sleep [4].
Chronic headache attributed to intracranial
fungal or other parasitic infection: This type of hronic Headache Attributed
C
headache fulfills criteria for headache attributed to Hypothyroidism
to intracranial fungal or other parasitic infection, This is an uncommon type of headache, usually
in which the intracranial fungal or other parasitic bilateral, non-pulsatile, and constant, in patients
infection remains active or has resolved within with hypothyroidism and remitting after nor-
the last 3 months. The headache has been present malization of thyroid hormone levels. It may
for >3 months. Examples include coccidioido- follow a chronic course if not recognized and
mycosis, neurocysticercosis, aspergillosis, and treated timely. There is a female preponderance
cryptococcosis [16]. and often a history of migraine in childhood [4,
17, 18].
DH Attributed to Systemic Infections
C CDH or Chronic Facial Pain Attributed to
Chronic headache attributed to systemic bacte- Disorder of the Cranium, Neck, Eyes, Ears, Nose,
rial infection. Chronic headache attributed to Sinuses, Teeth, Mouth, or Other Facial or
systemic viral infection. Chronic headache attrib- Cervical Structures.
uted to other systemic infection.
This type of headache is present for >3 months hronic Headache Attributed
C
and fulfills criteria for headache attributed to bac- to Disorder of Cranial Bone
terial, viral, or other systemic infection, in which This type of headache can appear in patients with
the systemic infection remains active or has chronic bone diseases like osteomyelitis, multi-
resolved within the last 3 months. Examples ple myeloma, or Paget disease and may lead to
include Lyme disease, tuberculosis, or HIV [4]. diagnosis of such conditions [4].
Cervicogenic Headache
DH Attributed to Disorders
C This CDH, typically unilateral, is caused by a
of Homeostasis disorder of the cervical spine and its component
bony, disc, and/or soft tissue elements, usually
hronic Headache Attributed to Sleep
C but not invariably accompanied by neck pain.
Apnea The diagnosis requires evidence of a lesion
This is a morning headache, occurring on more within the cervical spine or soft tissues of the
than 15 days/month, usually bilateral and with a neck, known to cause headache, and also evi-
duration of less than 4 hours, caused by sleep dence of causation: temporal relationship,
reduced cervical range of motion, and head- hronic Headache Attributed

C
ache made significantly worse by provocative to Temporomandibular Disorder (TMD)
maneuvers. The headache is abolished follow- This headache type is caused by a disorder
ing diagnostic blockade of a cervical structure involving structures in the temporomandibular
or its nerve supply. This needs to be distin- region. The head pain is produced or exacerbated
guished in particular from migraine and tension- by active jaw movements and, when unilateral, is
type headache or from the rarer TACs. Cervical ipsilateral to the side of the temporomandibular
spondylosis and osteochondritis may or may not disorder. It is usually most prominent in the pre-
be valid causes of cervicogenic headache [4]. auricular areas of the face, masseter muscles,
Cervicogenic headache remains a controversial and/or temporal regions. A review of a large
diagnosis, at the boundary between medical/sur- group of patients with TMD found that their
gical specialties. headache could be attributed to this condition in
only 5.1% of cases [20].
C
to Retropharyngeal Tendonitis hronic Headache Attributed to Other
C
This is a headache caused by inflammation or Disorders of the Cranium, Neck, Eyes,
calcification in the retropharyngeal soft tissues Ears, Nose, Sinuses, and Teeth
and usually brought on by stretching or compres- This is a headache and/or facial pain caused by a
sion of upper cervical prevertebral muscles and/ disorder, known to cause headache, of the cra-
or swallowing [4]. Upper carotid dissection (or nium, neck, eyes, ears, nose, sinuses, teeth,
another lesion in or around the carotid artery) mouth, or other facial or cervical structures not
should be excluded as well as disorders of other described above. Attention should be paid during
structures in the head and neck, i.e., Eagle syn- the history and physical examination to exclude
drome [19]. cervical spine, temporomandibular joint (TMJ),
or dental pathology as the culprit in chronic cra-
C nial, nuchal, or facial pain [3].
to Craniocervical Dystonia
This is a headache caused by dystonia involving
neck muscles, with abnormal movements or DH Headache Attributed
C
defective posturing of the neck or head due to to Psychiatric Disorders
muscular hyperactivity. Headache location cor-
responds to the location of the dystonic hronic Headache Attributed
C
muscle(s) [4]. to Somatization Disorder (Currently
Somatic Symptom Disorder in DSM-5)
C This type of headache occurs as part of the symp-
to Chronic or Recurring Rhinosinusitis tomatic presentation of a somatization disorder
This type of headache is caused by a chronic including all of the following: at least four pain
infectious or inflammatory disorder of the para- symptoms, two gastrointestinal symptoms, one
nasal sinuses and associated with other symp- sexual (other than pain), and one pseudoneuro-
toms and/or clinical signs of the disorder. It is logical. The patient’s suffering is authentic,
controversial whether chronic sinus pathology whether or not it is medically explained. Patients
can produce persistent headache. Recent studies typically experience distress and a high level of
seem to support such causation [4]. Sphenoid functional impairment. The symptoms may or
sinusitis may masquerade as an intractable head- may not accompany diagnosed general medical
ache, unresponsive to analgesics and interfering disorders or psychiatric disorders. There may be
with sleep, and can occur without associated a high level of medical care utilization, which
nasal symptoms [9]. rarely alleviates the patient’s concerns [4].
ainful Cranial Neuropathies

P trigeminal neuralgia [4]. Postherpetic trigeminal
and Other Facial Pains neuropathy is associated with three different
types of pain: a constant deep aching and burning
Classical Trigeminal Neuralgia pain; an intermittent, transient pain with a sharp,
The classical type of trigeminal neuralgia com- jabbing, or electric shock-like quality; and a
monly develops without apparent cause other sharp, radiating dysesthesia triggered by light
than neurovascular compression. It is diagnosed tactile stimulation of specific trigger areas (allo-
when at least three attacks of unilateral facial dynia) [21].
pain have occurred in one or more divisions of
the trigeminal nerve, with no radiation beyond hronic Occipital Neuralgia
C
the trigeminal distribution. Classical trigeminal This is a unilateral or bilateral paroxysmal,
neuralgia usually appears in the second or third shooting, or stabbing pain in the posterior part of
divisions of that nerve. Pain has at least three of the scalp, in the distribution of the greater, lesser,
the following four characteristics: recurring in or third occipital nerves, sometimes accompa-
paroxysmal attacks lasting from a fraction of a nied by diminished sensation or dysesthesia in
second to 2 minutes; severe intensity; electric the affected area and commonly associated with
shock-like, shooting, stabbing, or sharp in qual- tenderness over the involved nerve(s). This must
ity; and precipitated by innocuous stimuli to the be distinguished from occipital referral of pain
affected side of the face. Some attacks may be, or arising from the atlantoaxial or upper zygapoph-
appear to be, spontaneous, but there must be at yseal joints or from tender trigger points in neck
least three that are precipitated in this way to muscles or their insertions [4]. Occipital neural-
meet this criterion. Following a painful parox- gia occurs rarely and is probably overdiagnosed.
ysm, there is usually a refractory period during
which pain cannot be triggered [4]. Often, there urning Mouth Syndrome (BMS)
B
is a slight ipsilateral focal muscle twitch simulta- This represents an intraoral burning or synes-
neous with pain paroxysm—tic douloureux. The thetic sensation, recurring daily for more than 2 h
pain never crosses to the opposite side, but it may per day more than 3 months, without clinically
rarely occur bilaterally (especially in multiple evident causative lesions. The pain is usually
sclerosis). Mild autonomic symptoms such as bilateral, and its intensity fluctuates. The most
lacrimation and/or redness of the eye may occa- common site is the tip of the tongue. Subjective
sionally be present, but they are typically absent. dryness of the mouth, dysesthesia, and altered
The duration of pain attacks can change over taste may be present. There is a high menopausal
time and become more prolonged as well as female prevalence, and some studies show
severe, often leading to weight loss and even sui- comorbid psychosocial and psychiatric disorders
cide. Evolution is unpredictable, but, between [4, 22]. There may be multiple local or systemic
paroxysms, most patients are asymptomatic, and causes for the BMS (like candidiasis, lichen pla-
spontaneous remissions can occur. nus, hyposalivation, medication-induced anemia,
deficiencies of vitamin B12 or folic acid,
Postherpetic Trigeminal Neuropathy Sjögren’s syndrome, diabetes) and even infec-
(Trigeminal PHN) tions, like alpha-herpes viruses [23].
This type of chronic headache is characterized by
a unilateral head and/or facial pain persisting or ersistent Idiopathic Facial Pain (PIFP)
P
recurring for at least 3 months in the distribution This headache type was previously called “atyp-
of one or more branches of the trigeminal nerve, ical facial pain.” It consists of persistent facial
with variable sensory changes, caused by herpes and/or oral pain, with varying presentations but
zoster virus. It is more prevalent in the elderly recurring daily for more than 2 h per day more
and involves the first division of the trigeminal than 3 months, in the absence of clinical neuro-
nerve most commonly, as opposed to classical logical deficit. Persistent idiopathic facial pain
(PIFP) may originate from a minor operation or 7. Lipton RB, Serrano D, Buse DC, Pavlovic JM, et al.
Improving the detection of chronic migraine: devel-
injury to the face, maxillae, teeth, or gums but opment and validation of identify chronic migraine
persists after healing of the initial noxious event (ID-CM). Cephalalgia. 2016;36(3):203–15.
and without any demonstrable local cause. The 8. Dodick DW, Loder EW, Manack Adams A, Buse DC,
pain of PIFP can have sharp exacerbations and is Fanning KM, Reed ML, Lipton RB. Assessing bar-
riers to chronic migraine consultation, diagnosis and
aggravated by stress. The pain may be described treatment: results from the chronic migraine epide-
as either deep or superficial. With time, it may miology and outcomes (CAMEO) study. Headache.
spread to a wider area of the craniocervical 2016;56(5):821–34.
region [4]. An active dental cause has to be 9. Dodick DW, Silberstein SD. Chronic migraine.
In: Dodick DW, Silberstein SD, editors. Migraine.
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ough knowledge of the trigeminal nerve anatomy p. 193–242.
is required [11]. 10. Jensen R, Olesen J. Other refractory headaches:

chronic tension-type headache, new daily persistent
headache, cluster headache and other trigeminal
hronic Central Poststroke Pain (CPSP)
C autonomic cephalalgias, and posttraumatic headache.
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tions involving parts or all of the craniocervical agement. New York: Oxford University Press; 2010.
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limbs of the affected side [4]. Craniocervical pain mad T, Tepper S, Stillman M, Mills B, Thankachan
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Chronic Migraine: Epidemiology,
Mechanisms, and Treatment 4
Teshamae S. Monteith
hronic Migraine: Diagnosis

C criteria in the appendix section of the ICHD-3
and Classification include chronic migraine with pain-free periods
versus chronic migraine with continuous pain.
Chronic migraine is a highly disabling pri- Overall, the classification system can be both use-
mary headache disorders that accounts for the ful for both clinical and research purposes; how-
greatest portion of chronic daily headache [1]. ever, there are limitations and a continued need
Chronic migraine differs from episodic migraine for a biologically driven approach to identify clin-
by the frequency of headache days and associ- ically relevant heterogeneity in chronic migraine.
ated symptoms, and it has been suggested that Chronic migraine is no longer considered a
chronic migraine represents one end of the clini- complication of migraine and is recognized in indi-
cal spectrum [2]. According to the International viduals that have had at least five attacks fulfilling
Classification of Headache Disorders-3 (ICHD- criteria for migraine with/or without aura. The diag-
3), chronic migraine is diagnosed in individuals nosis allows for the patient perception of migraine
that have headaches that occur at least 15 days per at the onset if relieved by migraine-specific abortive
month for more than 3 months (Table 4.1) [3, 4]. treatments, such as triptans and ergotamine deriva-
Eight of the days must have features of migraine tives, so that treatment does not limit the diagnosis.
with or without aura, which includes sensitivity Patient perception has been included because asso-
to sensory stimulation, throbbing headache, and ciated features vary during the day and it is diffi-
gastrointestinal symptoms (nausea). Although not cult to keep a patient medication-free to determine
a part of the official classification, non-headache the natural history of an attack. Medication over-
symptoms including fatigue, cognitive impair- use of acute analgesics often occurs with chronic
ment, mood disturbance, neck pain, brainstem migraine. In the previous ICHD-2R classification
symptoms, and other systemic symptoms may system, medication overuse headache had to be
be present and can be equally disabling. The excluded before the diagnosis of chronic migraine
premonitory and postdrome phase of a migraine could be made [5]. According to revised ICHD-3,
attacks occurs before and after headache, respec- the presence of medication overuse headache no
tively; these phases are often lost or less distinct longer excludes a diagnosis of chronic migraine;
in individuals with chronic migraine. Alternative both should be coded together when present. Medi-
cation overuse headache will be discussed else-
where in this book (Chap. 14).
T. S. Monteith
In clinical practice, chronic migraine is often
Department of Neurology, Miller School of
Medicine, University of Miami, Miami, FL, USA underdiagnosed and undertreated. There are sev-
e-mail: tmonteith@med.miami.edu eral reasons why this may be the case. Patients

38 T. S. Monteith
Table 4.1 Diagnostic criteria for transformed migraine and chronic migraine
ICHD-3 episodic migraine Silberstein-Lipton TM ICHD-2R chronic migraine ICHD-3 chronic migraine
A. At least five attacks Daily or almost daily Headache on ≥15 days/month Headache on ≥15 days
fulfilling criteria B–D (>15 days a month) head for 3 months per month for at least
B. Headache attacks lasting pain for >1 month Occurring in a patient who 3 months
4–72 h (untreated or Average headache has had at least five attacks Occurring in a patient
unsuccessfully treated) duration of >4 h (if fulfilling criteria for 1.1 who has had at least
C. Headache has at least two untreated) migraine without aura five attacks fulfilling
of the following four At least one of the On ≥8 days per month, for at criteria for 1.1 migraine
characteristics: following: least 3 months, headache without aura and/or 1.2
1. Unilateral location History of episodic fulfills criteria for migraine migraine with aura
2. Pulsating quality migraine meeting any C1 and/or C2 below, that is, On ≥8 days per month
3. Moderate or severe IHS criterion 1.1–1.6 has fulfilled criteria for pain for at least 3 months 1
pain intensity History of increasing and associated symptoms of or more of the
4. Aggravation by or headache frequency migraine without aura following criteria were
causing avoidance of with decreasing Has at least two of a–d: fulfilled
routine physical severity of (a) Unilateral location Criteria C and D for 1.1
activity (e.g., walking migrainous features (b) Pulsating quality migraine without aura
or climbing stairs) over at least 3 months (c) Moderate or severe pain Criteria B and C for 1.2
D. During headache at least Headache at some intensity migraine with aura
one of the following: time meets IHS (d) Aggravated by or causing Headache considered by
1. Nausea and/or criteria for migraine avoidance of routine patient to be onset
vomiting 1.1–1.6 other than physical activity and at migraine and relieved
2. Photophobia and duration least one of a or b by a triptan or an
phonophobia Does not meet criteria (a) Nausea and/or vomiting ergotamine derivative
E. Not better accounted for for new daily persistent (b) Photophobia and Not better accounted for
by another ICHD-3 headache (4.7) or phonophobia by another ICHD-3
diagnosis hemicrania continua Treated or relieved with diagnosis
(4.8) triptans or ergotamine before
the expected development of
C1 above
No medication overuse and
not attributable to other
causative disorder
The diagnostic criteria for chronic migraine have evolved over time and results in variability in estimated prevalence
globally. The chart is adapted from Silberstein et al. Headache 2014 [4]. Episodic migraine refers to migraine occurring
<15 days per month and can be further divided into low-frequency migraine (1–4 days per month) and high-frequency
migraine (10–14 days per month)
sometimes report only the most severe headaches, data support the observation that non-migraine
while minimizing relatively mild to moderate headache may increase in frequency as the illness
headache days [6]. The diagnosis may also be a progresses so that transformed migraine may be a
challenge to make because migraine-associated transitional stage of chronification [8].
symptoms may be reduced over time or be so mild Currently, there is no universally accepted
that they are not diagnosed as having migraine. objective test for the diagnosis of chronic migraine.
The Lipton-Silberstein classification system The best accepted methods for the diagnosis of
defines transformed migraine when individu- chronic migraine, in addition to self-reported his-
als have headache 15 or more headache days per tory, are migraine diaries, which are often asso-
month (not necessarily migraine), with a current or ciated with poor compliance, missing data, and
past history of migraine [7]. Transformed migraine recall bias. As chronic migraine is underdiagnosed,
may be diagnosed in patients that would otherwise several attempts have been made to improve the
be classified as chronic tension-type headache and detection. Identify Chronic Migraine (ID-CM) is a
migraine [4]. Transformed migraine is not recog- simple self-administered tool that is both sensitive
nized in the ICHD-3 classification; however, some and specific and facilitates the accurate diagnosis
4 Chronic Migraine: Epidemiology, Mechanisms, and Treatment 39
of most people with chronic migraine [9]. Auto- to the overall functional impairment. In addition,
mated migraine classification with machine learn- longitudinal population studies have identified
ing techniques have also been developed for use in other risk factors for chronic daily headache such
patients undergoing magnetic resonance imaging as head and neck injury [17], high caffeine intake
with diffusion tensor imaging [10]. Early results [18], habitual snoring [19], insomnia [20], stress-
found that pain, analgesics, and left uncinate ful life events [21], caucasians, female sex, less
nuclei, an area that connects pain with emotions, education, and previously married (divorced,
were most useful for classification. According separated, widowed) [22].
to a meta-analysis of CSF and blood samples of The rate of new onset chronic migraine is 2.5%
chronic migraine, the most robust findings for in persons with episodic migraine after 1 year
biochemical markers include increased glutamate, according to the American Migraine Prevalence
calcitonin gene-related peptide (CGRP), nerve and Prevention Study (AAMPS) [23]. The clinical
growth factor, and decreased beta-endorphin [11]. progression to chronic migraine generally occurs
Pituitary adenylate cyclase-activating polypeptide gradually with an increase in attack frequency
(PACAP) appears to play a role in nociception over time; in other cases, chronic migraine may
and migraine, although an early study showed no occur suddenly. Moreover, there is a significant
change in interictal PACAP levels in the periph- variability in the frequency of headache depending
eral blood of women with chronic migraine [12]. on the frequency of sampling in epidemiological
Widely accepted and systematic detection meth- studies. An analysis from the Chronic Migraine
ods with high rates of accuracy are lacking. Epidemiology and Outcomes (CaMEO) Study, a
longitudinal survey of US adults with episodic and
chronic migraine, illustrated the natural fluctua-
Epidemiology and Impact tions over the course of 1 year between episodic
migraine and chronic migraine during 3-month
Chronic migraine is a debilitating primary head- intervals [24]. The investigators found that among
ache disorder affecting 1.4–2.2% [1] of the popu- 5465 respondents with episodic migraine, 92.4%
lation and is associated with a higher headache had episodic migraine in all periods of sampling
impact when compared to episodic migraine [1, or waves of data, while 7.6% had chronic migraine
13]. The prevalence of chronic migraine is 2.5– in at least one wave. There were 526 respondents
6.5 greater in women [1]. In comparison to epi- with chronic migraine at baseline of which 26%
sodic migraine, individuals with chronic migraine had chronic migraine at every point and 73.4%
have statistically lower household incomes, have had episodic migraine at least once. The studies
a higher likelihood of being occupationally dis- suggest that there are frequent transitions between
abled, and are less likely to be employed full time episodic migraine and chronic migraine in per-
[14]. According to the International Burden of sons with migraine at 3 months intervals during
Migraine Study, chronic migraine has three times a 12-month period. More studies are needed
the mean total annual cost of headache compared to understand the transitions between episodic
to episodic migraine [15], significantly greater migraine and chronic migraine and to better iden-
direct medical costs and indirect costs. Pharma- tify individuals in the pre-chronic migraine state
ceutical utilization made up the largest portion of who may be at a greater risk for personal, occupa-
direct medical costs in both groups. Family bur- tional, and social loss due to migraine progression.
dens were also greater with increased headache Predictors of progression have important clini-
frequency [16]. Patients with chronic migraine cal significance (Fig. 4.1). In addition, there are a
also have higher rates of anxiety, depression, number of migraine-specific and treatment-related
respiratory illness, higher rates of allergies, car- risk factors. In the American Migraine Preva-
diovascular disorder and heart disease, obesity, lence and Prevention Study of 5681 eligible study
chronic pain, and ulcers [14]. These common respondents, the Migraine Treatment Optimization
comorbidities in chronic migraine may contribute Questionnaire (mTOQ-4) was used to determine
40 T. S. Monteith
Sensitization
Insufficient acute pain relief

+
Risk factors
female sex Protective factors
preventive medication
genetic Decreased
Genetic predisposition higher education
threshold
+ being married/
predisposition obesity for generation of
migraine attacks social support
depression
exercise
stressful life
stress management
events
Attack frequency
+
Insufficient acute pain relief
Intake of acute medication

Nature ReviewsNeurology
Fig. 4.1 Multiple factors contribute to migraine chronification. (May A, Schulte LH. Chronic migraine: Risk factors,
mechanisms and treatment. Nat Rev Neurol 2016;12:455–64. Reprinted with permission from Springer Nature)
treatment responses and a logistic regression model in addition to less headache days. After a multi-
was used to examine transition from episodic variate analysis, predictors of remission included
migraine to chronic migraine. The study found that headache frequency (15–19 vs. 25–31, headache
ineffective acute treatment of episodic migraine days/month; odds ratio [OR] 0.29; 95% confidence
was associated with new onset chronic migraine interval [CI] 0.11–0.75) and absence of allodynia
over the course of 1 year [25]. When compared to (OR 0.45; 95% CI 0.23–0.89). As expected, those
the maximum treatment efficacy group, the very with persistent chronic migraine had increased dis-
poor treatment efficacy group had more than a two- ability, and those with remitted chronic migraine
fold-increased risk of chronic migraine. Medication had reduced disability.
overuse of acute analgesics is a commonly recog-
nized risk factor for chronic migraine and migraine
progression. The risk of migraine progression is Pathophysiology
associated with the use of butalbital-containing
compounds (>5 days per month) and opiate drugs Chronic migraine is thought to involve mul-
(>8 days per month) as compared to acetaminophen tiple levels of the central nervous system and
used as a reference [23]. A baseline high attack fre- include biochemical, physiological, functional,
quency is also associated with migraine progres- and structural alterations. In a meta-analysis of
sion as well as frequent and persistent nausea [26]. 375,000 individuals with migraine, 38 genetic
Predictors of remission and progression loci were found for migraine [28]. The GWAS
have been explored in epidemiological samples (genome wide association study) has some limi-
of chronic migraine. In a study of 383 respon- tations but implicates both neuronal and vascu-
dents over a 2-year period, 34% had persistent lar cells, indicative of a n eurovascular disorder.
chronic migraine and 26% had remittance of their They also point to supporting glia, pain signal-
chronic migraine state [27]. Predictors of remis- ing pathways and multiple influences that may
sion include the baseline headache frequency and lead to a progressive, maladaptive state. The
absence of allodynia; remission rates are associ- genetic underpinnings of chronic migraine are
ated with decreases in headache-related disability unknown but are likely polygenic similar to
Cortex Release of CGRP and PACAP

Cortical spreading depolarisation, altered connectivity Multiple potential sources or sites of action
Migraine aura and cognitive symptoms Headache and other symptoms
Target for neuromodulation Target for small-molecule antagonists and antibodies
Thalamus
Sensitisation and alteration of
thalamo-cortical circuits
Sensory sensitivity and allodynia
Target for neuromodulation
Trigemino-cervical complex
Hypothalamus Pain transmission or sensitisation

Headache and neck pain
Activation in premonitory phase
Premonitory symptoms Target for medications and
neuromodulation
Target for hypothalamic peptides
and modulators
Upper cervical nerves

Pain transmission or sensitisation
Neck pain and head pain
Target for local injections and
neuromodulation
Fig. 4.2 The diagram illustrates the multiple levels of the Emerging evidence supports the potential for targeted
peripheral and central nervous system involvement in the treatments in chronic migraine; however, more investiga-
pathophysiology of chronic migraine. There are a number tions are needed. (Charles A. The pathophysiology of
of targets for medications, antibodies, small molecule migraine: implications for clinical management. Lancet.
antagonists, peptides and modulators, neuromodulation 2018;17(2):174–82. Reprinted with permission from
devices, and injection therapies as treatment for migraine. Elsevier)
episodic migraine. Significant progress has been chronic migraine. There has been much debate
made for the past few decades in the under- as to the level in which peripheral trigeminal
standing of the peripheral and central pathways, nociceptive activation is involved in migraine
important neuropeptides, neurotransmitters, and attacks. An extracranial hypothesis that includes
receptors involved in migraine pathophysiology, an inflammatory profile has been suggested in a
although with somewhat lesser knowledge of small series of chronic migraine patients [29],
42 T. S. Monteith
although chronic tenderness of pericranial mus- left inferior, and right inferior frontal gyrus
cles may be a consequence of frequent attacks [36]. Significant positive correlations between
as well. It is plausible that both the peripheral the attack frequency and gray matter reductions
and central systems are involved (Fig. 4.2) One- have been shown in the anterior cingulate cortex.
quarter of patients experience migraine with Moreover, another imaging study of non-heme
aura, transient neurological disturbances in the iron deposition in the periaqueductal gray, an
visual, sensory, motor, and language systems. area of descending antinociceptive neuronal net-
The electrophysiological correlate for migraine work, found statistically significant differences
aura is cortical spreading depression (2-6 mm/ in episodic migraine and chronic daily headache
min), a slowly propagating wave of neuronal and as compared to controls and positive correlations
glial depression consisting of electrophysiologi- with the duration of illness. The investigators
cal hyperactivity followed by cortical inhibition hypothesized that iron homeostasis in the peri-
[30]. Cortical spreading depression can activate aqueductal gray matter is persistent and pro-
trigeminal nociception and trigger headache gressively impaired due to iron-catalyzed free
mechanisms, as supported by animal studies radical injury from repeated migraine attacks
[31]. Cortical spreading depression may also [37]. Taken together, the findings suggest that
activate or disinhibit central trigeminal sensory repeated migraine attacks might be associated
neurons, supported by preclinical studies [32]. with changes in brain structure.
As most migraine attacks do not begin with aura Historically, both cortical and brainstem
and migraine headache may occur during the regions have been implicated in the pathophysi-
aura phase, aura has been postulated as a brain ology of migraine [38]. Patients with chronic
state and other mechanisms of attack initiation migraine have enhanced cortical excitability as
have been proposed [33]. Alternatively, lowered compared to episodic migraine. The cortical excit-
thresholds of activation due to enhanced cycli- ability is thought to be intrinsic or due to reduced
cal brainstem activity may also contribute to intracortical inhibitory mechanisms [2, 38]. In
chronic migraine [34]. The hallmarks of chronic one study using transcranial magnetic stimula-
migraine are repetitive activation and sensiti- tion indexes of cortical excitability, the magnetic
zation of the trigeminovascular system, which suppression of perceptual accuracy was signifi-
includes the sensory peripheral projections to cantly reduced in 25 chronic migraine patients as
the pain-producing dura mater and central pro- compared to episodic subjects and controls [39].
jections to the trigeminal nucleus caudalis in the In a subset of the patients with chronic migraine,
brainstem. Central projections are then sent to PET imaging showed increased metabolism in
the trigeminothalamic tract, to the thalamus, and the pons and right temporal cortex; the medial
the cortex. frontal, parietal, and somatosensory cortices
The distinct pathological drivers associated and the bilateral caudate nuclei had decreased
with chronic migraine are poorly understood, metabolism. Imaging studies with PET have also
although there appear to be significant brain supported the role of the pons. In another study
changes [2]. For example, an imaging study of chronic migraine with suboccipital stimula-
suggested that the ICHD-3 diagnosis of chronic tors, activation in the dorsal pons was similar
migraine as compared to episodic migraine to that in episodic migraine; however, persistent
could be adequately classified based on regional activation after stimulation suggests the structure
changes in cortical thickness, surface area, and may play a key role in the pathophysiology of
volumes [35]. In another magnetic resonance chronic migraine [40]. Taken together, the acti-
imaging study with voxel-based morphometry, vation and inhibitory patterns of the brainstem,
there were significant gray matter reductions in the pons in particular, suggest that cortical excit-
the left and right anterior cingulate, left amyg- ability is “raised” and may result in a higher
dala, left and right insular lobe, left parietal oper- susceptibility to migraine triggers [41]. Another
culum, left parietal operculum, and left, middle, investigation to better understand light aversion
was performed in 18 episodic migraineurs, 17 migraineurs, 18 episodic migraineurs, and 19

chronic migraineurs, and 19 healthy controls. healthy controls suggested that the hypothalamus
The investigators used high resolution brain- might also be the mediator of chronic migraine
stem imaging to determine the effects of visual [46]. Moreover, the activation patterns suggested
stimulation on activation of the spinal trigeminal that the anterior hypothalamus might play a role
nucleus [42]. The study showed that individuals in attack generation and migraine chronifica-
with chronic migraine had enhanced activation tion as opposed to the posterior aspect, which
within the spinal trigeminal nucleus as compared appears to be important for the acute pain phase.
to healthy controls. Activation was also greater Many questions remain such as mechanisms of
in the spinal trigeminal nucleus when comparing migraine initiation, propagation, and termination,
migraine with headaches during scanning with which could then lead to a better understanding
migraine without headaches. In addition, there of chronic migraine mechanisms.
was enhanced activity of the right superior col- Resting-state FMRI is a type of functional
liculus in chronic migraine as compared to healthy brain imaging that can be used to assess regional
controls. The study provides evidence for visual interactions that occur when an individual is not
nociceptive integration on the brainstem level in performing a specific task. With this technique,
chronic migraine and ultimately illustrates sen- significant differences in functional connections
sory processing dysfunction. with affective pain regions were demonstrated
Migraine chronification is also associated in chronic migraine as compared to controls.
with dysfunctional thalamocortical pathways; In addition, there were significant correla-
specifically, electrophysiological studies have tions between the number of years with chronic
suggested that there is an increase in the strength migraine and functional connectivity strength
of connections between the thalamus and the between the anterior insula with the periaqueduc-
cortex in chronic migraine as compared to epi- tal gray and the anterior insula with the medial
sodic migraine between attacks [43]. In a MR dorsal thalamus [47].
spectroscopy investigation of the bilateral medial Central sensitization is a pivotal process that
walls of the brain in individuals with chronic occurs in chronic migraine. When central sensi-
migraine, the investigators assessed the metabo- tization occurs, the nervous system goes through
lite alternations as compared to matched episodic a process of windup resulting in a persistent
migraine and headache-free controls; the thala- state of high reactivity. Central sensitization is
mus, occipital lobe, and anterior cingulate cortex a maladaptive state mediated by sensitization
were analyzed as region of interests to deter- of the central trigeminovascular neurons in the
mine if N-acetyl-aspartate, a marker of neuronal nucleus caudalis, spinal cord, and posterior tha-
integrity, was reduced [44]. Reduced N-acetyl- lamic nuclei [48]. Clinically, central sensitization
aspartate metabolism and altered interregional often manifests as hypersensitivity to non-painful
N-acetyl-aspartate correlations were found, thus stimuli known as “allodynia in addition to per-
supporting the role of thalamocortical dysfunc- sistent headache. Dysfunctional pain modula-
tion in migraine chronification. tion, either due to descending pain facilitation
Recent studies suggest a key role for the hypo- of nociception or impairments in descending
thalamus in both migraine and chronic migraine. inhibitory pathways, contributes to central sen-
In a PET imaging study of nitroglycerin-triggered sitization. Cutaneous allodynia has been inves-
acute migraine attacks, brain activation patterns tigated in an intrinsic resting-state FMRI study
were elucidated during the premonitory phase; of chronic migraine, which showed modulation
the hypothalamus in particular is associated with of brain networks in women [49]. In the study,
many of the premonitory symptoms and was the frequency of moderate and severe headaches
activated early before migraine pain began [45]. was associated with decreased connectivity in
Interestingly, a functional MRI investigation the salience network, while cutaneous allodynia
using painful ammonia stimulation in 17 chronic was associated with an increased connectivity
44 T. S. Monteith
with the central executive network. The presence to the activation of the trigeminocervical com-
of cutaneous allodynia correlates with migraine plex. Opiates used to treat non-cephalic pain may
severity, migraine-associated symptoms, and lead to high rates of morbidity, mortality, misuse,
other migraine features such as aura [50]. and potentially medication overuse headache in
patients with chronic migraine. Poor sleep quality
may contribute to high frequencies of migraine,
Management and Treatment and migraine may aggravate sleep [14]. Obesity
is a risk factor for transformed migraine but can
A number of barriers to chronic migraine care also be a consequence of prophylactic treatment
exist. There are hurdles in obtaining a consul- and inactivity due to movement sensitivity expe-
tation, diagnosis, and treatment, resulting in rienced by migraineurs [54–56]. In one study of
a large unmet need [16]. The primary goals of women with migraine (4–20 days per month)
care for chronic migraine are to reduce headache that were overweight or obese, behavioral weight
frequency, relieve pain, restore function, and loss intervention yielded sustained reductions in
prevent progression. All patients with chronic migraine headaches similar to migraine educa-
migraine require acute and preventive treat- tion. Overall, the benefits of multidisciplinary
ments. Medication overuse when present should interventions that target comorbidities for reduc-
be addressed for optimal outcomes. A through tion in migraine days require further exploration
history and physical examination is necessary to in patients with chronic migraine.
rule out secondary causes of chronic headaches, The careful selection of migraine patients for
which may resemble chronic migraine. Systemic preventive treatments may reduce the likelihood
symptoms such as fever and weight loss or sec- of progression from episodic migraine to chronic
ondary risk factors such as systemic cancer and migraine [57]. There are five US FDA-approved
HIV disease are important considerations. Neu- preventive treatments for episodic migraine, which
rological symptoms or signs, sudden onset of include two anticonvulsants (topiramate and val-
headache, older age (>50), new onset, or change proate) and three antihypertensive beta-blockers
in clinical features are indications for further (metoprolol, propranolol, timolol). According to
evaluations [51]. Patients with chronic migraine expert consensus, oral preventive treatments for
should have an extensive evaluation of common episodic migraine such as antihypertensive (beta-
triggers: change in routine, stress, stress letdown, blockers, angiotensin receptor blockers, angioten-
changes in sleep patterns, hormonal changes, sin-converting enzyme inhibitors), antidepressants
environmental changes (weather change, humid- (tricyclic antidepressants, serotonin-norepineph-
ity, loud noises, exposure to bright/flickering rine reuptake inhibitors), and anticonvulsants may
lights, computer screens, foods, dehydration and be also helpful for chronic migraine; however, the
skipped meals. evidence is lacking except for topiramate [58].
There are a number of comorbidities that OnabotulinumtoxinA injection therapy is FDA
should be assessed in individuals with chronic approved for preventive treatment of chronic
migraine. Depression is a risk factor for the migraine but not episodic migraine. Smaller ran-
transformation of episodic migraine to chronic domized control studies of chronic daily headache
migraine [52]. The greater the severity of depres- (or high-frequency headache) include amitripty-
sion, the greater the risk of chronic migraine. line [59], sodium valproate [60], gabapentin [61],
Anxiety and depression are also strongly asso- and tizanidine [62, 63]. Open-label studies provide
ciated with both chronic migraine and migraine weaker evidence for memantine [64], pregabalin
progression. Non-cephalic pain is a risk factor for [65], milnacipran [66], atenolol, and zonisamide
new onset chronic migraine and chronic migraine [67]. Adherence is problematic as persistent use
progression [53]. Neck pain in particular is a of oral prophylactic medications among chronic
common symptom associated with migraine and migraine patients is low at 6 months and declines
when related to neck pathology may contribute even further by 12 months [68].
Acute treatment is based on studies for acute two large multicenter randomized double-blind,
migraine attacks in episodic migraine. According placebo-controlled clinical trials. In the TOP-
the American Headache Society evidence assess- CHROME study, efficacy and safety were evalu-
ment, triptans are migraine-specific treatments ated at doses ranging between 50 and 200 mg/day
considered effective (level A) [69]. Dihydroergot- (average dose 100 mg/day) [77]. Topiramate sig-
amine and ergotamine, some nonsteroidal anti- nificantly reduced the mean number of monthly
inflammatory agents, and neuroleptics may also migraine days (±SD) by 3.5 ± 6.3, compared with
help acute migraine days of chronic migraine. placebo (−0.2 ± 4.7, P < 0.05). In the Topiramate
Two-hour pain-free rates are lower in chronic Chronic Migraine Study, the active treatment arm
migraine as compared to episodic migraine. (mean maintenance dose 86 mg/day) resulted
Cutaneous allodynia, major depression, and the in a statistically significant mean reduction of
use of nonsteroidal anti-inflammatory drugs are migraine/migrainous headache days (topiramate
associated with poor treatment responses [70]. −6.4 vs. placebo −4.7, P = 0.010) and migraine
In contrast, acute medication optimization is headache days relative to baseline (topiramate
associated with use of triptans and preventive −5.6 vs. placebo −4.1, P = 0.032) [78]. Topi-
medications. Newer agents in the class of CGRP ramate was also effective in the treatment of
antagonists, ubrogepant and rimegepant [71], patients with chronic migraine with and without
and the 5-HT (1F) receptor agonist lasmiditan acute medication overuse, suggesting detoxifi-
[72] are non-vasoconstrictive drugs under clini- cation prior to initiating prophylactic therapy
cal development. Ultimately, there is a great need may not be required for all patients [79]. In the
for well-designed studies to test the efficacy and INTREPID study, a multicenter, randomized,
safety of novel therapeutics for chronic migraine. double-blind study comparing topiramate to pla-
cebo for the prevention of migraine progression,
topiramate failed to prevent new onset chronic
stablished and Emerging
E daily migraine at month 6 which may have been
Pharmacological Treatments due to unexpectedly low transition rates in the
placebo arm and short observation period [80].
Topiramate However, topiramate reduced both headache and
Topiramate is an anticonvulsant FDA approved migraine headache days [81]. The efficacy of pro-
for the treatment of migraine (Table 4.2). Topi- pranolol added to topiramate in chronic migraine
ramate has a broad mechanism of action includ- was also assessed in subjects inadequately con-
ing enhancing inhibitory effects and minimizing trolled with topiramate [82]. The study provided
excitatory affects that result in its antimigraine class II evidence that propranolol added to topi-
action. Topiramate regulates cell membrane ramate did not result in moderate to severe head-
ion channels (potassium, calcium, sodium), ache rate reduction at 6 months.
modulates neurotransmitter release (glutamate, Paresthesias are a common side effect in both
gamma-aminobutyric acid), and inhibits some chronic migraine clinical trials. In clinical prac-
carbonic anhydrase isozymes [73]. Electrophysi- tice, cognitive side effects are a common cause of
ological studies indicate that topiramate has discontinuation. Extended-release formulations
modulatory effects within the trigeminovascular may have significantly less cognitive side effects
and trigeminothalamic pathway and mechanisms due to stable steady-state plasma concentrations.
involved in cortical spreading depression [74, This is supported by verbal fluency studies that
75]. Studies also indicate that the inotropic glu- showed less impairment with topiramate extended
tamate receptor, specifically the kainate receptor, release as compared to the immediate release in
is a potential target. Topiramate also modulates healthy volunteers [83]. Extended release may
thalamocortical networks in humans [76]. improve compliance without significant conse-
The efficacy and safety of topiramate in the quences in plasma concentrations due to dos-
treatment of chronic migraine is supported by ing irregularities [84]. In addition, topiramate is
46
Table 4.2 Pharmaceutical preventive treatment for chronic migraine

Route of
Name Class administration Clinical phase Primary endpoints Safety profiles
Topiramate Anticonvulsant Oral Phase 3 (TOP- Significantly reduced the mean number Paresthesia, nausea,
CHROME, Topiramate of monthly migraine days/migrainous dizziness, dyspepsia,
Chronic Migraine Study) days fatigue, anorexia, cognitive
impairment, renal stones
OnabotulinumtoxinA Neurotoxin Intramuscular Phase 3 (PREEMPT 1) No significant between-group difference Neck pain, headache,
for onabotulinumtoxinA versus placebo weakness, ptosis, injection
was observed for headache episodes site pain
Phase 3 (PREEMPT 2) OnabotulinumtoxinA was statistically
significantly superior to placebo for
frequency of headache days
Fremanezumab Monoclonal Subcutaneous, Phase 3 randomized The least squares mean (±SE) reduction No serious adverse events
antibodies to CGRP intravenous controlled studies in the average number of headache days related to the study drug;
per month with quarterly and monthly injection site reactions were
dosing common
Erenumab Monoclonal Subcutaneous FDA approved Reduced monthly migraine days No serious adverse events
antibodies to CGRP related to the study drug;
receptor injection site reactions were
common
Galcanezumab Monoclonal Subcutaneous Phase 3, REGAIN Mean change from baseline in monthly No serious adverse events
antibodies to CGRP migraine headache days over the related to the study drug;
3-month period injection site reactions were
common
Eptinezumab Monoclonal Intravenous Phase 3 PROMISE 2 Reduction of monthly migraine days No serious adverse events
antibodies to CGRP related to the study drug;
injection site reactions were
common
T. S. Monteith
considered weight neutral, but a subset of patients Antinociceptive central effects of onabotu-
treated may experience weight loss. It acts as a linumtoxinA likely occur through axonal trans-
carbonic anhydrase inhibitor, which may lead to port. OnabotulinumtoxinA can be taken up
the development of renal stones. Post-marketing peripherally and undergoes transcytosis to cleave
evidence has shown an increase risk of oral clefts SNARE proteins at the trigeminal ganglion and
with first trimester fetal exposure (Category D). the trigeminal nucleus caudalis preventing down-
In addition, long-term studies of topiramate are stream events. Early investigations suggest the
needed to assess osteoporosis-fracture risk [85]. antinociceptive effects may therefore involve
different sites of the trigeminal system and
OnabotulinumtoxinA interaction with the central endogenous opioid
Botulinum toxin is a protein produced by the system [89].
bacteria Clostridium botulinum and exists in OnabotulinumtoxinA injected to 31 sites
seven antigenically and serologically distinct in the procerus, corrugator, frontalis, tempora-
forms named as A–G [86]. Onabotulinumtox- lis, occipitalis, and posterior cervical injections
inA delivered to extracranial dermatomes is including the trapezius is safe and efficacious
the first FDA-approved treatment for chronic for the treatment of chronic migraine. The FDA
migraine. In addition to its well-described inhi- approval was based on two-phase III clinical tri-
bition of acetylcholine from cholinergic nerve als over a 24-week randomized, double-blind
endings at the skeletal neuromuscular junction, phase followed by a 32-week open-label phase. In
the onabotulinumtoxinA mode of action is ini- PREEMPT 1, there were no between-group dif-
tiated by the cleavage of proteins required for ferences for the primary endpoint of mean change
trigeminal nerve activation and signaling. The from baseline in headache episode frequency at
toxin binds to afferent nerve terminals by con- week 24 [90]. Both migraine and headache days
necting with high affinity sites. The neuron were significant secondary endpoints. For the
confines the toxin into a vesicle once bound PREEMPT 2 trial, the primary endpoint was the
to the nerve terminal. The vesicle moves into mean change in headache days per 28 days from
the cell and once activated exits into the cyto- baseline to weeks 21–24 posttreatment [91]. Ona-
plasm and cleaves soluble N-ethylmaleimide- botulinumtoxinA was statistically significantly
sensitive factor attachment protein receptor superior to placebo for the primary endpoint,
(SNARE) proteins. SNARE proteins mediate frequency of headache days per 28 days relative
vesicle release of neurotransmitters but are also to baseline (−9.0 botulinum toxin A/−6.7 pla-
involved in the transport of channels and recep- cebo, P < 0.001). OnabotulinumtoxinA was
tors. The cleavage of SNARE proteins prevents significantly favored in all secondary endpoint
the cell from releasing vesicles of substance comparisons including change from baseline
P, bradykinin, CGRP, and glutamate [87]. in the frequency of migraine days, frequency of
In a recent study by Burstein et al., onabotu- moderate/severe headache days, cumulative total
linumtoxinA selectively inhibited peripheral C headache hours on headache days, frequency of
mechanonociceptors in the trigeminovascular headache episodes, in total HIT-6 scores, fre-
neurons [88]. OnabotulinumtoxinA injections quency of acute headache pain medication intakes,
into the C-meningeal nociceptors in the dura and frequency of triptan intake. In pooled stud-
inhibited responses to mechanical stimulation ies of PREEMPT 1 and PREEMPT 2 (Fig. 4.3),
and reversed and prevented the development of 1384 qualified adults with chronic migraine were
mechanical hypersensitivity. The experiments randomized to onabotulinumtoxinA (155–195 U)
showed that onabotulinumtoxinA prevents the or placebo injections every 12 weeks [92]. The
fusion of high threshold mechanosensitive ion analyses demonstrated a large mean decrease
channels to the nerve terminal membrane, thus from baseline in frequency of headache days,
interfering with the expression of the ion chan- with statistically significant between-group dif-
nel linked to mechanical pain. ferences favoring onabotulinumtoxinA over
48 T. S. Monteith
Weeks
0 4 8 12 16 20 24
0
(Mean Change from Baseline) OnabotulinumtoxinA(n=688)

Headache Days/28 Days
Placebo(n=696)
-3
-6
P<0.001
P<0.001 P<0.001
-9 P<0.001
P<0.001 P<0.001
Fig. 4.3 OnabotulinumtoxinA for the treatment of over placebo at week 24 (−8.4 vs. −6.6) P < 0.001) and at
chronic migraine: pooled results from the double-blind, all time points expressed as mean ± standard error. All
randomized, placebo-controlled PREEMPT studies. The secondary endpoints were met except frequency of acute
pooled PREEMPT results demonstrate a large mean headache pain medication intakes. Adverse events were
decrease from baseline headache days of 19.9 ± 0.1 ona- mild to moderate and few discontinued due to adverse
botulinumtoxinA group versus 19.8 ± 0.1 placebo group, events. (Dodick DW, et al. [92]. Reprinted with permis-
P = 0.498. The analyses show statistically significant sion from John Wiley and Sons)
between-group differences favoring onabotulinumtoxinA
placebo at week 24 (−8.4 vs. −6.6; P < 0.001) optimal dosing, injection frequency and sites for
and at all other time points. The study met all potentially improved outcomes.
secondary endpoints including mean change from The safety profile of onabotulinumtoxinA
baseline to week 24 in frequency of migraine/ has been extensively reviewed for the treat-
probable migraine days, frequency of moderate/ ment of chronic migraine and other indications.
severe headache days, total cumulative hours of Adverse events were generally considered mild
headache on headache days, frequency of head- or moderate, no unexpected treatment-related
ache episodes, frequency of migraine/probable adverse events were identified, and discon-
migraine episodes, and the proportion of patients tinuation rates were low. The most common
with severe (≥60) Headache Impact Test-6 score treatment-related side effects were neck pain,
at week 24, except frequency of acute headache muscular weakness, eyelid ptosis, musculoskel-
pain medication intakes. In an open-label pro- etal pain, injection site pain, headache, myal-
spective study comparing baseline to week 24, gia, and musculoskeletal stiffness. Long-term
Generalized Anxiety Disorder questionnaires treatment benefits and safety were reported in a
and Beck Depression Inventory II tests showed cohort of chronic migraine and medication over-
significant improvement in anxiety and depres- use headache patients over a course of 3 years
sion symptoms posttreatment [93]. Although of therapy [95]; no serious adverse events were
the PREEMPT trials did not show a superior reported. Optimal outcomes may be achieved
benefit of injections with 195 U as compared to with a greater consideration for the functional
155 U, an open-label prospective study showed anatomy including the peripheral nerves and
superior efficacy of 195 U as compared to 155 U muscles targeted during the PREEMPT clinical
over 2 years in chronic migraine with medica- program (Figs. 4.4 and 4.5).
tion overuse headache. Treatment-related adverse A number of investigations have tried to
events were transient and mild to moderate [94]. determine predictors or markers of onabotu-
Additional clinical trials are needed to inform the linumtoxinA response. One study found that
a Trigeminal nerve (CN V)

Supra-orbital
Supratrochlear Supra-orbital
CN V1 Infratrochlear
Supratrochlear
es
External nesal
erv
Lacrimal CN V1
Lacrimal
Spinal n
Infratrochlear
Zygomatico-
temporal External nasal
CN V2
Zygomaticofacial
Infra-orbital Zygomatico-
Greater temporal
Auriculotemporal occipital (C2) Infra-orbital CN V2
CN V3 Buccal Zygomatico-
Third occipital (C3)
Mental facial
Lesser occipital
Great auricular (C2,C3) Auriculo-
(C2,C3) Great auricular temporal
(C2,C3) CN V3
Mental
Posterior Buccal
rami Anterior
rami
Anterior view Lateral view
b Posterior rami
Anterior rami
Greater
occipital (C2)
Third
occipital (C3) Great
Lesser occipital auricular
(C2) (C2-C3)
Cutaneous
branches of
posterior rami
(C4-C8)
Trans-
verse
cervical
(C2-C3)
Supraclavicular
(C3-C4)
Fig. 4.4 Important functional anatomy behind the geminal (CN V) and occipital (C2, C3) sensory nerves and
PREEMPT injections paradigm includes the distribution of (b) cervical sensory nerves (C2, C3). (Moore KL, et al. [96].
peripheral nerves: (a) anterior and lateral view of the tri- Reprinted with permission from Wolters Kluwer Health)
pretreatment vasoactive intestinal peptide and (STG) and pars opercularis compared to nonre-
CGRP levels were predictors of response to sponders. Disease duration was negatively cor-
onabotulinumtoxinA and interictal plasma related with cortical thickness in frontoparietal
levels of CGRP can be lowered with onabotu- and temporo-occipital regions in the responders
linumtoxinA [68, 97]. Another study of chronic only. The investigators were also able to distin-
migraine patients found structural and func- guish between responders and nonresponders
tional brain changes in onabotulinumtoxinA based on seed based resting-state functional
responders versus nonresponders [98]. The connectivity analysis. The authors concluded
responders showed significant cortical thicken- that elucidating tools to detect central nervous
ing in the right primary somatosensory cortex, system changes might lead to markers for dis-
anterior insula, and left superior temporal gyrus ease de-chronification.
50 T. S. Monteith
Midpupilary Limbus Orbital

a line line rim b
Occipital
Protuberance
Upper 1/3 Hairline

of forehead
Frontalis
Helix
Supraorbital
Orbital rim notch
Lateral Corrugator
canthus
Limbus
Nuchal Ridge
Medial Procerus
canthus
Mastoid
Process
Inion
Tragus Mid-Hetix
c Tragus Line
Fig. 4.5 The fixed-site, fixed-dose PREEMPT injection as depicted by orange dots; trapezius, as depicted by red
site locations of the pivotal trials: (a) corrugator, as dots, and (c) temporalis, as depicted by purple dots.
depicted by purple dots; procerus, as depicted by the red (Blumenfeld AM, et al. [99]. Reprinted with permission
dot; frontalis, as depicted by orange dots, (b) occipitalis from John Wiley and Sons)
area, as depicted by purple dots; cervical paraspinal area,
Monoclonal Antibodies CGRP is a 37-amino acid neuropeptide formed

to the Calcitonin Gene-Related from alternative splicing of the calcitonin/CGRP
Peptide or Its Receptor gene located on chromosome [100]. CGRP is
found in nociceptive tissue and is a strong cere-
A number of preclinical and clinical studies over- bral vasodilator. CGRP is uniquely increased in
whelmingly support a role of calcitonin gene- the extracerebral circulation during the head-
related peptide (CGRP) in the pathophysiology ache phase of migraine [101], but not neuropep-
of both migraine and chronic migraine [100]. tides such as substance P, VIP, and NPY. CGRP
Dural Cerebral
a vessel vessel b
To thalamus
Hypothalamus
Cortex
C-fibers PAG
TG
Cerebellum
PC
SPG
IV
FN
5-HT
NA
CGRP
ACh
cellular
localization Dopamine
fiber
localization GABA
CGRP
Fig. 4.6 Illustration of CGRP distribution and expression dopamine, and GABA (gamma-aminobutyric acid), are
as it relates to migraine. Overview of CGRP expression in also included in the image, visualizing the complexity of
the trigeminal vascular system (a) and in the central ner- transmitter interactions. TG trigeminal ganglion, SPG
vous system (b). Figure (a) shows fibers and cell bodies sphenopalatine ganglion, PAG periaqueductal gray, PC
(in red) that express CGRP in the trigeminal ganglion and Purkinje cells, LC locus coeruleus, SSN superior saliva-
in the peripheral and central connections. The illustration tory nucleus, IV 4th ventricle, FN facial nucleus, TNC tri-
(b) shows CGRP expression in the CNS. There is a rich geminal nucleus caudalis, MRN raphe magnus nucleus,
CGRP expression generally in gray matter and in the neu- STN spinal trigeminal nucleus, Me5 mesencephalic tri-
ron, but not in fiber structures such as that seen in, e.g., geminal nucleus, Med medial cerebellar nucleus, Pn pon-
corpus callosum. Some of the CGRP-containing areas are tine nucleus, IO inferior olive. (Edvinsson L, Warfvinge K
shown in the image. Other transmitter circuits, 5-HT [102]. Reprinted with permission from Sage Publications)
(serotonin), NA (noradrenalin), Ach (acetylcholine),
and its receptor components, RAMP1 and CLR, for potential preventive treatment of chronic
are found abundantly in the trigeminovascular migraine are underway.
system (Fig. 4.6) and are released in the periph- Erenumab is a monoclonal antibody that
eral endings in the meninges and in the central targets the CGRP receptor. A phase 2 random-
endings in the medullary and upper cervical ized double-blind, placebo-controlled study of
dorsal horn [103]. Taken together, the role of erenumab showed that erenumab 70 mg and
CGRP in migraine is evidenced by its release 140 mg reduced monthly migraine days ver-
during acute migraine attacks [104] and nor- sus placebo (both doses −6.6 days vs. placebo
malization by triptans [105] and small molecule −4.2 days; difference −2.5, 95% CI −3.5 to
CGRP receptor antagonists [106], as well as −1.4, P < 0·0001) from weeks 9 to 12 [107]. The
persistent CGRP elevation in chronic migraine study drug also met several secondary endpoints
as mentioned previously. CGRP function-block- including achievement of at least 50% reduction
ing monoclonal antibodies represent the first from baseline in monthly migraine days (i.e.,
mechanism-based preventive treatment for both 50% responder rate), change from baseline in
migraine and chronic migraine. To date, there days on which acute migraine-specific drugs
are four monoclonal antibodies to the CGRP were used, and change from baseline in cumu-
peptide or receptor with phase II/III evidence to lative headache hours. Erenumab was the first
support efficacy and safety for the treatment of monoclonal antibody to the CGRP receptor that
both episodic and chronic migraine (Fig. 4.7). was FDA approved for the preventive treatment
Additional efforts to target the PACAP pathway of migraine.
52 T. S. Monteith
Components of Monoclonal
Drug Source lgG class Directed against
a monoclonal antibody antibody type
Eptinezumab Yeast lgG1 CGRP ligand
Variable region
Galcanezumab Murine lgG4 CGRP ligand
Light chain
VH
VL
CH1
Variable region CL
(b) Humanised
Light chain Fab Fremanezumab Murine lgG2 CGRP ligand
(>90% human)
CH2 ‘-zumabs’
Fc
CH3
(a) Antibody Erenumab Murine lgG2 CGRP receptor

structure
(c) Fully human

(100% human)
‘-umabs’
Fig. 4.7 Overview of structure of antibody and monoclo- ligand; erenumab is fully human and directed against the
nal antibodies: novel mechanisms targeting the CGRP CGRP receptor. The potential therapeutic significance of
pathway. Eptinezumab, galcanezumab, and fremane- these differences is currently unknown. (Ong JJY, et al.
zumab humanized and are directed against the CGRP [108]. Reprinted with permission from Springer)
In another phase 3 study of fremanezumab for to 3, was met. The least squares mean change from
chronic migraine, subjects were randomized to baseline (SE) was 4.8 days for the 120 mg dose
quarterly, monthly, and placebo injections [109]. and 4.6 days for the 240 mg dose as compared to a
The least squares mean (±SE) reduction in the reduction of 2.7 days for placebo (P < 0.001). Sec-
average number of headache days per month was ondary endpoints met included statistically signifi-
4.3 ± 0.3 with fremanezumab quarterly, 4.6 ± 0.3 cant improvement compared to placebo response
with fremanezumab monthly, and 2.5 ± 0.3 with rates and measures of daily activities.
placebo (P < 0.001) for both comparisons with Eptinezumab is a CGRP receptor antibody
placebo. For secondary endpoints, the number of that is 100% bioavailable. In a randomized, pla-
migraine days, headache-related disability, 50% cebo-controlled Phase 3 study (PROMISE 2) of
responder rates, and days with acute medication eptinezumab with quarterly infusions, there was
use were significantly reduced with quarterly and a significant reduction in monthly migraine days
monthly dosing. The study confirmed the long- from 8.2 days at baseline compared to 5.6 for pla-
lasting benefits of subcutaneous injections, which cebo, P < 0.001 [111]. Key secondary endpoints
may be beneficial for improving drug compliance. that were met included significant rapid day one
In the phase 3, randomized, double-blind, pla- prevention and significantly greater responder rates
cebo-controlled trial (REGAIN), two doses of gal- that were sustained for month 1 through 3 (50%,
canezumab administered subcutaneously (120 or 75%, and 100%). Collectively, the observed safety
240 mg once monthly, following a 240 mg starting profiles across the four monoclonal antibodies were
dose) were compared with placebo for the treat- similar to placebo-treated subjects. There were no
ment of chronic migraine [110]. The primary end- severe adverse effects attributed to the study drug.
point, the overall mean change in the number of CGRP human or humanized monoclonal
monthly migraine headache days from months 1 antibodies are large molecules with a site of
action that is likely in the periphery, outside the over sham was found. Few sham-controlled stud-
blood-brain barrier. Fremanezumab, a human- ies exist for chronic migraine prevention. A ran-
ized monoclonal antibody, was used to test the domized controlled trial of acupuncture versus
selective inhibitory effect on the activity of topiramate in 66 consecutive patients with chronic
second-order trigeminovascular dorsal horn migraine over a 12-week period was conducted
neurons that receive peripheral input from the [116]. In the acupuncture group, the median
cranial dura [112]. The investigators found selec- change in the mean number of m oderate/severe
tive central inhibition of high threshold but not headache days during 4 weeks for patients with
wide dynamic range class of dorsal horn neurons higher baseline headache days (>20 days) was
[113]. Additional studies on the evoked activity significantly greater than that for lower baseline
of mechanosensitive primary afferent neurons in headache days (≤20 days) (median ± interquartile
the trigeminal ganglion show that thinly myelin- range: −12 ± 2 vs. −10 ± 1 days, P = 0.01) in the
ated Aδ meningeal nociceptors are possibly the acupuncture group. Patients with throbbing symp-
peripheral site of action of fremanezumab for toms had a better prognosis and higher scores in
headache prevention [112]. Other animal stud- general. Their expectations predicted responses
ies have shown existing CGRP receptor-binding to both groups. Long-term studies are needed to
sites and expression of the receptor in the tri- determine sustained benefits of acupuncture.
geminal ganglion, outside the blood-brain barrier
[114]. Taken together, the investigators postulate Behavioral Therapy
that the selectivity may explain differences in Cognitive behavioral therapy, mindfulness, relax-
responder rates of CGRP monoclonal antibodies, ation therapy, and biofeedback are commonly
but confirmatory studies are needed. Additional used non-pharmaceutical interventions for the
studies will need to determine if there a difference treatment of migraine. For some individuals,
between antibodies to CGRP versus its receptor. access to behavioral therapies is a major limita-
Further quantification of neutralizing anti-drug tion. However, internet-based treatment programs
antibodies and the potential impact on efficacy utilizing relaxation, biofeedback, and stress man-
is yet to be determined. The biological differ- agement have proved to be effective for chronic
ences of those that had a 100% response to the headaches and have the potential to reach a larger
treatment, the so-called super responders, should number of patients with less cost [117].
also be elucidated. In addition, the efficacy of Several clinical trials have tested cognitive
CGRP monoclonal antibodies for the treatment behavioral therapy for chronic migraine. Cog-
of medication overuse headache, refractory cases nitive behavioral therapy is a common form of
of chronic migraine, and special populations (i.e., psychotherapy to assist with the management of
vascular disease) should be determined. emotional and physical symptoms, coping, and
maladaptive thinking and behaviors that may
be associated with chronic pain. A randomized
Nonpharmacological Treatments placebo-controlled trial of 135 pediatric patients
and Other Interventions with chronic migraine compared amitriptyline
with cognitive behavioral therapy versus ami-
Acupuncture triptyline and headache education [118]. The
Acupuncture is a Chinese technique that uses thin primary endpoint was headache days. In children
needles inserted in the skin at specified acupunc- and adolescents with chronic migraine, amitrip-
ture points to restore Qi, vital energy, and treat tyline with cognitive behavioral therapy had a
a variety of conditions. In a Cochrane review of greater reduction in headache days and migraine-
migraine, the authors found adding acupuncture related disability compared to the use of amitrip-
to symptomatic treatment of attacks reduces the tyline with headache education. At baseline, there
frequency of headaches, and the benefits may be were a mean (SD) of 21 (5) days with headache
similar to prophylactic drugs [115]. A small effect per 28 days. At the 20-week endpoint, days with
54 T. S. Monteith
headache were reduced by 11.5 for the cognitive further research is needed in larger populations
behavioral therapy plus amitriptyline group ver- to investigate behavioral interventions in addition
sus 6.8 for the headache education plus amitrip- to pharmacotherapies and withdrawal protocols.
tyline group (difference, 4.7 [95% CI, 1.7–7.7]
days; P = 0.002). The secondary endpoint, the Peripheral Neurostimulation
mean (SD) PedMIDAS, was 68 (32) points. The for Chronic Migraine
PedMIDAS decreased by 52.7 points for the CBT Peripheral neurostimulation has been used to
group versus 38.6 points for the headache educa- treat refractory chronic migraine for years. To
tion group (difference, 14.1 [95% CI, 3.3–24.9] date, there are three FDA-approved devices for
points; P = 0.01). The findings support the effi- the acute and preventive treatment of migraine
cacy of cognitive behavioral therapy in treatment and no specific approvals for chronic migraine.
of pediatric populations with chronic migraine. Single-pulse transcranial magnetic stimula-
Behavioral therapy may also be effective for tion (TMS) is approved for the acute treatment
the treatment of comorbidities associated with of migraine with aura and for migraine preven-
chronic migraine. Behavioral therapies may be tion. The efficacy of TMS on chronic migraine
of particular benefit, as stress is associated with was reviewed in a meta-analysis of random-
poor outcomes to acute treatment in chronic ized, double-blind, sham-controlled trials [126].
migraine [119]. These interventions may address According to the results, TMS for the treatment
pain catastrophizing and treat psychiatric disease, of chronic migraine was not significant (OR 2.93;
both strongly associated with chronic migraine, 95% CI 0.71–12.15; P = 0.14). A small sample
migraine-related disability, and impact [120, size may have accounted for the results. Further
121]. In addition, behavioral therapies are widely studies are needed as a preliminary randomized
accepted approaches to treatment of insomnia. investigation using high-frequency deep TMS
In a study of behavioral insomnia treatment for showed a reduction in the frequency and intensity
chronic migraine with comorbid insomnia, out- of migraine attack, drug overuse, and depressive
comes were compared in patients that received symptoms [127]. Supraorbital transcutaneous
30-min biweekly sessions of cognitive behavioral stimulation with the Cefaly device is also FDA
therapy for insomnia versus training in the daily approved for the acute and preventive treatment
practice of skills pertaining to keeping a consis- of migraine but not for chronic migraine. In a
tent food/liquid intake, range of motion exer- small open-label study of 23 consecutive chronic
cises, and acupressure as a control [122]. Both migraine patients designed to determine the
groups received reduction in headache frequency, efficacy of supraorbital transcutaneous stimula-
but only the cognitive behavioral treatment inter- tion with the Cefaly device, 35% of the patients
ventional group had significantly larger increases enrolled had 50% reduction in monthly migraine
in total sleep time and sleep efficiency. days and 50% reduction in monthly medication
Chronic migraine with medication overuse is use over 4 months [128]. In addition, there was
associated with high rates of relapse after with- greater than 50% reduction in acute medication
drawal treatment [123], yet few studies have consumption in over half the patients.
tested behavioral interventions. In a study com- The gammaCore device is FDA approved as
paring pharmacological prophylaxis to mindful- a noninvasive vagus nerve stimulation device for
ness-based training for the treatment of chronic the acute treatment of cluster headache and has
migraine after withdrawal from medication over- been approved for migraine as well [129]. Poten-
use, headache frequency and medication use was tial antimigraine mechanisms are supported by
similar after 1-year follow-up [124]. Another animal models that show vagus nerve stimulation
pilot study showed benefits of biofeedback added suppresses acute activation of the trigeminocervi-
to traditional pharmacotherapy for reducing cal neurons [130], cortical spreading depression
headache frequency and acute medication use [131], and treat trigeminal allodynia [132]. The
[125]. Although initial studies are promising, evidence for migraine attack treatment is based
on pain-free rates of moderate to severe attacks randomized in a double-blind and placebo-con-

in the PRESTO study [133], a randomized, sham- trolled study using bupivacaine versus placebo
controlled study showing efficacy, tolerability, [140]. After weekly injections for 4 weeks, there
and safety with no serious or adverse events. The was a significant reduction in duration of head-
evidence for noninvasive vagus nerve stimulation ache hours and the VAS score. Another study
for the treatment of chronic migraine is limited using a bilateral greater occipital nerve block
by trial design. Another small study using trans- with bupivacaine 0.5% or sham with normal
cutaneous stimulation of the auricular branch saline showed superiority in reducing moderate
of the vagal nerve (t-VNS) showed efficacy and or severe headache days for the week following
safety [134]. The results of the EVENT study, the injection [141]. After the greater occipital
a multicenter, prospective double-blind, sham- nerve block, there was an increase in pressure
controlled pilot study of noninvasive vagus nerve pain thresholds in the trigeminal area supporting
stimulation for chronic migraine, suggest that an effect on the central sensitization at the tri-
persistent use may reduce the number of head- geminal nucleus caudalis. Nerve blocks may be
ache days over time [135]. particularly useful for certain populations, such
A protocol with 12 transcranial direct current as in pregnancy.
stimulation sessions was investigated in a ran- The sphenopalatine ganglion is a target of
domized, sham-controlled trial in subjects with interest for the treatment of migraine as studies
chronic migraine [136]. Intragroup comparisons have suggested a link between parasympathetic
exhibited greater reduction in headache impact ganglia and the sensory trigeminal system. Para-
and pain intensity and a higher quality of life sympathetic activity may contribute to migraine
after treatment with anodal stimulation of the by activation or sensitization of the intracranial
left primary motor and dorsolateral prefrontal nociceptors and the sphenopalatine ganglion, the
cortex but not in the sham group. Larger studies largest extracranial parasympathetic ganglion of
are needed to establish efficacy and determine the the head [142]. Furthermore, immunohistochem-
optimal site of cortical stimulation. ical studies have shown CGRP receptor compo-
The effectiveness of occipital nerve stimula- nents and CGRP-immunoreactive fibers were
tion has been tested in multiple-randomized pla- found in the sphenopalatine ganglion [143]. In
cebo-controlled trials; a meta-analysis showed a one randomized placebo-controlled trial, repeti-
modest effect size for chronic migraine. Frequent tive transnasal sphenopalatine ganglion blockade
complications included lead migration, infection, was found to be effective for the acute treatment
and need for surgical revision [137]. A small of chronic migraine [144]. Long-term efficacy
series of patients with a combination of occipi- was also established with blockade twice per
tal nerve and supraorbital nerve stimulation has week for 6 weeks [145]. Taken together, periph-
shown positive benefits [138]; however, large eral nerve blocks appear promising; however,
randomized controlled studies are needed to con- large, multicenter, randomized, placebo-con-
firm these findings given the potential for surgi- trolled trials are needed for wider acceptance in
cal complications. the treatment of chronic migraine.
eripheral Nerve Blockade

P
Peripheral nerve blockade is generally cost- efractory Chronic Migraine
R
effective and safe. Occipital nerve blockade for and Clinical Trial Considerations
the treatment of chronic migraine has shown
mixed results for short-term prophylaxis. In a Tertiary headache centers are referral cen-
mixed cohort consisting of episodic and chronic ters, often treating refractory cases of chronic
migraine, occipital nerve blockade was no bet- migraine. The term refractory chronic migraine
ter than placebo [139]. In another study of is not recognized as a part of the IHCD-3 but
chronic migraine, greater occipital blockade was has important clinical and research implications.
56 T. S. Monteith
A proposed definition of refractory chronic integrated headache care networks have been
migraine was published by the Refractory Head- established; however; further, research is needed
ache Special Interest Section of the American to assess sustained benefits and predictors of out-
Headache Society [146]. The definition requires come [152].
significant impairment of quality of life despite Clinical trials should be designed to include
trigger management and adequate trials of acute clinical meaningful endpoints that may be useful
and preventive medications. Patients should in guiding treatment considerations for refractory
have a poor response to two of four drug classes cases. In addition to headache days with mod-
including beta-blockers, anticonvulsants, tricy- erate to severe intensity, frequency of migraine
clics, and calcium channel blockers when tried episodes and migraine days as suggested by the
for at least 2 months. The criteria also require a Task Force of the International Headache Society
lack of response to triptans and dihydroergota- Clinical Trials Subcommittee [153], responder
mine (DHE) intranasal or injectable formulation rates, quality of life measures, disability assess-
and either nonsteroidal anti-inflammatory drugs ments, acute medication usage, discontinuation
(NSAIDs) or combination analgesic. Modifiers rates, safety, and tolerability profiles are mean-
for medication overuse and disability were also ingful considerations [154]. Attempts should be
proposed. The European Headache Federation made to recruit real-world patients who have not
Expert Group of refractory chronic migraine responded to multiple preventive medications,
characterizes refractory chronic migraine patients have experienced continuous headache [155],
by their enormous disability, high risks of seri- and have significant comorbidities to obtain real-
ous adverse events, and potential exposures to world insights. Over the past several decades,
uncontrolled applications on therapeutics not there has been progress in novel therapeutics
yet validated [147]. In contrast to the American for chronic migraine. Treatment options should
Headache Society criteria, medication overuse is be both efficacious and cost-effective, with lost
not included, and adequate treatment of psychi- productivity taken into consideration for the
atric or other comorbidities is proposed. For the development of health policies. Taken together,
American Headache Society criteria, failure to partnerships with academia, industry, patient
respond to onabotulinumtoxinA is not included groups, and federal agencies are needed to fur-
as it was not yet approved for chronic migraine ther progress, improve care, and reduce disability
at the time of publication. Further studies will be associated with chronic migraine.
needed to evaluate the definitions of refractori-
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Yogi’s Headache: Chronic
Tension-Type Headache 5
Duren Michel Ready, Weiwei Dai,
Linda Kirby Keyser, and Cristina Cabret-Aymat
If baseball great Yogi Berra were to comment on pericranial muscle tenderness to palpation [4]. The
tension-type headache, he might say, “That head- challenge with identifying TTH by “what it is not”
ache is so common, you’d never see it.” Tension- begs the question, what is it? We are left then with
type headache (TTH) is the second most common the fundamental answer, “It hurts.”
condition worldwide, surpassed only by dental The heterogeneous characteristics led the
carries in incidence. It occurs so commonly that first International Headache Society Classifi-
its incidence is considered a normal part of life [1]. cation Committee to choose the term “tension-
TTH has become known as a “featureless” head- type” in order to represent an uncertain etiology
ache and defined by what it is not [2]. It has been while acknowledging that physical and psycho-
called “muscular contraction”, “psychogenic”, logical “tension” somehow plays a role [5]. As
“psychomyogenic”, “stress”, and “nonmigrainous” TTH’s pathogenesis has remained unclear, the
headache. The pain related to TTH typically lacks terminology has remained in the subsequent
localization (mostly diffuse and bilateral), mild to editions of the International Classification of
moderate in severity, and not pulsatile or worsened Headache Disorders (ICHD) (now in its third
by activity. There is an absence of neurological and edition). It was hoped that codifying TTH’s
autonomic features such as aura, lacrimation, nasal varied or uncertain etiology could facilitate
congestion, and rhinorrhea). The pain is described future research [2].
as an ache or an external pressure-type (vise-
like) sensation [3]. There is often accompanying
Infrequent Episodic Tension-Type Headache
Description: Infrequent episodes of head-
ache, typically bilateral, pressing, or tight-
D. M. Ready (*) · L. K. Keyser · C. Cabret-Aymat
Central Texas Headache Fellowship, Headache
ening in quality and of mild to moderate
Medicine, Baylor Scott and White, Temple, TX, USA intensity, lasting minutes to days. The pain
e-mail: duren.ready@bswhealth.org does not worsen with routine physical activ-
W. Dai ity and is not associated with nausea, but pho-
Neurology, Presbyterian Hospital, tophobia or phonophobia may be present.
Rio Rancho, NM, USA

64 D. M. Ready et al.
Diagnostic Criteria 4. Not aggravated by routine physical

A. At least ten episodes of headache
activity such as walking or climbing
occurring on <1 day per month on aver- stairs
age (<12 days per year) and fulfilling D. Both of the following:
criteria B–D 1. No nausea or vomiting
B. Lasting from 30 min to 7 days 2. No more than one of photophobia or
C. At least two of the following four phonophobia
characteristics: E. Not better accounted for by another
1. Bilateral location ICHD-3 diagnosis
2. Pressing or tightening (non-pulsat-
ing) quality
3. Mild or moderate intensity Unfortunately, the absence of clear diagnostic
4. Not aggravated by routine physical criteria in the ICHD 2 allowed individuals with
activity such as walking or climbing TTH to be diagnosed as having mild migraine,
stairs as there is a significant overlap between these
D. Both of the following: two conditions. Many migraine characteristics
1. No nausea or vomiting may be seen in TTH: worsened by physical activ-
2. No more than one of photophobia or ity (27.7%), pulsating quality (17.5%), anorexia
phonophobia (18.2%), photophobia (10.6%), unilateral head-
E. Not better accounted for by another ache (10%), or nausea (4.2%) [6]. The comorbid-
ICHD-3 diagnosis ity of migraine and TTH is even more common
in children with 58.4% of children with migraine
also having TTH and 68.1% of children with
TTH also having migraine [7] (Table 5.1).
Frequent Episodic Tension-Type Headache The lifetime incidence of tension-type head-
Description: Frequent episodes of headache is estimated to be between 30 and 78% [8].
ache, typically bilateral, pressing or tight- The annual US prevalence for chronic tension-
ening in quality and of mild to moderate type headache (CTTH) is estimated to be 2.2%
intensity, lasting minutes to days. The pain [9]. The worldwide prevalence has been consis-
does not worsen with routine physical tently estimated to be between 2 and 3% [10].
activity and is not associated with nausea, There is a slight female predominance in epi-
but photophobia or phonophobia may be sodic tension-type headache (ETTH) about 5:4.
present. Typically, TTH develops prior to age 30 with
Diagnostic Criteria
A. At least ten episodes of headache

occurring on 1–14 days per month on Table 5.1 Clinical features of tension-type headache
average for >3 months (≥12 and (TTH) vs. migraine
<180 days per year) and fulfilling crite- Clinical features of TTH Clinical features of migraine
ria B–D Bilateral pain Unilateral pain (chronic
B. Lasting from 30 min to 7 days migraine can be bilateral)
Pressing, burning pain Pulsatile pain
C. At least two of the following four
Mild to moderate pain Moderate to intense pain
characteristics:
Not aggravated by Aggravated by physical
1. Bilateral location physical activity activity
2. Pressing or tightening (non-pulsat- Nausea and vomiting Nausea and vomiting usually
ing) quality generally absent present
3. Mild or moderate intensity Only photophobia or Usual
phonophobia photophobia ± phonophobia
5 Yogi’s Headache: Chronic Tension-Type Headache 65
peak prevalence between 40 and 49 and subse-

quent decrease with age in both sexes [9]. C. At least two of the following four
As the incidence of TTH is much greater characteristics:
than migraine, it has a greater societal burden. 1. Bilateral location
Rasmussen et al. reported that 5% of the work- 2. Pressing or tightening (non-pulsat-
ing population (age 25–64) missed 4 days/year ing) quality
due to headache, 2% missed 20 days/year from 3. Mild or moderate intensity
headache, and 59% of people with TTH felt that 4. Not aggravated by routine physical
it interfered with their activities [11]. A Danish activity such as walking or climbing
study found that lost workdays from TTH was stairs
three times higher than migraine [12]. These lost D. Both of the following:
workdays accounted for approximately 10% of 1. No more than one of photophobia,
all lost workdays. phonophobia, or mild nausea
Beyond the societal costs, the individual expe- 2. Neither moderate or severe nausea
rience and resulting disability is also great. These nor vomiting
costs produce suffering through impaired per- E. Not better accounted for by another
sonal functioning, lost wages, and overall reduced ICHD-3 diagnosis
quality of life. Unfortunately, these costs are dif-
ficult to quantify which may lead to minimizing
TTH impact. Tension-type headache frequency
(instead of severity) appears to produce the great- Tension-Type Headache
est impact on disability and quality of life [3]. as a Spectrum
When TTH chronifies into chronic tension-
type headache (CTTH), it is associated with an …nothing is more helpful to a clear understanding,
prompt recognition, and sound memory than a well
even greater societal cost. Considering its signifi- ordered arrangement into classes, primary and sub-
cant incidence and cost, it is difficult to under- ordinate…(Yet) Nature, as the saying goes, makes
stand why it is neglected, and this neglect has left no jumps and passes from extreme to extreme only
us with few effective interventions [13]. through a mean. She always produces a species
intermediate between higher and lower types, spe-
cies of doubtful classification linking one type with
another and having something in common with
Chronic Tension-Type Headache both…
Description: A disorder evolving from fre- John Ray, who invented the concept of species
(1682)
quent episodic tension-type headache, with
daily or very frequent episodes of headache,
typically bilateral, pressing or tightening in An overwhelming number of migraineurs
quality and of mild to moderate intensity, have comorbid TTH, especially those with
lasting hours to days, or unremitting. The chronic migraine. This concurrence is what gave
pain does not worsen with routine physical rise to the convergence hypothesis [14]. The low-
activity but may be associated with mild grade background headache that is observed in
nausea, photophobia, or phonophobia. medication-overuse induced chronic migraine is
Diagnostic Criteria phenotypically similar to TTH [15]. CTTH also
shares many clinical features with fibromyalgia,
A. Headache occurring on ≥15 days per and they are often comorbid [16]. Additionally,
month on average for >3 months migraine, fibromyalgia, and TTH are more com-
(≥180 days per year), fulfilling criteria mon in women, may in some have a genetic basis,
B–D many similar triggers, and are comorbid with
B. Lasting hours to days, or unremitting depression and anxiety [17]. A recently proposed
pain model for CTTH postulated a referred pain
from trigger points in the craniocervical muscles Fundamentals

and mediated via the spinal cord and the trigemi-
nal nucleus caudalis. In TTH, there is increased nociceptive input into
Pain is ultimately an individual perceptual expe- the central nervous system. Injection of algo-
rience. Don Price identified the components of the genic solution produces increased nociception
peripheral pain experience as sensory discrimina- to pressure, thermal, and electrical stimulation.
tive (signal) and affective motivational (suffering). This increased sensitivity is seen in cephalic
These distinct components, once integrated in the and extracephalic musculature [18]. Subse-
cerebral cortex, become the pain experience. The quently, amplified nociceptive input from peri-
sensory discriminative pathway commences when cranial and cervical muscles provokes changes
stimuli transmitted from the peripheral nervous in second-order neurons in the spinal cord
system are transmitted to second-order neurons in dorsal horn and the spinal trigeminal nucleus.
the dorsal horn of the spinal cord and then ascends Over time, these second-order neurons undergo
through the spinothalamic track to the thalamus plastic changes increasing sensitivity to stimu-
and ultimately to the contralateral sensory cortex. lation. The end result is central sensitization.
This signal is transmitted along heavily myelin- A likely product of the central sensitization
ated nerve fibers allowing for precise recognition is increased muscle contraction that is seen in
of the quality, quantity, and location of the signal. CTTH [21]. The increased baseline muscle tone
The affective motivational pathway branches appears to be a consequence rather than a cause
off the spinothalamic tract to form the para- of the increased pain. The central sensitization
brachial track and is then bilaterally distrib- has been confirmed in CTTH by examining the
uted throughout the cortex to the limbic system nociceptive flexion reflex R3 component [22],
(amygdala, insula, hippocampus, caudate, ante- suprathreshold (single or repetitive) electrical
rior cingulate gyrus, prefrontal cortex, and the thresholds [23], and cortical potential evoked
supraorbital cortex). by supraorbital laser heat stimulation [24]. In
This pathway is responsible for the subjective a properly functioning system the hyperexcit-
experience associated with the signal. Limbically ability of the interneurons would be inhibited
augmented pain (pain greater than the sum of its by input from the periaqueductal gray. The
parts) suggests that pain and mood share many absence of effective descending pain modula-
common pathways. The shared common path- tion confirms the involvement of central mecha-
ways help us understand how unmanaged stress, nism in CTTH [3].
past traumas, or depression amplify suffering
beyond the sum product of stress.
Differences Between ETTH and CTTH
Tension-Type Headache In ETTH, the pericranial myofascial mechanisms

Pathophysiology and Clinical are likely significant. However, in CTTH altera-
Findings tions in central pain processing are generally
accepted as causative [15]. High density EEG
Historically it was believed that TTH was the brain mapping has demonstrated abnormal pro-
result of muscle contraction and head and neck cessing of sensory evoked potentials in CTTH
muscle ischemia [18]. Subsequent electromyo- and descending modulation of nociceptive input
graphic (EMG) studies refuted this etiology [19]. [25]. A causative central mechanism is supported
Furthermore, studies have demonstrated normal by evidence of specific disruption of the trigemi-
muscle lactate levels in CTTH, thereby making nal pathway via suppression of the R2 compo-
increased muscle contraction an unlikely etiol- nent of the blink reflex. However, this mechanism
ogy for TTH [20]. was only observed in CTTH [26].
Chemical pressure stimulus that is perceived as painful)

and pressure pain tolerance thresholds (PPTol—
Multiple algogenic chemical mediators (gluta- the maximum pressure stimulus that is tolerated)
mate, bradykinin, prostaglandin E2, glucose or in cephalic and extracephalic regions are lower
pyruvate) have been identified in tender muscle in CTTH when compared to controls [38, 39].
tissue in CTTH [27]. These substances may be Increased pressure pain detection has also been
released at trigger points locally and in distal pain- identified in infrequent TTH [40, 41]. Interest-
free tissues [28]. Algogenic substance release ingly, the increased pressure pain sensitivity
decreases nociceptive threshold, generating a is not evenly distributed. In the temporalis, the
cycle of peripheral sensitization in TTH [29]. In anterior aspect is the most sensitive [42].
addition, calcitonin gene-related peptide (CGRP),
a potent migraine provocateur, has been demon-
strated in people with “pulsatile” CTTH [30]. Myofascial Trigger Points
Trigger points are a palpable hard nodule in

Pericranial Tenderness a “taunt band” of skeletal muscle. “Active”
trigger points are painful spontaneously, and
Pericranial muscle tenderness is a common find- “latent” trigger points are painful when palpated.
ing in TTH. The increased tenderness to palpa- Active trigger points are associated with higher
tion is present in adults with both frequent ETTH bradykinin levels and other chemical mediators
and CTTH. However, in children, it seems to be [28]. They are also associated with local and
only present in CTTH [31–33]. When present, referred pain [28, 43]. When active trigger points
pericranial tenderness correlates with headache are present in TTH, patients have greater head-
frequency and intensity. Typically the muscle ache intensity, frequency, and duration [44]. In
tenderness is diffused, perceived as a spasm, or CTTH there are more active trigger points than
associated with a “trigger point” in a tight mus- controls, which suggest that they are involved in
cle. Pericranial tenderness can be present even on TTH pathophysiology [45].
headache-free days. Given the consistent finding Multiple clinical trials have demonstrated the
of pericranial tenderness, it is considered to be a significance of active trigger points in CTTH
precipitant and not a product of TTH [3]. [46]. Trigger points have been identified in the
Pericranial tenderness initiates a feedback suboccipital [47], upper trapezius [48], superior
loop that can, over time, induce central sensitiza- oblique [49], sternocleidomastoid [50], tempo-
tion in the cortex by increasing attention to and ralis [51], and lateral rectus [52] muscles. These
emotional response to pain [34]. It has recently widespread trigger points support the Fernandez-
been demonstrated that the central sensitization de-las-Peñas et al. model involving peripheral
associated with this phenomenon can be acceler- nociceptor sensitization through active trigger
ated by inadequate sleep [35]. points and then central sensitization via the con-
tinued afferent discharge to the trigeminal nucleus
caudalis. In this model the muscle tenderness is
Pain Pressure Point the product, and the trigger point referred pain
becomes one of the significant causes of CTTH
The scalp, neck, and jaw muscle and tendon ten- [53]. Trigger point activity should not obscure
derness is observed during and between attacks. the need to address other factors associated with
There appears to be some correlation between TTH and its progression such as forward head
the observed muscle tenderness and TTH sever- posture [54], muscle atrophy [55], altered muscle
ity and frequency [36, 37]. This tenderness is the pattern recruitment [56], or psychological factor
best documented finding in ETTH and CTTH [57]. These additional peripheral factors add to
[1]. Pressure pain thresholds (PPT—the lowest the central sensitizing process.
europlastic Changes and Central

N A 12-year longitudinal study found that
Sensitization patients who developed CTTH had normal ten-
derness scores and pain pressure threshold prior
Central nervous system hyperexcitability and to the onset of TTH symptoms. These findings
reduced inhibitory pain mechanisms are involved suggest that sensitization is a consequence and
in TTH nociception [58]. CTTH patients report not a trigger of CTTH [65]. The persistent trig-
hypersensitivity to stimulus in cephalic and extra- ger point activation induces negative neuroplas-
cephalic non-symptomatic locations, demonstrat- tic changes in second-order neurons in the dorsal
ing increased synaptic nociceptive transmission horn and spinal trigeminal nucleus producing
within the central nervous system [59]. Lowered increased pericranial and cervical muscle tender-
pressure pain threshold has been demonstrated in ness [66]. Diminished descending nociceptive
the trapezius, frontalis, and temporalis muscles in inhibition at the dorsal horn is supported by the
TTH and CTTH [60]. finding that in CTTH there are deficiencies in
Pressure pain thresholds for infrequent TTH diffuse noxious inhibitory pain control (DINC)
are normal. However, in frequent TTH and mechanisms [67–69].
CTTH, they are decreased [3]. This lowered MRI of the brain in CTTH patients reveals
threshold is consistent with what is observed in significantly reduced gray matter density in the
other central pain conditions [61]. Fibromyal- pain matrix (cingulate, insular, orbitofrontal
gia (FMS), a classical central pain disorder, is cortex, right posterior temporal lobe, bilateral
highly comorbid with CTTH. In ETTH, FMS is parahippocampus, dorsal rostral and ventral

estimated to be present in 35% of patients. Once pons, and right cerebellum) [70]. However, the
it progresses to CTTH, the incidence climbs as reduction in gray matter may suggest neuronal
high as 44% [62, 63]. damage, but that is not always the case [71]. The
This central neuronal sensitization appears to gray matter density reduction is positively cor-
be important in CTTH pathogenesis [59]. Neuro- related with headache burden over time. These
plastic changes, such as the nociceptive flexion findings are similar to other chronic central pain
reflex R3 component [22] and evoked cortical disorders and suggest that it is a consequence of
potential via supraorbital laser heat stimulation, the continued pain state [72].
have been reported [24]. However, the most sig-
nificant change is pericranial muscle tenderness
to palpation. In adults, this is the most typical Stress and Genetics
finding [64]. This tenderness is not limited to the
pericranial musculature but is also observed in While stress is generally accepted to be one of the
the neck and shoulders. most significant TTH triggers, its causative path-
way is unclear [68]. Stress, whether psychological
or environmental, seems to have a greater impact
than genetics [15]. Stressors (and the failure to
Clinical Signs of Central Sensitization [4] recover from stressors) are additive TTH risk fac-
1. Generalized pericranial muscle and
tors [15]. These stressors may include hunger,
nerve tenderness thirst, lack of restorative sleep, and homeosta-
2. Widespread pressure and electrical pain sis disruptions. Patients may often report a TTH
sensitivity on a “bad” day. This effect may be by a direct
3. Comorbid with fibromyalgia syndrome mechanism or by worsening comorbidity, such as
4. Presence of non-restorative sleep depression, anxiety, or insomnia [3].
5. Comorbid with anxiety, depression,
While no specific genetic locus has been iden-
mood disorders, coping mechanisms tified in CTTH, epidemiological studies have
found that first-degree relatives of CTTH patients
have a 3.1-fold increase in the odds of having Secondary Headache

CTTH [73, 74]. This would suggest that develop-
ing CTTH is a product of genetic and environ- Since many TTH features are nonspecific, it
mental factors [75]. However, it would appear should only be diagnosed after any second-
that stress-producing environmental factors exert ary headache disorder has been excluded [81].
a greater influence than genetics [76]. Stress Headaches associated to giant cell arteritis
increases attention and vigilance to pain which may resemble TTH but typically presents with
amplifies the pain experience. When compared severe unilateral pain and jaw claudication [3].
to controls, TTH sufferers demonstrate greater A nonspecific headache may be the product of
stress-induced pain sensitivity. This in turn trig- a homeostatic disorder such as anemia, hypo-
gers a “stress” headache [77]. Additionally, stress thyroidism, hepatic, or renal disease. A systemic
enhances myofascial tissue activation and sensi- infection (bacterial or viral) may also have head-
tization peripherally and decreases nociceptive ache as a symptom. Because of the symptom
thresholds centrally [68]. overlay between primary and secondary head-
ache symptoms, it is essential to elicit the tempo-
ral pattern of the headache [15].
ension-Type Headache Clinical
T
Issues
Cervicogenic
Population-based studies have shown that
increased pain sensitivity increases the preva- It is not uncommon for cervicogenic headaches
lence and frequency of tension-type headache to present with TTH characteristics. The pathol-
[78]. The nonspecific and widespread sensitivity ogy may involve the discs, osseous structures,
in TTH suggests central nervous system impair- or structural alignment [15]. Common clinical
ment by increased excitability in dorsal horn and features such as side-locked pain, pain worsened
supraspinal neurons [4]. The increased sensitivity by moving the head, pain that is provoked by
is observed ictally and interictally [79]. pressing the fingers into the neck muscles, and
Cervical range of motion is also impaired in pain that radiates from the back to the front can
TTH with a more pronounced forward head pos- be seen in both TTH and many secondary head-
ture while sitting and standing [54]. These find- aches [82].
ings seem to correlate with headache frequency
and duration and the cervical range of motion
impairment directly linked to the degree of for- Comorbidities
ward head posture.
Insomnia is one of the most common comor-
bidities seen in TTH. Continued sleep depriva-
ension-Type Headache Clinical
T tion appears to lower pain thresholds [83]. One
and Physical Findings prospective trial demonstrated that insomniacs
were more likely to develop TTH over a decade
The experience of muscle pain occurs when mus- [84]. Polysomnographic studies in TTH detected
cle nociceptors are excited. These free nerve end- notably greater rates of insomnia, daytime tired-
ings respond to mechanical (thermal/chemical) ness, anxiety, and reduced subjective sleep qual-
stimulation and endogenous algogenic neurotrans- ity compared with controls. Remarkably, TTH
mitters (bradykinin/serotonin/prostaglandin E2) patients had no sleep-time differences or addi-
[29]. The marked heterogeneity of TTH patho- tional slow-wave sleep (a marker of increased
physiological and significant environmental con- sleep quality). These findings suggest that TTH
tributions suggests multiple pathways that may be patients may have greater sleep requirements
contributing in tandem or isolation [80]. [35]. Addressing this comorbidity is essential as
disturbed sleep has been shown to be a poor prog- Neurology) published TTH treatment guidelines
nostic factor in TTH [85]. in 2010 [94]. These guidelines recommended the
Temporomandibular disorder (TMD) may be use of nonpharmacological interventions despite
a secondary cause of headache and can resemble the weakness (or in some cases the absence) of
TTH. Temporomandibular joint (TMJ) pain usu- robust scientific evidence. Acute ETTH treatment
ally originates from the joint or the muscles of recommendations included simple analgesics
mastication. This disorder is common in TTH and NSAIDs followed by caffeinated combina-
and migraine [86]. The relationship between tion analgesics. The guidelines argue against
TMD and these primary headaches appears bidi- the acute use of triptans, muscle relaxants, and
rectional with each condition worsening the other opioids. The typical admonition about avoiding
[87]. Similar to CTTH, TMD has also been asso- medication-overuse headache was also included.
ciated with cutaneous allodynia (a marker for Amitriptyline, followed by mirtazapine, and ven-
central sensitization) suggesting a pathophysi- lafaxine were recommended for TTH prophy-
ological mechanism for the bidirectional influ- laxis. The guidelines pointed out that the efficacy
ence [88]. of prophylactic medication is limited and fre-
quently causes problematic adverse effects.
A likely explanation for promoting non-
Mood/Behavioral pharmacological intervention (in spite of their
weak evidence) is that many of these treatments
As seen in other chronic pain conditions, mood promote positive lifestyle changes that enhance
disorders are common in CTTH [89]. One meta- resilience. This may block the most common
analysis reported that children and adolescents trigger of TTH “stress.”
with TTH had more psychopathological symp-
toms similar to what is seen in migraine [90].
It is estimated that the chance of developing a Acute Treatment
secondary depression is 25% in CTTH. CTTH
patients additionally exhibit higher anxiety rates Consistent with the EFNS guidelines, clinical
[91]. In combination, depression and anxiety practice demonstrates that NSAIDs are first-line
may accelerate headache frequency by lowering therapy for TTH [95]. Ibuprofen (between 400
pain threshold [92]. There are also higher rates and 800 mg) is a reasonable first choice for acute
of catastrophizing and avoidance in CTTH [18]. ETTH [4]. One trial demonstrated the benefit of a
COX-2 inhibitor, lumiracoxib (200–400 mg), for
ETTH [96] (Table 5.2).
ETT/CTTH Treatment Triptans have been demonstrated to effec-
tively treat acute TTH in individuals with comor-
Treatment for TTH involves pharmacological, bid migraine [97]. However, medication cost will
behavioral, physical, and procedural therapies. likely limit triptan usage in TTH.
It is further subdivided into acute and preventive
therapy [15]. Interventions seem to be effective
in ETTH and may prevent progression to CTTH Prophylactic
[4] where their effectiveness may be limited [89].
Unfortunately, research has not demonstrated Tricyclic antidepressants, especially amitripty-
a robust response [93]. As in migraine, as TTH line, are the first-line therapeutic agents for TTH
becomes chronic, it becomes more difficult to (both ETTH and CTTH) [2]. Most studies initi-
treat [89]. ate amitriptyline between 10 and 25 mg titrating
The European Federation of Neurologi- upward to 75 mg in CTTH [15]. Clomipramine
cal Sciences (now the European Academy of may be superior to amitriptyline, but adverse
Table 5.2 Recommended drugs for acute treatment of tension-type therapy

Substance Dose (mg) Level Comment
Ibuprofen 200–800 A Gastrointestinal side effects, risk of bleeding
Ketoprofen 25 A Side effects as for ibuprofen
Aspirin 500–1000 A Side effects as for ibuprofen
Naproxen 375–550 A Side effects as for ibuprofen
Diclofenac 12.5–100 A Side effects as for ibuprofen, only doses of 12.5–25 mg tested in TTH
Paracetamol 1000 (oral) A Less risk of gastrointestinal side effects compared with NSAIDs
Caffeine comb. 65–200 B See belowa
a
The level of recommendation considers side effects and consistency of the studies. There is sparse evidence for optimal
doses. The most effective dose of a drug well tolerated by a patient should be chosen; NSAID, nonsteroidal anti-inflam-
matory drugs; TTH, tension-type headache; a combination with caffeine 65–200 mg increases the efficacy of ibuprofen
and APAP but possibly also the risk for developing medication-overuse headache. Level of recommendation of combi-
nation drugs containing caffeine is therefore B
events often limit its use. Nortriptyline typically Table 5.3 Recommended drugs for prevention of ten-
sion-type headaches
has a better side effect profile to amitriptyline,
and it may be a reasonable alternative for those Daily dose Level of
Substance (mg) recommendation
who have difficulty tolerating amitriptyline. Dox-
Drug of first choice
epin (especially if there is comorbid insomnia) Amitriptyline 30–75 A
is a reasonable second-line TCA choice [80]. Drugs of second choice
Protriptyline has been shown to be beneficial in Mirtazapine 30 B
CTTH [3], but side effects may limit its utility. Venlafaxine 150 B
Mirtazapine (an antidepressant that acts at Drugs of third choice
alpha -2 and histamine -1 receptors increasing Clomipramine 75–150 B
serotonin and norepinephrine) has demonstrated Maprotiline 75 B
efficacy at 30 mg daily dosing even in amitripty- Mianserin 30–60 B
line nonresponders [98]. Unfortunately this dos- The level of recommendation considers side effects and
number and quality of the studies
age produces fatigue and weight gain and lower
doses were not effective.
Venlafaxine was shown to benefit ETT patients Procedural Interventions
with comorbid depression, but not in CTTH [99].
Another SNRI, duloxetine at 60 mg/day, demon- Trials of botulinum toxin A for TTH have yielded
strated significant headache improvement in an contradictory results. One trial showed benefit for
open-label trial in chronic migraine and CTTH headache duration and patient assessment scores
patients with major depression [100]. while failing to demonstrate any improvement in
Typically, muscle relaxants have limited util- headache-free days [103]. A latter trial showed
ity in TTH. Tizanidine, a centrally acting anti- significant improvement for headache days,
spasticity agent, demonstrated some benefit with intensity, and related disability [104]. Unfortu-
doses between 6 and 18 mg/day. Additional ben- nately, these benefits have not been confirmed in
efit was seen for tizanidine 4 mg combined with placebo-controlled double blinded trials [105].
amitriptyline 20 mg in CTTH over amitriptyline Pericranial trigger point injections with lido-
alone [101]. caine in patients with frequent TTH were shown
Topiramate in a prospective open-label trial to reduce headache frequency and severity [106].
produced a 50% improvement in CTTH sever- Fernández-de-las-Peñas, et al. developed a pre-
ity and frequency [102]. Other membrane-stabi- liminary clinical prediction rule to identify CTTH
lizing medications have no evidence supporting patients who might benefit from short-term suc-
their use [3] (Table 5.3). cess with a muscle trigger point therapy. The
clinical rule has four variables: headache duration Electromyography biofeedback that allows
<8.5 h/day, headache frequency <5.5 days/week, patients to learn control over pericranial muscle
bodily pain <47, and vitality <47.5.1 One-month tension has demonstrated effectiveness for TTH
improvement was associated with two variables: [111]. This meta-analysis reported a significant
headache frequency <5.5 days/week and bodily medium to large benefit that was stable over
pain <47 [107]. 15 months. The greatest improvement was seen
Acupuncture trials and systematic reviews in headache frequency.
have also yielded conflicting results. One review Exercise and physical therapy have demon-
demonstrated superiority over sham acupuncture strated benefit in TTH. Some recent trials have
at both early and late follow-up [108]. The com- demonstrated benefit for physical therapy in
bined results also demonstrated superiority over CTTH for headache frequency, duration, and
pharmacological intervention in headache fre- intensity [112–114].
quency and intensity, functioning, and response.
In contrast, a more recent meta-analysis con-
cluded that acupuncture (when compared to sham Conclusion
acupuncture) had limited efficacy for reducing Tension-type headache remains an underdiag-
TTH frequency [109]. nosed and undertreated entity with poorly
understood pathophysiology. However, the
burden of tension-type headache, both indi-
Behavioral Therapy vidually and for society is significant and the
inescapable association with stress suggests
Cognitive behavioral therapy (CBT) and relax- that TTH may be a marker for a variety of
ation therapies have been shown to have a social and personal circumstances requiring
robust synergistic effect in lowering severity our attention. Sufferers deserve attention and
CTTH when combined with amitriptyline [110] care. These headaches may just simply be tell-
(Table 5.4). Younger patients tend to be more ing us that we need to be taking better care of
responsive to behavioral therapies [95]. ourselves.
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Chronic Cluster Headaches
6
Soma Sahai-Srivastava
Chronic cluster headaches are a rare cause of The first vivid description of cluster headache
chronic headaches. They are the most prominent dates to 1745, by Gerhard van Swieten, pub-
and common type of trigeminal autonomic ceph- lished in Latin. It serves as a stark reminder of
alalgias (TAC) and were described in 1941 by the scourge of this rare primary headache [3]: “A
Horton, who also first used oxygen therapy to healthy, robust man of middle age was, each day,
abort an acute cluster attack [1]. In 1952, Kunkle at the same hour troubled by pain above the orbit
first used the term “cluster” to describe these of the left eye, where the nerve leaves through
headaches [2]. There are many synonyms for the bony frontal opening; after a short time the
cluster headache, including “suicide headache” left eye began to redden and tears to flow; then
due to rare reports of suicidal behavior within he felt as if his eye was protruding from its orbit
this patient population. with so much pain that he became mad. After a
few hours all this evil ceased and nothing in the
eye appeared at all changed.”
An earlier description, in Observationes
Synonyms for Cluster Headache
Medicae, published in1641, Nicolaas Tulp, a well-
Ciliary neuralgia
known physician from Amsterdam, mentioned two
Erythromelalgia of the head
different types of “recurring headache”: migraine
Erythroprosopalgia of Bing
and a second entity which resembles cluster head-
Horton’s neuralgia or headache
ache [4]. In recent years, patient advocacy organi-
Harris-Horton disease
zations have raised the general awareness of this
Hemicrania angioparalytica
entity [5]. This has contributed to new discoveries
Histaminic cephalalgia
in neuroimaging, medication therapies, and neuro-
Hemicrania neuralgiformis
stimulation, which have created a better under-
Migrainous neuralgia (of Harris)
standing of the pathophysiology and created new
Petrosal neuralgia (of Gardner)
treatment options.
Sluder’s neuralgia
Sphenopalatine neuralgia
Vidian neuralgia
Epidemiology
Fishera reported a lifetime prevalence of cluster

S. Sahai-Srivastava headaches at 124 per 100,000 and a 1-year prev-
Clinical Professor of Neurology, Keck school of alence of 53 per 100,000, with an overall male-
Medicine, Los Angeles, CA, USA
e-mail: sahai@usc.edu to-female sex ratio of 4.3:6.0 [6]. Approximately

78 S. Sahai-Srivastava
10–20% of patients with episodic cluster

develop the chronic form, which is defined as Cluster Headache Has Two Forms
a remission period of more than a month [7]. 1. Episodic: Occurs in periods lasting

In the general population, more recent studies 7 days to 1 year separated by pain-free
suggest that prevalence of cluster headache is periods lasting 1 month.
nearer to 1/1000 to 1/2000. However, in several 2. Chronic: Attacks occur for more than
European countries, extensive epidemiological 1 year without remission or with remis-
studies indicate a more variable prevalence: 119 sion lasting less than 1 month.
per 100,000 in Germany [8], 326 per 100,000 in
Norway [9], and 279 per 100,000 in Italy [10]. Diagnostic Criteria for Cluster
These studies suggest cluster incidence is likely Headache
to be dependent upon the awareness and training A. At least five attacks fulfilling criteria
specialists who see these patients. Cluster head- B–D.
ache is a hidden underdiagnosed condition, and B. Severe or very severe unilateral orbital,
there may be a delay of over 5 years in accurate supraorbital, and/or temporal pain last-
diagnosis and treatment [11]. Cluster headache ing 15–180 min (when unilateral).
in women is often misdiagnosed as migraine C. Either or both of the following:
and can present with an overlap of symptoms 1. At least one of the following symp-
between the two entities. Women are more likely toms or signs, ipsilateral to the
to be diagnosed after 10 years of symptom onset headache:
than males, and significantly fewer women than a. Conjunctival injection and/or
men are diagnosed correctly at an initial physi- lacrimation
cian visit [12]. b. Nasal congestion and/or rhinorrhea
c. Eyelid edema
d. Forehead and facial sweating
Clinical Features e. Forehead and facial flushing
f. Sensation of fullness in the ear
Diagnostic criteria for both episodic and chronic g. Miosis and/or ptosis
cluster headaches have been established [13]. 2. A sense of restlessness or agitation
The beta version of ICHD-3 has eliminated the D. Attacks have a frequency between one
term “primary” and “secondary” previously every other day and eight per day for
used to distinguish between chronic cluster more than half of the time when the dis-
headaches that arise de novo or evolve from order is active.
the episodic version. Cluster headaches are E. Not better accounted for by another
considered chronic when attacks fulfilling the ICHD-3 diagnosis.
criteria for cluster headaches occur without
remission or with remission periods lasting less
than 1 month, for at least 1 year. The European Age of onset of cluster headaches is usually
Headache Federation has established a con- 20–40 years. The male-to-female ratio is higher
sensus statement on refractory chronic clus- in chronic cluster headache (15.0) compared to
ter headache, with the purpose of identifying episodic cluster headache (3.8). Some authors
patients who may be eligible for invasive treat- however, report that chronic cluster headaches
ments such as neurostimulators. Chronic cluster are slightly more common in women than in
headache, with at least three severe attacks per men [15]. Cluster headaches are strictly unilat-
week despite at least three consecutive trials of eral, side-locked, orbital, supraorbital, or perior-
adequate preventive treatments, is considered bital headaches that are accompanied by at least
refractory [14]. one of seven autonomic features ipsilaterally or
6 Chronic Cluster Headaches 79
are accompanied by a sense of restlessness and/ onset, lifetime depression, comorbid migraine,
or agitation. The maximum duration of these and having recent attacks were independent risk
attacks, according to the ICHD-3 beta version factors for allodynia in this study. The authors
criteria, is 3 h. Taga et al. reviewed migraine- suggest that central sensitization, as in migraine,
like features in a large cohort of 569 cluster is frequently seen in cluster headache.
patients and found migrainosus features in 46% Due to the challenges in diagnosing clus-
of patients [16]. After adjusting for confounding ter headaches, a two-question cluster headache
factors, they noted a more frequent association screening tool has been validated with the follow-
with females, a relatively younger age of onset, ing questions: (1) attack duration <180 min and
longer attack duration, and accompanied by more (2) the presence of conjunctival injection and/or
frequent sweating (OR 1.63, CI 1.02–2.21), mio- lacrimation during attack [21]. This two-question
sis, and osmophobia. Another study with 155 tool had a sensitivity of 81.1% and a specificity
cluster patients reported that 24.5% experienced of 100%.
at least one migrainous feature during every clus- The chronobiology of chronic cluster head-
ter headache attack. Nausea and vomiting were aches is not as predictable as that of the episodic
the most frequently reported of the migrainous type, and there are reports of both nighttime and
features [17]. The clinical presentation in cluster daytime attacks among the chronic patients
headache patients with and without migrainous [22–24]. Spring and fall are well-known cluster
features was not significantly different, with the periods [25], though for chronic cluster patients,
exception of aggravation of pain by effort (20.6% this seasonal rhythmicity may either completely
vs. 4.1%) and facial sweating (13.2% vs. 0.85%) disappear or become modified [26]. Limited
which were more frequent in cluster patients with scientific evidence indicates that in one-third of
migrainous features [16]. cases cluster remission occurs regardless of age
Because cluster aura is seldomly discussed and that features of cluster headache become
among clinicians, and there is little awareness less prominent over time [27]. Cluster attacks
even among patients, patients with cluster aura can be provoked by alcohol, histamine, and
may be misdiagnosed as suffering with migraine nitroglycerine.
with aura. Silberstein reported 6 cluster patients Cluster headache profoundly affects every
out of a series of 101 with an associated aura, aspect of life from work to activities of daily liv-
5 visual and 1 olfactory [18]. Chronic clus- ing, and patients report worse working memory,
ter patients often describe a “shadow or aura” disturbance of mood, and poorer quality of life
around the eye affected by cluster attacks, compared to healthy controls. Self-reported anxi-
described as a sensation of pressure or discom- ety is higher in those with chronic cluster than for
fort. Some cluster patients describe a sense of an episodic patients, with 75% of the former com-
impending event that can precede an attack and pared with 38% of the latter groups on a measure
which in many cases persists between attacks. of anxiety [28]. Jensen reports that 82% of clus-
This description is provided from the author’s ter headache patients from a tertiary center had
own unpublished observation of a series of decreased work ability during a cluster period and
chronic cluster patients and has not been previ- half of the patients considered it profound [29].
ously described. A hemiplegic variant of cluster
has been recently described by Siow et al. in a
series of four patients, one of them with an auto- Differential Diagnosis
somal dominant inheritance [19]. A recently
published “Leiden University Cluster head- The main differential diagnoses of chronic clus-
ache neuro-Analysis” (LUCA) study reported ter headache include chronic migraine and other
that 36% of cluster patients had allodynia dur- TACs such as chronic paroxysmal hemicranias
ing attacks [20]. Female gender, younger age at (CPH) and hemicrania continua.
these studies [30]. Other authors suggest that the

Differential Diagnosis of Chronic Cluster prevalence of cluster in general population could
Headache be underestimated, particularly when patients
Primary Headaches have less painful attacks, shorter bouts, and
Chronic migraine attacks without autonomic symptoms [31] or have
Trigeminal autonomic cephalalgias migraine symptoms (photophobia, phonophobia,
nausea) associated with their cluster attacks [32].
Chronic paroxysmal hemicrania All patients with side-locked, short-lasting, uni-
Hemicrania continua lateral headache and autonomic features should
Chronic SUNCT receive an adequate trial of oxygen therapy during
Chronic SUNA their headache, as this is a very simple and effec-
tive means of identifying clusters, which are the
Trigeminal neuralgia only headaches that respond to such treatment. It
Persistent idiopathic facial pain is helpful to have oxygen available in a headache
Rebound analgesic headaches clinic for a trial in such patients, such that it could
Secondary Headaches be administered in an urgent care setting.
Vascular-vertebral artery dissection or According to the ICHD-3 beta version cri-
aneurysm teria, CPH attacks last 2–310 min and do not
include the criteria “sensation of restlessness or
Aneurysm of anterior communicating agitation.”
artery
Carotid aneurysm
Occipital lobe AVM
Chronic Paroxysmal Hemicrania Has Two
AVM middle cerebral territory
Forms
Giant cell arteritis
1. Episodic: Occurs in periods lasting

7 days to 1 year separated by pain-free
Lower brainstem or upper spinal cord
periods lasting 1 month.
2. Chronic: Attacks occur for more than
Meningioma
1 year without remission or with remis-
Brainstem or upper cord infarction
sion lasting less than 1 month.
Intracranial lesions
Diagnostic Criteria for Paroxysmal
Hemicrania
Pituitary adenoma (prolactinoma)
A. At least 20 attacks fulfilling criteria

Sphenoid wing meningioma
B–E.
B. Severe unilateral orbital, supraorbital,
Facial trauma
and/or temporal pain lasting 2–30 min.
Orbital/sinus
C. At least one of the following symptoms
Tolosa-Hunt syndrome
or signs, ipsilateral to the headache:
1.
Conjunctival injection and/or
lacrimation
Chronic migraine can be difficult to distin- 2. Nasal congestion and/or rhinorrhea
guish from chronic cluster, especially in women, 3. Eyelid edema
due to the presence of nausea and photophobia. 4. Forehead and facial sweating
Moreover, previous reports have shown that 27% 5. Forehead and facial flushing
of patients with migraine have at least one uni- 6. Sensation of fullness in the ear
lateral autonomic symptom, and this may explain 7. Miosis and/or ptosis
the excess of cluster diagnosis in the first step of
D. Attacks have a frequency above five per d . Forehead and facial sweating
day for more than half of the time. e. Forehead and facial flushing
E. Attacks are absolutely prevented by f. Sensation of fullness in the ear
therapeutic doses of indomethacin. g. Miosis and/or ptosis
F. Not better accounted for by another 2. A sense of restlessness or agitation
ICHD-3 diagnosis. or aggravation of pain by movement
D. Responds absolutely to therapeutic

doses of indomethacin
Pivotal questions to ask patients are whether E. Not better accounted for by another
they feel restlessness or agitation during attacks ICHD-3 diagnosis
and what is the duration of their headaches.
Duration may last up to 5 hours in CPH and
3 hours or less in cluster. Thus, it may be difficult Short-lasting unilateral neuralgiform head-
to distinguish between the two based solely on aches include attacks of moderate to severe
duration. The other tool that can help to distin- strictly unilateral head pain at least once a day
guish CPH from chronic cluster is an adequate and can mimic chronic cluster headaches due to
trial of indomethacin. However, there are a few prominent lacrimation and redness of eye unilat-
case reports of cluster patients responding to erally with attacks.
indomethacin, particularly in women. There are
also reports of CPH patients being only partially
responsive to indomethacin. In cases where indo- Short-Lasting Unilateral Neuralgiform
methacin is contraindicated, e.g., gastrointestinal Headache Attacks Have Two Subforms
issues, this is less helpful. 1. Chronic SUNCT: Occurs in periods

Hemicrania continua is a continuous side- lasting 7 days to 1 year separated by
locked unilateral headache that is indomethacin- pain-free periods lasting 1 month.
responsive. However, chronic cluster patients 2. Chronic SUNA: attacks occur for more
may have allodynia around the eye involved with than 1 year without remission or with
attacks and may have some unilateral, continu- remission lasting Less than 1 month.
ous, baseline pain symptoms, which could con-
fuse the diagnosis. As a general rule, for any case Diagnostic Criteria
of unilateral side-locked headache, an adequate A. At least 20 attacks fulfilling criteria

trial of indomethacin should be considered. B–D.
B. Moderate or severe unilateral head
pain, with orbital, supraorbital, tempo-
Diagnostic Criteria for Hemicrania Continua ral, and/or other trigeminal distribution
A. Unilateral headache fulfilling criteria
lasting 1–600 s and occurring as single
B–D stabs, series of stabs, or in a sawtooth
B. Present for >3 months, with exacerba- pattern.
tions of moderate or greater intensity C. At least one of the following symptoms
C. Either or both of the following: or signs, ipsilateral to the headache:
1. At least one of the following symptoms 1.
Conjunctival injection and/or
or signs, ipsilateral to the headache: lacrimation
a. Conjunctival injection and/or 2. Nasal congestion and/or rhinorrhea
lacrimation 3. Eyelid edema
b. Nasal congestion and/or rhinorrhea 4. Forehead and facial sweating
c. Eyelid edema 5. Forehead and facial flushing
Chronic cluster patients may overuse symp-

6 . Sensation of fullness in the ear tomatic medications to treat their attacks and
7. Miosis and/or ptosis may develop medication-overuse headache
D. Attacks have a frequency of at least one (MOH). MOH further complicates chronic clus-
a day per day for more than half of the ter headaches and may present with the devel-
time when the disorder is active. opment of a background headache. This may
E. Not better accounted for by another be either featureless or have some migrainous
ICHD-3 diagnosis. quality. MOH, in these cases, is described as a
bilateral, dull, and featureless daily headache
resulting from a wide range of monotherapies or
The two subtypes are chronic SUNCT (short- varying combinations of simple analgesics, caf-
lasting unilateral neuralgiform headache with con- feine, opioids, ergotamine, or triptans [35]. A
junctival injection and tearing) and chronic SUNA personal or familial history of migraine appears
(short-lasting unilateral neuralgiform headache to be strongly associated with the development
with cranial autonomic symptoms). Both these of MOH in cluster headache, and patients with a
subtypes have short forms and present with dra- this history of migraine must be carefully moni-
matically painful sharp stabs that last seconds, tored for MOH. Medication withdrawal should
along with autonomic features, but no sense of be considered in every chronic cluster headache
agitation or restlessness. SUNCT has both con- patient [36]. Because MOH can add a bilateral,
junctival injection and tearing, along with other featureless, or migrainous element when super-
autonomic symptoms criteria, whereas SUNA has imposed on cluster, it is important to ask every
other autonomic symptoms but not the conjuncti- patient to describe the headache as it was before
val injection and tearing. The key to this condition the offending analgesic was started.
is the recognition that there are hundreds of attacks
in a day that may last no more than seconds.
These types of headaches can be triggered Secondary Cluster Headaches
without a refractory period. The main differ-
ence from cluster headaches is the duration of Cluster headaches may be triggered by eye
pain which lasts seconds (1–600) in SUNCT/ trauma, orbital pathology, cataract surgery, or
SUNA. This can be difficult clinically to dis- even injections in the trigeminal sensory distri-
tinguish if patients are having attacks lasting bution, e.g., by palatal injections for dental pro-
10 minutes or longer. Among the TACs, the seven cedures [37]. Several cases of cluster headaches
cranial autonomic symptoms are common to all, have been reported in men and, in one case, a
but the “sense of restlessness and agitation” is woman with multiple sclerosis. MR imaging for
specific to cluster headaches and hemicrania con- one of these cases showed a pontine demyelin-
tinua and is absent in CPH, SUNCT, and SUNA. ating lesion involving the trigeminal nerve root
Persistent idiopathic facial pain (PIFP), previ- inlet area on the same side as the pain [38–40].
ously termed “atypical facial pain”, is a disorder of Vascular pathology, e.g., aneurysms of the ante-
the face that is often in the differential diagnosis rior [41] or posterior circulation or arteriovenous
of trigeminal neuralgia [33, 34]. In some cases of malformations [42–44], can cause cluster-like
chronic cluster headaches, where patients report attacks that may be indistinguishable from pri-
residual and persistent mild periorbital pain mary cluster headaches [45].
between cluster attacks in the setting of second- Structural pathology in the cervical spinal
ary problems like temporomandibular joint dys- cord in the lower brain stem, e.g., meningioma
function, there may be a concern for PIFP. PIFP [46] or infarction [47, 48], can mimic cluster
symptoms are persistent rather than intermittent, headache attacks. Sellar or parasellar pathol-
and the pain is usually unilateral without auto- ogy, e.g., pituitary adenoma or parasellar menin-
nomic signs or symptoms. gioma, can also mimic clusters [49, 50]. It may
be clinically impossible to distinguish between mapped them in color on T1-weighted MR scans

primary and secondary cluster headaches. Every of the brain in the areas of ipsilateral hypothala-
chronic cluster patient should have at least one mus, anterior cingulate cortex, and other areas
brain imaging in his or her lifetime, preferably an involved in the common pain matrix. Activation
MRI of the brain with orbital views, and also an was observed in three broad categories: (1) areas
MR angiogram to exclude secondary causes, e.g., known to be involved in pain processing, such as
lesions of the cerebral blood vessels or posterior cingulate, insula, prefrontal cortex, and contra-
fossa lesions. lateral thalamus, (2) areas activated specifically
in cluster headache but not in other head pain,
and (3) extra-cerebral areas consistent with large
Pathophysiology and Imaging intracranial blood vessels. Basal ganglia and
Studies cerebellum activation may be accounted for by
preparation for movement, since patients typi-
Previously, the pathophysiological basis for cally like to pace during a cluster. Hypothalamic
cluster headaches was considered to be vascu- hyperactivity ipsilateral to the headache side in
lar: Inflammation of the walls of the cavernous CH was observed during the attacks in all the
sinus was thought to explain all the autonomic PET and fMRI studies [53]. Furthermore, voxel-
symptoms associated with cluster. The cavern- based morphometry (VBM) structural imag-
ous sinus has a convergence of both C-fibers ing shows structural changes in cluster patients
transmitting pain and the sympathetic nerve [54, 55]. NAA/Cr ratio is reduced, and this is a
fibers. Angiograms done on patients while hav- permanent feature of cluster which is an expres-
ing cluster headaches showed vasodilation of the sion of neuronal dysfunction, the mechanism of
ophthalmic artery or engorgement of the venous which is yet unknown. Episodic clusters seem to
plexuses in this area. Other findings include supe- originate in the hypothalamus, and many studies
rior ophthalmic vein narrowing and localized have shown hypothalamic hypometabolism [56].
narrowing of the internal carotid artery during Persistent hypothalamic activation may be the
an acute attack followed by dilation. Increased factor that contributes to generate a central per-
corneal indentation and intraocular pressure and missive state, which predisposes to activation of
skin temperature around the eye during painful the trigeminal system, mediating pain, and of the
attacks have also been reported. parasympathetic reflex, producing the autonomic
The advent of functional neuroimaging has symptoms [57].
debunked the vascular theory, in favor of the Chronic cluster functional neuroimaging
neurovascular theory, which is driven by a cen- seems to suggest that the thalamus may be cen-
tral hypothalamic generator, causing a release tral to the refractory nature of these headaches. A
of proinflammatory vasodilators, e.g., calcitonin PET-CT study with six chronic cluster patients
gene-related peptide (CGRP), vasoactive intes- showed hypometabolism at the level of the thala-
tinal peptide (VIP), neurokinins, and histamine, mus ipsilateral to the cluster pain, suggesting that
with resultant neurogenic inflammation of the a thalamic genesis is a possible origin of refrac-
vasculature. The activation of the trigeminal tory cluster headache [58]. May and colleagues
system during cluster attacks is indicated by the scanned nine chronic cluster patients with H215O
elevation of CGRP plasma levels in the external PET during nitroglycerine-induced attacks and
jugular vein [51]. CGRP is a potent vasodila- were the first to clearly demonstrate inferior
tor and neurotransmitter, and plasma levels are hypothalamic gray matter activation ipsilateral to
elevated during and between cycles of episodic the headache side. Moreover, they observed an
cluster headache [52]. The vascular events are, increased regional cerebral blood flow in the con-
therefore, a marker of brain activation and not tralateral ventroposterior thalamus, the anterior
the driver. May et al. first demonstrated activa- cingulate cortex, and in the insulae bilaterally
tion in acute attacks of cluster headache and as well [59]. Following this observation, others
confirmed these data in a spontaneous headache migraine, many of the acute and preventative
attack of a chronic CH patient during an ongo- treatments for migraine are potentially effective
ing H215O PET study [60]. In refractory chronic for cluster treatment.
cluster patients treated with invasive occipital
nerve stimulation, the hypothalamic hyperactiva-
tion still persists during the stimulator-on condi- Management of Acute Attacks
tion and despite its clinical efficacy [61].
Another important neuroimaging finding is The American Academy of Neurology has pub-
the presence of hypometabolism in the perigenual lished evidence-based guidelines for the treatment
anterior cingulate cortex (ACC) of episodic clus- of chronic cluster [66]. Acute abortive treatment
ter patients scanned interictally. Perigenual ACC should be prescribed to chronic cluster patients to
plays a major role in the central descending opia- treat individual attacks, which often occur many
tergic pain control system, and its deficiency may times daily. All the abortive treatments for epi-
be a mechanism that predisposes to the disorder sodic type may remain effective for chronic clus-
and to its recurrence [52]. The involvement of ter headaches. Since cluster headaches are rapid
the opiatergic system in cluster headache patho- onset and short-lasting, the ideal abortive agent is
physiology and opioid receptor availability in the parenteral, intranasal, or inhaled.
rostral ACC and hypothalamus decreases with
the duration of CH [62], and low-dosage opioid Oxygen
(levomethadone) induces complete and long-last- Oxygen responsiveness is the “sine qua non” of
ing CH remission [63]. Moreover, in refractory clusters, and barring rare cases can be used to
chronic cluster patients who responded to occipi- some degree as a clinical diagnostic test to sepa-
tal nerve stimulation, an increased metabolism rate cluster from other unilateral short-duration
was observed in perigenual ACC in comparison headaches. Oxygen responsiveness is, however,
to nonresponders [61], further underscoring the not a diagnostic criterion for clusters, accord-
fact that one of the pathophysiological mecha- ing to the ICHD-3, even though no other head-
nisms of treatment efficacy in CH is the restora- ache disorder responds to oxygen administration.
tion of normal opioid analgesia. Initial cerebral The pitfall in assessing oxygen responsiveness is
blood flow studies done with SPECT imaging not administering it at a sufficient flow rate, suf-
showed variable results, perhaps due to differ- ficient duration, and with an appropriate mask.
ences in methodology [64, 65]. Inhalation of 100% oxygen, at 7–15 L/min, for
In conclusion, the most striking neuroimag- 15 minutes by a non-rebreather mask is an effec-
ing findings in cluster headache are the posterior tive method to abort cluster attacks [67, 68]. If the
hypothalamic activation during the attacks, with cluster is oxygen-responsive, then it is an effec-
concomitant pain neuromatrix activation and opi- tive means to reduce the need for multiple daily
oid system involvement as underlined by changes doses of other acute abortive medications, e.g.,
in perigenual ACC. triptans, therefore avoiding the issue of rebound
analgesic headache. It is this author’s opinion
that every strictly unilateral headache patient
Treatment should be given at least one oxygen trial during
an acute attack of pain. Sometimes when patients
Management of chronic cluster headache is report being unresponsive to oxygen, it is because
broadly divided into treating acute attacks, add- they have not received an adequate flow rate or
ing long-term preventative treatment to decrease high oxygen percentage or a nasal cannula was
the frequency and intensity of daily attacks, and used instead of a non-rebreather mask. Oxygen
treatment of comorbidities, e.g., insomnia and is effective in 70% or more of patients and may
sleep apnea. It is fortunate that in other than oxy- start working within 5 minutes [69]. However, in
gen therapy that sets cluster headache apart from others, it may take up to 15 minutes to work and
may decrease the impending attack or decrease 5 mg) and the 5 mg nasal spray are both more
the intensity of pain. The author considers a 50% effective than placebo [78–80].
reduction in pain level, a good indicator that oxy-
gen therapy can be used for acute attacks in those Ergotamine Derivatives
patients. A chronic cluster patient may report Dihydroergotamine (DHE) nasal spray can also
an improvement in the continuous “shadow or be effective in the treatment of acute attacks of
aura” discomfort, which may then indicate oxy- cluster headache [81]. The intranasal option of
gen responsiveness during an acute cluster attack. both triptans and ergotamine derivatives may
Hyperbaric oxygen has also been shown to inter- be useful for chronic cluster patients who are
rupt a cluster cycle, but in clinical practice, the treating multiple attacks daily for many years.
cost may be a limiting factor [70]. While there However, with frequent use of DHE, drug holi-
have been no placebo-controlled, double-blinded days are recommended, as there is a risk of
studies of oxygen in the cluster population, it is fibrotic complications affecting the heart, lungs,
universally recognized by headache specialists as and retroperitoneum. Parenteral DHE given either
first-line treatment, based on nearly 75 years of intramuscularly (0.5–1 mg dose) or by intrave-
clinical experience. nous route can be effective, which may provide
rapid relief within a few minutes; however there
Triptans have not been clinical trials on this compound
Sumatriptan: Subcutaneous sumatriptan 3–6 mg for cluster headaches [82, 83]. Oral ergotamine is
is a first-line treatment for acute cluster attacks. generally too slow in onset to provide meaning-
It has a rapid effect, within 5–7 minutes and high ful relief in a timely manner. Some patients may
response rate of about 75% of all cluster headache benefit from rectal ergotamine, but this method is
patients (i.e., pain-free within 20 minutes) [71]. cumbersome and unpopular.
In cluster headache, subcutaneous sumatriptan
can be prescribed at a frequency of twice daily, Lidocaine
on a long-term basis if necessary without risk of Intranasal application of 1 ml of 4–6% lidocaine
tachyphylaxis or rebound [72, 73]. Clinical trials solution ipsilateral to the pain or a spray deep
are underway to assess the efficacy of sumatriptan in the nostril on the painful side results in mild
4 mg subcutaneously, which may allow for three to moderate relief in most patients, though only
times daily dosing [74]. There are auto-injectors a few patients obtain complete pain relief [84].
and a needle-free device that are simple to use, Intranasal lidocaine serves as a useful adjunct to
especially for patients who find it difficult to pre- other abortive treatments but is rarely adequate on
pare the injection in the midst of severe eye pain its own. Intranasal cocaine was historically used
[75]. Chronic cluster patients generally need to take several decades ago, when there were few other
abortive treatment several times daily. Fortunately, choices for treatment, and is not used by clini-
sumatriptan continues to be effective for years and cians anymore [85]. The aim of intranasal appli-
generally is well tolerated. Sumatriptan 20 mg cations is to block the sphenopalatine ganglion,
nasal spray is another option for patients who may which controls the activation of the cranial para-
prefer a non-injectable and less painful treatment sympathetic outflow from the superior salivary
option [76]. Sumatriptan 100 mg oral tablets three nucleus of the facial nerve and is responsible for
times daily taken prior to an anticipated onset of the autonomic features of cluster headache [86].
an attack or at regular times does not prevent the
attack, and regular oral triptans may induce medi- Octreotide
cation-overuse headache in susceptible patients, so Matharu et al. showed that octreotide 100 μg
this approach is generally not recommended [77]. when administered subcutaneously is effective
Zolmitriptan is an additional medication with in aborting an acute attack with the headache
a fairly rapid onset of action that is very well response rate of 52%, whereas that with placebo
tolerated by patients. Oral zolmitriptan (2.5 or was 36% [87].
Indomethacin Busch has demonstrated functional connectivity

Cluster headache is one of the TACs that does not between the ophthalmic branch of the trigeminal
respond to indomethacin; however, there have and sensory occipital nerves in humans, but it is
been some case reports of chronic cluster head- still unclear as to which level in this pathway the
aches responding to either 50 mg intravenous GON produces its inhibitory effect. Our recom-
indomethacin [88] or oral indomethacin [89]. It is mendation for clinicians is similar to that of the
unclear whether these patients had undiagnosed expert consensus, to use corticosteroids in com-
CPH which can mimic cluster and response to bination with a local anesthetic [96].
indomethacin is typical.
Other Drugs Long-Term Prophylactic Treatments

Opiates, nonsteroidal anti-inflammatory drugs
(NSAIDs), and combination analgesics have no The aim of long-term preventive therapy in
role in the acute management of cluster headache. chronic cluster patients is to decrease the fre-
quency and intensity of daily attacks, to shorten
reater Occipital Nerve (GON) Injection
G a cluster cycle and to maintain remission with
There are consistent data that support the use minimal side effects for a longer period. There is
of GON injections of steroids to abort an acute very little data on the use of preventative agents
cluster attack; however, they generally provide in chronic cluster patients, and most of the infor-
only temporary relief in chronic cluster [90]. mation below pertains to the episodic patient.
Anthony reported that cluster attacks could be The lack of data for chronic cluster should not
arrested by GON injections in 1985, using a prevent the clinician from trying preventative
mixture of short- and long-acting corticosteroids agents that have shown effectiveness in episodic
[91]. Subsequently this has been confirmed by cluster headaches.
many studies on episodic cluster and a double-
blind, placebo-controlled trial with a mixture of Verapamil
short- and long-acting steroids on cluster patients Currently, verapamil is the preventative drug of
[92, 93]. Lambru et al. performed GON unilat- choice in both episodic and chronic cluster head-
erally in an open-label prospective study on 83 ache [28–30]. Clinical experience has demon-
chronic cluster patients at 3-monthly intervals strated that higher doses are needed than those
and showed an overall positive response in 57% typically used in cardiologic indications. The
patients after the first injection of a combina- most common side effects include constipation,
tion of steroids and lidocaine [94]. There has dizziness, nausea, hypotension, pedal edema, and
been debate however as to why these blocks fatigue. Verapamil can cause heart block by slow-
work and whether their effect is due to steroids, ing conduction in the atrioventricular node. About
anesthetic, or both. Busch et al. performed sub- 20% of cluster headache patients on verapamil
occipital injections of 1% lidocaine on cluster have cardiac conduction problems, and these can
patients and found that local anesthetic alone develop after months of stable dosing and are not
was not effective in terminating cluster headache dose-dependent [31]. Observing for PR interval
attacks [95]. Clinical studies have had mixed prolongation on ECG can monitor for the poten-
results perhaps due to the variations in types of tial development of heart block. After performing
steroids and anesthetics used and also differing a baseline ECG, patients are usually started on
injection techniques. With regard to the possible 80 mg three times daily, and thereafter the total
mechanism of action of GON in cluster, it is still daily dose is increased in increments of 80 mg
unclear whether it is a systemic steroid effect every 10–14 days. Dosages commonly employed
or due to inhibition of central pain-processing range from 240 to 960 mg daily in divided doses.
mechanisms at the brainstem level. Using occipi- The author usually switches to the long-acting
tal nerve blockade and nociceptive blink reflexes, version of verapamil, after the effective daily
dose of the shorter-acting version is reached. An the number of nighttime attacks and can be
ECG is performed prior to each dose increment. used at doses between 1 and 10 mg depending
The dose is increased until the cluster attacks are on the patient preference. Several double-blind
suppressed, significant side effects intervene, or clinical trials have shown melatonin to be effec-
the maximum dose of 960 mg daily is achieved. tive [102, 103].
ECGs should be performed periodically with
long-term therapy. Corticosteroids
Corticosteroids are highly effective and the most
Lithium rapid-acting agent for achieving remission during
Lithium is an effective agent for cluster head- an acute episodic cluster period but not useful,
ache prophylaxis, with 78% of chronic cluster for safety reasons, in chronic cluster headaches.
patients achieving remission of attacks, and some They are widely used for episodic cluster to ter-
consider a first-line treatment for chronic cluster minate a cycle and achieve remission; however
headache [97, 98]. Since it is effective at lower there are no clinical trials. Treatment should be
doses than typically needed for bipolar disorder, limited to a short intensive course of a tapering
it can be used very successfully to treat chronic dose because of the potential for side effects.
clusters. Typical starting dose is 150 mg twice The starting dose of oral prednisolone 1 mg/kg
daily, and the dose can be titrated up to 1200 mg to a maximum of 60 mg once daily for 5 days
daily. Lithium has a long half-life and may take is an acceptable dose widely used by neurolo-
up to 1 week to become effective, at which time gists. Treatment should be limited to 2–4 weeks
serum level should be checked. The therapeutic and tapered down by 5–10 mg every 3–5 days.
range for chronic cluster is likely lower (0.4– In this way, the risk of side effects due to long-
0.8 mol/L) than for mania (0.8–1.1 mol/L) [99], term steroid use (diabetes, hypertension, avas-
but the therapeutic level in cluster headache has cular necrosis of femoral heads) is minimized.
not been established. Side effects of lithium are Unfortunately, recurrence often occurs as the
dose-dependent and include nausea, tremor, leth- dose is tapered. For this reason, corticosteroids
argy, blurred vision, and diarrhea at lower doses are used as an initial therapy in conjunction with
and confusion, ataxia, extrapyramidal signs, preventives, until the latter are effective. Oral and
and seizures at higher doses. Side effects from intravenous formulations have also been success-
long-term use include hypothyroidism and neph- fully used in combination [104].
rogenic diabetes insipidus. Therefore renal and A recently study showed that in parallel with
thyroid function tests should be performed prior the decrease in cluster frequency after corticoste-
to initiation of therapy and at least on a 3-monthly roid administration, there was decrease in plasma
basis. The concomitant use of NSAIDs, diuretics, CGRP levels and an increase in the urinary excre-
verapamil, and carbamazepine requires careful tion of melatonin metabolites [105], which is
monitoring, as they can increase the serum levels indirect evidence that steroids decrease the acti-
of lithium. vation of the trigeminal system and modulate the
hypothalamic pathways.
Melatonin
In cluster patients, there is disruption of the Triptans
biological clock in the suprachiasmatic nucleus Whereas the short-acting triptans are used for
(SCN) of the hypothalamus, which regulates the acute abortive treatment of cluster attacks, several
circadian secretion of melatonin from the pineal long-lasting triptans may produce a longer dura-
gland, mostly at night. Hypothalamic dysfunction of therapeutic action, with the potential for
tion in cluster is reflected by altered melatonin use as prophylactic agents [106]. Frovatriptan,
production in patients during an attack cycle, as the triptan with the longest half-life (about 26 h)
well as between cycles [100, 101]. Melatonin [107], has been used to prevent nighttime cluster
supplementation can be effective in reducing attacks [108]. Another relatively longer-acting
triptan, naratriptan, has also been used for pre- is very little evidence to support its intrave-
ventative treatment, though mostly in the setting nous use at this time. Intravenous valproate is
of acute clusters [109–111]. Short-term prophy- very well tolerated, and the author has used it
laxis can be provided with other longer-acting to achieve remission of cluster attacks in two
triptans like eletriptan, but its long-term use episodic cluster patients. Oral sodium valpro-
in chronic cluster headache remains to be seen ate can be an effective preventative treatment
[112]. These triptans may be useful as add-on to to achieve pain remission in episodic cluster
other preventative treatment, reducing the num- patients [121, 122]. There are several boxed
ber of daily attacks in the chronic cluster patients, warnings for this drug, including hepatotoxic-
assuming that the acute medications being used ity, pancytopenia, and pancreatitis, and there
can be used concomitantly. is a risk of fetal malformations. Baseline liver
function testing should be obtained, and a thor-
Antiepileptics ough discussion regarding effects on fetus and
In the last decade, tremendous experience has potential for polycystic ovary disease is man-
been gained in treating migraine headaches with dated in females of child-bearing age. The
antiepileptics. They have been utilized to treat extended release version is very useful, with
clusters, and this class of agents has emerged as starting dose of 250 mg, titrating weekly to
an option for chronic cluster patients. The dosing 1000–1500 mg.
of antiepileptics is the same as typically used for Zonisamide has been used in both episodic and
migraine headaches. chronic cluster patients with good response. It is
Topiramate is an FDA-approved migraine generally very well tolerated with minimal side
preventative agent and is generally well toler- effects. Recommended doses are similar to those
ated. Topiramate was effective in achieving for epilepsy, and once nightly dose of 100 mg can
remission of two chronic cluster patients [113]. be titrated up every 2 weeks to 600 mg daily. Due
There are several studies that show its effective- to very long half-life, effective levels may take
ness as a preventative agent in episodic cluster several weeks to be achieved.
[114–117]. Starting dose of 25 mg at bedtime S-lysergic acid diethylamide (LSD) and psilo-
and titrating up gradually to a dose of 100– cybin, which are controlled hallucinogen drugs,
200 mg is recommended. There is a long-acting may abort an acute cluster attack, terminate the
version of topiramate now available, which may cluster cycle, and delay the next expected clus-
be better tolerated. Well-known side effects ter period [123]. Interestingly, these drugs were
include a small risk of kidney stones, pares- effective at subhallucinogenic doses, and effec-
thesias, weight loss, and cognitive side effects. tive treatment required only 1–3 doses [124]. A
Topiramate can also sometimes heighten anxi- 2006 survey of 53 cluster headache reported that
ety, which is already heightened in many cluster psilocybin extended remission periods in 10%
patients. cases [125]. However, controlled trials of these
Gabapentin has also been shown to be effec- agents are lacking.
tive in treating chronic cluster patients in several Calcitonin gene-related peptide (CGRP) is a
small series [118–120]. There is a long-acting marker of trigeminal system activation and plays
version of gabapentin, which has not been tested an important role in the pathogenesis of migraine
for cluster headaches but might provide some and likely of cluster. Therapeutic blockade of this
benefit, especially with nighttime dosing. peptide has emerged as an important target in the
Divalproex sodium has the advantage of treatment of migraine [126–128]. There are now
an intravenous formulation and therefore can results from randomized controlled phase III tri-
be used in an acute setting, for example, in a als using monoclonal antibodies specifically for
headache infusion center, to provide a rapid chronic cluster headache which are strongly posi-
loading dose, which can be maintained orally tive [129], but these agents are not yet commer-
on a long-term basis for prevention, but there cially available.
Methysergide was one of the few drugs avail- Intranasal Agents

able in the 1960s and the 1970s for migraine Intranasal application of capsaicin cream has
prevention and has shown to be effective in pre- been shown in three studies to be effective in
venting cluster attacks [130]. It is a consideration preventing episodic cluster attacks [138–140]. A
in patients with short cluster periods that last less single study has also shown that intranasal appli-
than 4–5 months. Because methysergide is an cation of civamide is effective in preventing epi-
ergot, if used for prevention, triptans and similar sodic cluster attacks [141].
agents cannot be used for rescue. It is rarely used
by clinicians because of potentially serious side
effects; prolonged treatment has been associated Interventional and Surgical
with rare fibrotic reactions (retroperitoneal, pul- Treatment
monary, pleural, and cardiac). Methysergide is
administered at a daily dose of 4–8 mg and can Refractory cluster patients who have failed medi-
be increased up to 12 mg (starting with 1 mg/ cal treatment may be candidates for neurosurgical
day). A drug holiday of 1 month, after every procedures or, more recently, for neurostimula-
6 months of methysergide treatment, is required, tion. The main targets of destructive procedures
along with imaging for evidence of pulmonary, or neurostimulation include the sphenopalatine
cardiac, renal, or abdominal pathology yearly ganglion, trigeminal ganglion, occipital nerve,
in patients on prolonged methysergide therapy. vagus nerve, and hypothalamus.
Methysergide is now no longer available in the
United States. phenopalatine Ganglion (SPG)-
S
Clomiphene citrate is another agent which in Targeted Procedures
three case reports has been shown to achieve com- The SPG can be blocked only temporarily by
plete remission of headache attacks, at 100 mg/ intranasal topical application of local anesthetic,
day dose in chronic cluster headaches [131, 132]. and the aim of invasive procedures is to perma-
The mechanism of action of clomiphene in cluster nently destroy the SPG by surgery or radiofre-
headache may be due to its ability to enhance tes- quency ablation. The most invasive procedure on
tosterone production and to bind to hypothalamic the SPG, ganglionectomy, was reported in 1970
estrogen receptors. In chronic cluster patients, it on a series of 13 refractory cluster patients, of
may be useful to check serum testosterone levels, which only 2 patients achieved pain remission
since testosterone replacement therapy given to [142]. In 2009, a study reported percutaneous
supplement low serum levels can result in remis- radiofrequency ablation of the SPG via the infra-
sion of refractory cluster headaches [133]. zygomatic approach under fluoroscopic guid-
Pizotifen is widely used in Europe but is not ance on 15 refractory chronic cluster headache
available for use in the United States. The typical patients. There was a significant improvement in
dose is 3 mg/day. Side effects commonly seen are mean attack intensity, mean attack frequency, and
fatigue and weight gain. pain disability index up to 18 months after proce-
dure. The authors noted that precise needle place-
Antihistaminics ment with the use of real-time fluoroscopy and
Histamine has been implicated in the pathogen- electrical stimulation prior to attempting radio-
esis of cluster. Spontaneous cluster attacks in frequency ablation may reduce the incidence of
some patients are associated with increased uri- adverse events [143]. The side effects from these
nary excretion of histamine [134], and whole destructive procedures of the SPG include per-
blood histamine levels show a statistically signif- manent hypesthesia or dysesthesia in the palate,
icant rise during attack [135]. However double- maxilla, or posterior pharynx, and therefore these
blind controlled trials of histamine antagonists are not commonly recommended.
were ineffective in treating cluster headaches Recently, however, there is emerging evidence
[136, 137]. that stimulation, rather than ablative procedures
on the SPG, may be more effective in long-term abandoned due to risk of corneal injury and the
therapy. Initial studies used temporary electrical dreaded pain of anesthesia dolorosa.
stimulation. Electrical stimulation using a tempo- Taha et al. reviewed a series of seven patients
rary stimulating electrode and a standard percu- with chronic cluster headache refractory to medi-
taneous infrazygomatic approach with a needle cal treatment who received percutaneous stereo-
placed in the ipsilateral SPG in the pterygopala- tactic radiofrequency rhizotomy and reported
tine fossa under fluoroscopic guidance was used variable effects ranging from no relief to pain-free
to abort an acute cluster attack in five refractory at 20 years follow-up [148]. Destructive surgery
chronic cluster patients [144]. Shytz reported for block trigeminal sensory or autonomic pathways
the first time that low-frequency SPG stimulation should only be considered in patients with strictly
might induce cluster-like attacks with autonomic unilateral attacks, as those whose attacks alter-
features, which can subsequently be treated by nate sides may find an upsurge of attacks on the
high-frequency SPG stimulation. Efferent para- side contralateral to surgery. Sometimes, cluster
sympathetic outflow from the SPG may initiate attacks persist even after complete destruction
autonomic symptoms and activate trigeminovas- of the trigeminal sensory pathway [149]. Ford
cular sensory afferents, which may initiate the et al. reported on a series of six who were treated
onset of pain associated with cluster headache for refractory cluster headache by Gamma Knife
[145]. radiosurgery of the trigeminal nerve root entry
The authors suggested that high-frequency zone. The maximum dose of radiation was 70 Gy
SPG stimulation might exert its effect by physio- to the isocenter. Pain-free state was obtained in
logically blocking parasympathetic outflow. This four of the patients with minimal side effects, and
led to the Pathway CH-1 study, which is a ran- the onset of action was a few days to a week. The
domized, sham-controlled study of implantable main drawback of Gamma Knife radiosurgery is
on-demand SPG neurostimulator in patients with the unpredictability of the degree, the duration,
refractory chronic cluster headaches. Twenty- and even the likelihood of a positive response.
eight patients completed the randomized experi-
mental period, and pain relief was achieved in Occipital Nerve-Targeted Therapy
67% of stimulation-treated attacks compared to Since 2007, occipital nerve stimulation has been
7.4% of sham-treated (p < 0.0001). Nineteen of used in treating refractory chronic migraines
28 (68%) patients experienced a clinically sig- [150, 151] and used to successfully treat refrac-
nificant improvement. Five adverse events were tory chronic cluster headaches as well [152].
reported that included transient, mild/moderate Burns et al. reported a retrospective assessment
loss of sensation within distinct maxillary nerve of 14 patients with medically intractable CCH,
regions. This implantable on-demand SPG stimu- implanted with bilateral electrodes in the suboc-
lation using the ATI Neurostimulation System is cipital region for occipital nerve stimulation, and
now approved in Europe and has dual beneficial at a median follow-up of 17.5 months, 10 of 14
effects, acute pain relief and attack prevention, patients reported improvement in the number of
with an acceptable safety profile compared to daily cluster attacks [153]. Fontaine et al. reported
similar surgical procedures [146]. a series of 13 patients with medically refractory
chronic cluster, of whom 10/13 showed improve-
Trigeminal Ganglion-Targeted Therapy ment in their daily attack rate by >50% that
In one clinical series reported in 1987, seven was sustained beyond 12 months [154]. More
therapy-resistant patients with cluster head- recently, Miller et al. reported a cohort of 51
ache (six of whom were chronic) were treated chronic cluster headaches, which decreased daily
by percutaneous retro-gasserian glycerol injec- attacks by 46% and reduced triptan use by 65%
tions under general anesthesia. Cluster attacks [155]. There is one case of successful treatment
did cease but only temporarily [147]. Injection of chronic refractory drug-resistant cluster head-
of glycerol in the trigeminal ganglion has been aches with a combined supraorbital and occipital
nerve stimulator [156]. Stimulator placement is The Cluster Patient Perspective

an invasive procedure that requires general anes-
thesia, and long-term adverse events of concern The European Headache Alliance collected a list
include lead migration and battery depletion. of recommendations from cluster patient asso-
ciations with the purpose of improving overall
Vagus Nerve-Targeted Therapy cluster headache management. The seven recom-
Noninvasive VNS (nVNS), which stimulates the mendations that have emerged for physicians tak-
carotid vagus nerve with the use of a personal ing care of clusters include the following:
handheld device, has been tested for chronic
migraine and showed promising results [157]. 1. Cluster headache diagnosis is easy if you con-
Recently, the US Food and Drug Administration sider few clinical clues.
(FDA) has approved a handheld, neck-applied 2. Prescribe sumatriptan and oxygen.
noninvasive vagus nerve stimulation device 3. Suggest patient avoid hiding and be active in a
(gammaCore) for the treatment of pain from epi- patients’ support group.
sodic cluster headache in adults. The FDA release 4. Take patient seriously and listen to him/her.
was based on the prospective, placebo-controlled 5. Provide quality information and address

ACT1 and ACT2 trials. In ACT1, Silberstein myths about cluster treatment.
et al. enrolled 85 participants with episodic clus- 6. Be sensitive to cluster impact on the patient’s
ter headache; 34% of those in the vagus nerve significant other.
stimulation group reported pain reduction after 7. Acknowledge that cluster is a serious medical
treatment vs. 11% of the placebo group [158]. disorder that can have a significant impact on
ACT2 assessed 27 patients, with 182 total the person and support him/her [164].
attacks. Results showed 47.5% of those treated
with the active device were pain-free 15 min later In summary, chronic cluster headaches are
vs. 6.2% of those receiving placebo [159]. Gaul debilitating and challenging for the clinician and
et al. showed that prophylactic treatment with patient. However, there is more awareness now
VNS can lead to rapid, significant, and sustained within the medical community and among the
reductions in chronic cluster headache attack fre- general public, and the chances of early recog-
quency within 2 weeks after its addition to usual nition are higher. Functional imaging modalities
standard of care [160]. Since the nVNS device is have made it possible to better understand the
safe with no major side effects, once available in neuroanatomy and pathophysiology of chronic
the market, it may be considered for treatment of cluster headaches. A larger repertoire of medi-
acute attacks in chronic cluster patients. cations and surgical options are available for
the clinician. There is a need for randomized
Hypothalamic-Targeted Therapy clinical trials to test many of the treatments that
Stereotactic stimulation of posterior hypothalamic have anecdotally been effective in treating these
gray matter in a patient with intractable clus- patients.
ter headache was first performed in Italy [161].
Subsequently hypothalamic neurostimulators
implanted by Franzini’s group were successful in
treating refractory chronic clusters; however, this
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New Daily Persistent Headache
7
Lauren R. Natbony, Huma U. Sheikh,
and Mark W. Green
Introduction migraine and/or tension-type headache [2]. Most

patients have mild to moderate pain intensity
New daily persistent headache (NDPH) was first which is bilateral, although there can be varia-
described by Vanast in 1986 as a “benign syn- tions. It typically presents in individuals with no
drome, combining features of common migraine prior headache history.
and tension headache and occurs (sic) daily from
the first day the headache begins” [1]. It is cur-
rently classified as a type of primary long-dura- Epidemiology
tion chronic daily headache (CDH), of which
there are three additional types: chronic migraine There have been only a handful of studies to help
(CM), chronic tension-type headache (CTTH), determine epidemiology, although most of them
and hemicrania continua (HC). What makes have similar results. Castillo et al. in 1999 looked
NDPH unique is that it starts abruptly and is at 2252 subjects in Spain and found that the prev-
daily from onset. Many patients will remember alence of NDPH was around 0.1% [3]. In 2002,
the exact day of onset, and some will be able to Bigal reported NDPH to be about 10% of patients
describe exactly what they were doing at the time who presented to a headache specialty clinic, as a
the headache started. The pain of NDPH lacks subset of patients with chronic daily headache [4].
characteristic features and may have elements of Most recently in 2009, Grande et al. determined
a 1-year prevalence of 0.03% [5]. NDPH also
appears to be slightly more prevalent in the pedi-
L. R. Natbony (*) atric population, with 13% of pediatric patients
Neurology, Center for Headache and Facial Pain, with CDH having a diagnosis of NDPH [6]. Other
Icahn School of Medicine at Mount Sinai, reports have confirmed this slightly higher preva-
New York, NY, USA lence among the adolescent population [7].
e-mail: lauren.natbony@mountsinai.org
The most common age of onset of NDPH
H. U. Sheikh appears to be in the third and fourth decades.
Neurology, Mount Sinai, New York, NY, USA
In Vanast’s 1986 study, the age of onset was
M. W. Green reported to be between 16 and 35, with ear-
Neurology, Icahn School of Medicine at Mt. Sinai,
New York, NY, USA lier onset in women [1]. In 2002, Li and Rozen
conducted a retrospective review over a 3-year
Anesthesiology, Icahn School of Medicine at Mt.
Sinai, New York, NY, USA period with a total of 56 patients diagnosed with
primary NPDH. They found the peak age of onset
Rehabilitation Medicine, Icahn School of Medicine at
Mt. Sinai, New York, NY, USA in the teens and 20s for women and in the 40s for

98 L. R. Natbony et al.
men [8]. Other studies have shown that the age is more persistent and refractory [2]. There is the
range for onset can be from 6 to 70, with a mean possibility to diagnose someone with “probable
of 35 years of age [9]. In the cohort by Robbins NDPH,” if the 3-month timeline has not been
et al. of 71 patients, the median age of onset was met; however, this is put in place to prevent mis-
26 in women and 28 in men. They also noted that diagnosis [15].
most patients were female (71.8%) and Cauca- The latest diagnostic criteria do not mention
sian (80.3%) [10]. In the latest study published any particular phenotype of the headache. This
by Rozen in 2016, the average age of onset was was updated after much controversy regarding
reported to be in the mid-30s [11]. the diagnostic criteria, which previously did not
allow for the presence of migrainous features
[16]. The ICHD-3 does not preclude a diagno-
Diagnostic Criteria sis of NDPH in those with history of headache,
even those with CM or CTTH. It specifies that,
The diagnostic criteria have evolved over time. if a prior headache history does exist, the patient
While the first diagnostic criteria for NDPH must not report an increasing frequency of that
were proposed in 1994 in the Silberstein-Lipton headache prior to onset of NDPH. Moreover,
classification of CDH, the condition was not patients should not describe an exacerbation fol-
included in the International Classification of lowed by a period of medication overuse [2].
Headache Disorders (ICHD) until 2004 with the
publication of ICHD, 2nd edition (ICHD-2). In
the Silberstein-Lipton criteria, the components ICHD-3 Diagnostic Criteria for NDPH
needed to diagnose NDPH included (1) headache A. Persistent headache fulfilling criteria B
for 15 or more days per month, (2) for more than and C
3 months, (3) lasting more than 4 h/day, and (4) B. Distinct and clearly remembered onset,
beginning abruptly over fewer than 3 days with- with pain becoming continuous and
out being preceded by increasing frequency of unremitting within 24 h
migraine or tension-type headache. A subdivision C. Present for >3 months
of NDPH was also proposed based on the pres- D. Not better accounted for by another

ence of medication overuse [12]. In the ICHD-2, ICHD-3 diagnosis
the diagnostic criterion was phenotypically a ten-
sion-type headache that started abruptly and was
continuous from onset [13]. It excluded patients
with prominent migraine features. In 2008, Kung Clinical Features
et al. proposed a more simplified criteria that did
not include the presence or absence of migrain- The most prominent clinical feature is continu-
ous features [14]. ous pain from onset [10]. Most patients identify
In the newest edition of ICHD, ICHD-3 beta, the day or month when the headache first began.
NDPH is an abrupt onset of primary chronic Some are even able to remember the exact time
daily headache at a specific time remembered the headache started and exactly what they were
by the patient. The onset of CDH occurs within doing. Grande and Aseth conducted a cross-sec-
24 hours and remains continuous from onset with tional study of the Norwegian population using a
no remissions and no pain-free periods. Head- headache questionnaire and follow-up interview.
ache must be continuous for more than 3 months. Headaches were classified according to ICHD-2
Secondary causes first need to be ruled out. The criteria. In the total of four patients who were
key to diagnosis lies in the patient’s recollection classified as having NDPH, all of them were able
of abrupt onset of headache. The latest version to recall the exact day of onset of their headache,
now has two subtypes, one that is self-limited and and all previously recalled infrequent tension-
usually resolves without treatment and one that type headaches [5]. In the retrospective review
7 New Daily Persistent Headache 99
by Li and Rozen, 82% of the 56 patients could overuse was present in about 45% of patients
point to the exact day when headache symptoms [10]. Grande and Aaseth also found that three of
began [8]. This percentage was lower in another the four patients in their study with NDPH were
study, showing about 42.3% of 71 patients with believed to have an element of medication-over-
NDPH recalled the day of onset of headache, use headaches [5].
with almost double remembering the month of A large percentage of patients with NDPH
onset [10]. Grengs and Mack described NDPH have a prior history of headache. In the case
in a population of children. They reviewed 104 series from Robbins et al., about 25% had
patients with NDPH, and 92 of them were able to another primary headache disorder prior to the
remember the month of onset [17]. onset of NDPH, most commonly either tension-
Multiple studies consistently show that type or migraine [10]. In Li and Rozen’s 2002
patients with a diagnosis of NDPH commonly study, about 38% of patients noted that they
have associated features that are typical of had a previous history of episodic headaches,
migraine, including nausea, photophobia, and either migraine or tension-type headaches.
phonophobia [8]. These symptoms are typically None reported chronic daily headaches in the
intermittent and may occur with exacerbations of past or escalation of headache frequency prior
baseline pain. There are also rare case reports that to the onset of NDPH [8]. Thus, abrupt onset
describe a visual aura or bilateral facial flushing of continuous daily headache in a patient with
[10]. Even in the first case series described by a history of episodic headache is suspicious for
Vanast, some of the patients had migrainous fea- NDPH.
tures though many of the patients also reported Comorbidities are common in NDPH patients.
other neurological symptoms, including dizzi- A recent article by Uniyal et al. assessed 55
ness, diplopia, or tinnitus [1]. The prognosis in patients with NDPH compared to age- and sex-
this first case series was different from subse- matched healthy individuals with chronic low
quent studies, and, therefore, it was unclear if back pain. They found significantly higher rates
these were all truly primary NDPH. In an epi- of psychiatric comorbidities, including anxi-
demiological study by Grande and Aaseth, they ety, depression, somatoform disorders, and pain
detected a total of four patients from the gen- catastrophization in patients with NDPH [18]. In
eral population with NDPH, two of whom had a cohort of 71 NDPH patients, about a third of
migrainous features including photophobia and patients also reported a history of either anxiety
nausea [5]. or depression [19]. Other frequent comorbidities
Robbins et al. studied a group of 71 patients were hypertension and hyperlipidemia [10].
with daily headaches using ICHD-2 criteria for
NDPH. They compared this group to another
group labeled NDPH-R, in whom migrainous Etiology and Pathophysiology
features were not excluded. NDPH diagnosis was
made using revised ICHD-2 criteria, according Currently, the exact pathogenic mechanism that
to Kung et al., and designated as NDPH-R. They underlies NDPH is unknown though there are
found that there were 40 extra patients that several proposed etiologies. Some of the confu-
would be classified with NDPH if migrainous sion arises because it is not clear whether this is a
features were included in the diagnostic criteria single type of headache disorder or there are mul-
[14]. The majority of patients described bilateral tiple pathologies with a similar presenting phe-
pain, and the baseline pain was in the range of notype [11]. Some have argued that NDPH is a
4–6/10. Including all patients, according to both syndrome and not a discrete disorder [20]. Rozen
criteria, 45.1% of patients described throbbing did a retrospective analysis of medical records
pain, and almost 90% described bilateral pain. of patients who were diagnosed with NDPH. A
Nausea, photophobia, and phonophobia were headache specialist saw all the patients at a head-
present in about half of patients. Medication ache clinic from 2009 to 2013, and secondary
NDPH was ruled out by imaging and history. Stressful Event

These patients were asked about a triggering In the Li and Rozen series, 12% of patients attrib-
event prior to the onset of their NDPH. Ninety- uted onset of headache to a stressful life event
seven patients were identified in this study with [8]. Stress is thought to be a causative factor for
NDPH. Of those, 65 were women and most the development of chronic headaches in general.
were Caucasian. A little more than half could
not recognize a triggering event. For those who Surgical Procedure
could, 22% remembered a flu-like illness prior In the 2002 review by Li and Rozen, about 12%
to NDPH, 9% remembered a stressful event, 9% attributed the onset of their headaches to a sur-
recalled surgical procedure prior to onset of their gical procedure [8]. In Rozen’s 2016 retrospec-
NDPH, and the rest (about 7%) recognized some tive analysis, about 9% of patients with NDPH
other event, including medication exposure or a had onset of their headache after a surgical pro-
syncopal event [21]. Further studies have verified cedure. Most of the patients who had onset of
these results along with pointing out a few other NDPH after a surgical procedure were intubated,
triggers including tapering of SSRIs, exposure and all of them also had associated greater occip-
to the HPV vaccine, and menarche [10]. There ital nerve and upper cervical facet irritation dur-
was not much difference in the triggering events ing their exam on initial visit [21]. This finding
across genders [8]. has led to a hypothesis that cervical arthritis and
upper cervical facet irritation may be a risk factor
for the development of NDPH [8].
Triggering Events While not a triggering event, per se, cervical
joint hypermobility has been postulated to be a
lu-Like Illness or Infection
F potential cause of NDPH. Rozen and colleagues
A flu-like illness or infection has been postu- noticed similar physical characteristics of tall
lated in many case series as a triggering event. stature with thin body habitus and long necks in
This finding has led to the theory of increased 12 patients with NDPH. Hypermobility of the cer-
inflammation of the central nervous system as vical region was noticed to be a pervasive sign on
a possible causative factor. In the series by Li exam in 11 of the 12 NDPH patients. Widespread
and Rozen in 2002, about a third of patients systemic joint hypermobility was seen in 10 of
noted that their headaches started in relation the 12 patients [25]. As joint hypermobility is a
to a flu-like or other infection [8]. A study by risk factor for the development of chronic pain
Rozen and Swidan found that a significant per- in the rheumatology literature, the authors con-
centage of patients (19/20) with primary NDPH cluded that cervical spine hypermobility might
had elevated tumor necrosis factor alpha (TNFα) be a predisposing factor for the development of
(a cytokine believed to be involved in inflam- NDPH. It is thought that cervical hypermobil-
mation) in the cerebrospinal fluid (CSF) [22]. ity can bring on headaches since there is a con-
Since a viral illness is frequently thought to be vergence of trigeminal and cervical afferents in
a triggering event, some surmise that the initial the trigeminal nucleus caudalis [26]. Of course,
inflammation becomes ongoing in these patients, spontaneous CSF leak can result in a phenotypi-
leading to the chronic headache of NDPH [23]. cally similar headache and is more common in
TNFα has been known to induce calcitonin this same population.
gene-related peptide production, a factor in the
development of pain syndromes based in the tri-
geminal pathway [24]. In the initial case series Differential Diagnosis
by Vanast, 84% had elevated EBV titers out of
32 patients described to have NDPH [1]. This The differential diagnosis for new daily head-
finding has added to the theory that a viral infec- aches is broad and includes both primary and
tion may bring on this headache disorder. secondary headache types (Table 7.1).
Table 7.1 Differential diagnosis of new daily headaches CTTH, like CM, develops in a minority of
present for >3 months
episodic tension-type headache (ETTH) patients
Primary headaches Secondary headaches in the setting of escalating attack frequency.
New daily persistent Intracranial hypotension Just like in CM, the diagnosis of CTTH may be
headache
missed in patients diagnosed with NDPH due to
Chronic migraine Intracranial hypertension
Chronic tension-type Cerebral venous sinus underestimation or under-recognition of preexist-
headache thrombosis ing ETTH attacks.
Hemicrania continua Postmeningitis/chronic HC is a strictly unilateral, continuous head
meningitis pain accompanied by ipsilateral cranial autonomic
Medication overuse signs during periods of headache exacerbation. It
Sphenoid sinusitis
responds absolutely to therapeutic doses of indo-
Posttraumatic headache
methacin [2]. Like NDPH, HC typically starts as
Chronic subdural hematoma
Neoplasm/mass lesion
daily and continuous from onset. While HC was
Giant cell arteritis previously diagnosed only with ipsilateral head
Carotid/vertebral artery pain, many cases of HC featuring bilateral head
dissection pain responding definitively to indomethacin have
Cervical facet syndrome now been reported [29]. Additionally, 11% of cases
(cervicogenic) of NDPH may be unilateral, and cranial autonomic
Intranasal contact point
headache
symptoms may be present with exacerbations
Arteriovenous malformation in 26% of patients [9]. Thus, symptom overlap
Dural arteriovenous fistula between these two syndromes can occur, and a trial
Chiari malformation of indomethacin may be needed to rule out HC. In
Temporomandibular joint NDPH, pain may improve temporarily with indo-
dysfunction methacin; however it will not be abolished.
Adapted from Evans [9]
Secondary Headaches (NDPH Mimics)

Primary Headache Disorders
A diagnosis of NDPH can be made only after sec-
NDPH is one of four headache types in the CDH ondary causes are excluded. The more recent the
category that also includes CM, CTTH, and onset of NDPH, the more concern there should be
HC. It is possible that many NDPH patients have for secondary causes. Secondary pathology should
one of these disorders and are misclassified. be especially considered when NDPH occurs over
CM is fairly prevalent in the population and the age of 50. New-onset daily headaches with a
develops in persons who have a history of epi- normal neurologic examination can be due to var-
sodic migraine (EM) in the setting of increasing ious other causes especially when seen within the
attack frequency [2]. The process of transforma- first 2 months after onset. When headaches have
tion from EM to CM is typically gradual over been present for more than 3 months with a nor-
several weeks to months or even years [27]. This mal neurologic examination, the yield of testing
gradual transformation distinguishes CM from is low. Two disorders in particular that can mimic
NDPH. It is possible that patients with NDPH the presentation of NDPH are spontaneous CSF
simply have CM with an abrupt onset in the set- leak and cerebral venous sinus thrombosis. Addi-
ting of an environmental trigger. In a study by tional secondary causes are discussed below.
Mack of a group of pediatric patients with CDH,
he found that 30% of patients with CM reported pontaneous Intracranial Hypotension
S
an abrupt transition from EM. He concluded that Spontaneous intracranial hypotension (SIH)
pediatric patients with or without a headache his- from a spinal CSF leak typically presents as
tory could develop an acute CDH [28]. daily headache with a positional component. The
pain is generally not present on waking, worsens obscurations, pulsatile tinnitus, abducens nerve
during the day, and is relieved by lying down. palsies, and varying visual field defects, it can
However, the longer a patient has a CSF leak- also present with severe daily headache without
induced headache, the less pronounced the posi- evolution. Neurologic examination typically
tional component becomes. Thus, since patients shows papilledema in IIH; however, IIH without
who are ultimately diagnosed with NDPH pres- papilledema is an increasingly recognized entity
ent to headache centers months to years after [15]. The headache of both IIH and NDPH is
headache onset, care should be taken to explic- often bilateral, daily, continuous, throbbing, and
itly delineate the initial headache characteristics accompanied by nausea. Both may respond to
or else the diagnosis of spontaneous intracranial migraine prophylactic medications, especially
hypotension can easily be missed. Magnetic topiramate [32]. Patients with IIH may have
resonance imaging (MRI) abnormalities of the normal brain imaging or nonspecific abnor-
brain and spine are present in about 90% of malities such as an empty sella and partial or
cases and may reveal diffuse pachymeningeal complete obstruction of one or both transverse
enhancement with gadolinium and in some cases sinuses; thus lumbar puncture and measurement
subdural fluid collections [30]. Tonsillar descent of opening pressure are needed for diagnosis.
and posterior fossa crowding may also be seen. An opening pressure of greater than 25 cm H2O
It is important to note however that a slow-flow in adults and 28 cm H2O in children is diagnos-
CSF leak may have less prominent MRI abnor- tic [2].
malities. Low pressures, such as 0–5 cm H2O, are
usually identified with lumbar puncture; how- Viral Meningitis
ever higher pressures have been recorded with Viral meningitis and a chronic post-viral head-
a documented leak. While opening pressures are ache may be misclassified as NDPH. Almazov
increasingly recognized as unreliable markers, and Brand evaluated children and adolescents at
elevated protein and prolactin are suspicious for a pediatric neurology clinic in Israel and found
SIH in selected patients. In cases where SIH is that patients suffering from headache that mostly
suspected, spinal myelography with MRI or CT fit a chronic tension-type headache pattern had
should be considered. an extremely high prevalence of meningismus.
Additionally, most experienced the onset of
Cerebral Venous Thrombosis headache in the setting of an upper respiratory
Cerebral venous thrombosis (CVT) can present infection [33]. It is therefore important to look
with headache in up to 90% of cases and is often for signs and symptoms of underlying infection
the initial symptom. Headache can be the only before diagnosing NDPH. For diagnosis of viral
symptom with a normal neurological examination meningitis, CSF analysis must be performed dur-
in 32% of cases [31]. The headache can be hemi- ing the acute period.
cranial, bilateral, or poorly localized, constant
or intermittent with exacerbations. The onset is Reversible Cerebral Vasoconstriction
typically gradual over several days but also can Syndrome
be thunderclap and then become chronic. Focal Reversible cerebral vasoconstriction syndrome
neurologic signs such as papilledema, cranial (RCVS) is an acute disorder characterized by
nerve palsies, decreased level of consciousness, severe headache and other neurological symp-
and seizure can accompany headache. toms in the setting of multifocal, segmental
vasospasm that is reversible [34]. There can be
I diopathic Intracranial Hypertension multiple thunderclap headaches at the onset of or
Idiopathic intracranial hypertension (IIH) can during the acute period of this disorder. MRI scans
present with a daily headache. While this syn- are typically normal, and a vascular study done
drome is often accompanied by neuro-ophthal- during the first few weeks after headache onset
mological symptoms including transient visual should show vasoconstriction. However, since
vasospasm typically resolves after a few weeks, this diagnosis include jaw pain/fatigue with
vascular imaging may be normal if obtained well chewing and ipsilateral visual deficits. GCA
after the onset [35]. Thus, it is important to get a rarely occurs under the age of 50 with most
thorough history of the headache pattern at onset, biopsy proven large series having no patients
or the initial thunderclap headache pattern may under the age of 50 [40]. An elevated erythro-
be missed. cyte sedimentation rate (ESR) helps to diagnose
The long-term headache prognosis of RCVS GCA; however a normal ESR does not rule it
is variable, and the phenotypic headache may out. A case series of 167 patients with GCA was
mimic NDPH. One large prospective study of undertaken at the Mayo Clinic, 90.4% of whom
67 patients in France with RCVS demonstrated had positive temporal artery biopsies. Nine
a 35.8% presence of mild persistent headache (5.4%) of the patients had a normal ESR, all
at follow-up visits 3–6 weeks after hospital of whom had a positive temporal artery biopsy.
discharge [36]. More recently, 16 patients with Of those nine patients, eight had either a new
RCVS were followed over 99 weeks. 42.9% of headache or prominent scalp tenderness, and in
patients not lost to follow-up developed a per- two patients, headache was the only presenting
sistent headache after RCVS despite no further symptom [41].
thunderclap attacks and radiologic resolution of
vasospasm [37]. ontact Point Headache
C
Contact point headache is thought to be due to
Sphenoid Sinusitis contact between the lateral nasal wall and the
Sphenoid sinusitis may cause a severe intrac- nasal septum. It typically presents with peri-
table, new onset daily headache that interferes orbital pain and has been noted to respond to a
with sleep and is not relieved by simple analge- septoplasty [42]. The diagnosis is frequently
sics. The headache is not specific in location; it established by the application of local anesthetic
often occurs in the vertex. There may be pain or agent and a vasoconstrictor to the identified
paresthesia in the distribution of the fifth cranial potential contact point, which temporarily allevi-
nerve, photophobia, lacrimation, fever, and nasal ates the headache.
drainage [38].
Systemic Illness
ervical and Vertebral Artery
C A daily continuous headache can be the present-
Dissections ing feature of a systemic illness thereby mimick-
Dissections can present with headache or neck ing NDPH. Bechet’s disease (BD), for example,
pain alone [39]. Occasionally, the headache can can present with a chronic headache even without
last for months or years and lead to a pattern of signs of central nervous system involvement such
chronic daily headache. Conventional angiogram as meningitis and venous sinus thrombosis [43].
is the gold standard for diagnosis; however mag- Human immunodeficiency virus (HIV) infection
netic resonance imaging (MRI) with dissection is a rare cause of chronic daily headache, and
protocol or computerized tomography angiogram HIV risk factors should routinely be queried.
(CTA) can visualize a dissection in most cases. Hypothyroidism can produce headache in about
14% of patients [44].
iant Cell Arteritis
G
Approximately half of giant cell arteritis (GCA) Other
patients can present with an unremitting, per- Other mimics include dural arteriovenous fistula,
sistent headache reminiscent of NDPH. How- unruptured intracranial saccular aneurysms, Chi-
ever, the pattern of GCA is typically unilateral, ari malformation, posttraumatic headache, tem-
unlike that of NDPH and can be associated with poromandibular joint dysfunction, cervical facet
other neurological or ophthalmological signs syndrome, intracranial neoplasm or mass lesion,
and symptoms. Features that further suggest primary or secondary CNS angiitis [45].
Evaluation treatment. The lumbar puncture can rule out indo-

lent infection and also determine CSF pressures.
NDPH is a diagnosis of exclusion. Initial investi- Given that patients may have a CSF leak without
gations should include MRI of the brain with and typical MRI changes or positional headache, an
without contrast, magnetic resonance venogram opening pressure, while helpful if low, does not
(MRV), and magnetic resonance angiography rule the entity out, and further spine imaging may
(MRA) of the head and neck (if headache presents be necessary. Additionally, while TNFα levels
with a thunderclap onset). Gadolinium contrast may be elevated in the CSF, in NDPH, this level
must be given to look for the pachymeningeal is not routinely checked as it does not change
enhancement associated with CSF hypotension. treatment or outcome and the original report has
While diagnosis of cerebral venous thrombosis not been successfully replicated by other studies.
(CVT) is best made with an MRV, the highest sen- In most instances, laboratory and neuroim-
sitivity is within the first 5 days of onset or after aging studies are normal. Elevated EBV titers
6 weeks. If suspicion remains high for CVT and have been identified, but the significance of this
the MRV normal, digital subtraction venography is unknown [46]. Li and Rozen investigated
can be performed. Further imaging can be consid- 49 patients who received either brain MRI or
ered based on the presenting symptoms. CT. Sixty-six percent had normal studies, while
Laboratory screening should include ESR, the remainder had nonspecific imaging findings
antinuclear antibody (ANA), Lyme antibody, felt not to be related to headache [8]. Data of CSF
viral titers including Epstein-Barr virus (EBV), analysis in NDPH is sparse. Rozen et al. reported
human herpes virus 6 (HHV6), parvovirus and on CSF from adolescents with NDPH. A low
cytomegalovirus (CMV), thyroid function, com- and almost nonexistent CSF protein level was
plete blood count (CBC), and serum chemistries documented in four out of four of the adolescent
(Table 7.2). HIV and syphilis testing can be con- patients with NDPH. Serum protein was normal
sidered based on patient risk factors. A lumbar in all patients. The cause of the low CSF protein
puncture should be considered if the above stud- level was unknown [8]. Additionally, clinical
ies are negative and for patients refractory to series of NDPH do not typically report the timing
of CSF analysis with regard to headache onset or
opening pressure measurements. In the Li and
Table 7.2 Laboratory studies Rozen series, 41% of patients had CSF analy-
CBC Headache may be a symptom of sis at some point after headache onset. While no
decreased hemoglobin patients had elevated opening pressures, there
concentration (seen in thrombotic
thrombocytopenic purpura)
was no mention of low opening pressures [8].
TSH Headache may be a symptom in
14% of cases of hypothyroidism
Chemistry profile Renal failure and hypercalcemia Treatment
can cause headaches
ESR Elevated in (giant cell) arteritis Primary NDPH is felt to be the most treatment
ANA Headache with clinical signs of
refractory of all headache disorders by many
lupus or autoimmune disease
Lyme antibody Lyme disease frequently presents headache specialists. Treatment is rarely fully
with headache effective, and the goal, as in many primary
HIV antibody and Upper respiratory symptoms at headache disorders, is at least 50% reduction in
polymerase chain onset and daily generalized headache days. Even with aggressive treatment,
reaction headache; test all patients with
many patients do not improve. Patients may start
risk factors
Viral titers (IgM, Possible precipitants of NDPH to overuse medications (in up to 45% of NDPH
IgG) for EBV, patients) though correction of overuse does not
CMV, HHV6, seem to alter the course of NDPH as it can in
parvovirus chronic migraine [10].
Pharmacologic Treatment Antidepressants

There are case reports and small series of effi-
Takase et al. published the largest uncontrolled cacy of venlafaxine (75 mg/day) and nortripty-
series of 30 patients in Japan who met ICHD-2 line (100 mg/day) [51].
criteria for NDPH. Patients were first adminis-
tered a muscle relaxant (tizanidine or baclofen). Tetracycline Derivatives
If no effect was observed, tricyclic antidepres- Rozen reported on the use of doxycycline
sants (amitriptyline), selective serotonin reuptake (a TNFα inhibitor) 100 mg twice a day for
inhibitors (SSRIs) (fluvoxamine or paroxetine), 3 months in four patients with treatment-
valproic acid, and beta-blockers were then resistant NDPH and elevated CSF TNFα levels
administered. Twenty-seven percent of patients (>8.2 pg/ml). All patients had failed at least
rated drug treatment as very effective, 3% rated five preventative agents, three of four patients
as moderately effective, 20% rated as mildly failed inpatient headache treatment, and another
effective, and 50% rated as ineffective [47]. failed outpatient infusion therapy. Duration of
The authors concluded that NDPH has a poor NDPH ranged from 8 months to 3 years. An
prognosis and is resistant to currently available infection preceded the onset of daily headache
treatment. In a retrospective study by Meineri in three of four patients. All patients had a pos-
et al., 18 NDPH patients were tried on amitrip- itive response to doxycycline, and two patients
tyline, fluoxetine, and valproic acid. No drug was became pain-free (those with the highest CSF
reported as effective [48]. TNFα levels). Average time to improvement
At present, there is very limited peer- on doxycycline was after 2 months of therapy;
reviewed evidence for pharmacologic treatment however, one patient responded within 2 weeks
of NDPH and no formal evidence-based guide- [52]. Given that time of onset to action is about
lines. Most therapies that are reported to show 2 months, Rozen recommended a 3-month
benefit are presented in either abstracts or case treatment trial for all patients.
reports. Thus, most headache specialists select
therapy based on NDPH phenotype (migrainous Leukotriene Antagonists
or tension type). Muscle relaxants such as tiza- The use of montelukast in NDPH is not actually
nidine and baclofen may be helpful [47]. Some documented in the literature. Rozen anecdotally
patients may respond to triptans for headache found symptom improvement when montelukast
escalations [8]. In children and adolescents, 10 mg twice a day was used along with doxycy-
the most commonly used medications include cline [53].
the tricyclic antidepressants (amitriptyline) and
antiepileptics (topiramate, gabapentin, valproic odium Channel Blockers
S
acid) [49]. A review of therapies that has been Mexiletine (1050–1200 mg/day) showed some
presented in the literature can be found below as benefit in a report of three patients refractory
well as in Table 7.2. to multiple preventative treatments. There was
improvement in pain severity but limited reduc-
Antiepileptics tion in headache frequency. All patients had side
Rozen presented five patients in whom suc- effects such as nausea, fatigue, tremor, and dizzi-
cessful treatment was obtained with topiramate ness, which were dose dependent [54].
or gabapentin. In two cases, a topiramate dose
of 75 mg twice a day was used. For gabapen- Corticosteroids
tin, there is no consistent dose recommended. Prakash and Shah reported on nine patients with
One patient received 2700 mg/day and a second “postinfectious” NDPH. All patients were given
1800 mg/day [50]. high-dose intravenous methylprednisolone for
5 days, while six patients were given oral ste- Interventional Procedures
roids for 2–3 weeks. All patients improved
with seven patients getting almost complete Nerve Blocks
pain relief within 2 weeks and two patients Given that some NDPH patients appear to have
needing 6–8 weeks of treatment [55]. Of note, cervicogenic signs on examination, nerve blocks
five out of the nine patients in this study did and/or facet blocks should be considered in
not technically meet the ICHD-3 criteria for selected patients. Robbins et al. reported on periph-
NDPH at time of treatment as steroids were eral nerve block responses in patients with NDPH.
initiated several weeks after the headaches 0.5% bupivacaine was used to block the greater
began (ICHD criteria necessitates 3 months of and lesser occipital, auriculotemporal, supraor-
headache [2]). Thus, while high-dose steroids bital, and supratrochlear nerves. Fifty-four percent
might be effective early in the course of pre- of patients had an acute response to nerve block-
sumed NDPH, those with established diagno- ade; however this correlated to only 1 day of pain
ses of NDPH and more prolonged cases may relief. No semipermanent procedures such as nerve
not respond. ablation were tried [10]. Afridi et al. reported ben-
Prakash et al. subsequently studied 37 efit of greater occipital nerve blocks in ten patients
patients in India with a diagnosis of NDPH with NDPH. Of ten patients, four had complete but
treated with a combination of intravenous meth- temporary response, and six had partial response.
ylprednisolone for 3–5 days (followed by oral Sensitivity around the greater occipital nerve was
therapy for 7–10 days), intravenous sodium val- associated with a response to injection [60].
proate for 3–5 days (followed by oral valpro-
ate for 3–12 months), and an antidepressant for Botulinum Toxin
2–12 months (amitriptyline or doxepin) with or There are three case reports of good to response
without naprosyn for 1–3 weeks. Forty-six per- to onabotulinumtoxinA (BTX). Spears docu-
cent of patients showed an excellent response mented a case of a 67-year-old man who had
(no or less than one headache per month), 30% complete response to three rounds of 100 units
had a good response (>50% reduction in head- of BTX [61]. Tsakadze and Wilson presented an
ache frequency or days per month), and 14% had abstract of three patients treated with 100 units
a poor response. Those with shorter duration of of BTX every 3 months. All three patients had
headache had a better outcome [56]. It is unclear >75% relief and one patient had 100% relief [62].
whether the positive response was due to the ini- Trucco and Ruiz reported on a 19-year-old patient
tial course of steroids or the medications that fol- treated with 195 units of BTX every 3 months for
lowed. NDPH. The pain was partially relieved after the
first cycle and subsided almost completely after
Dihydroergotamine the third cycle. While the pain became tolerable,
There has been limited data to support the use the patient never became headache-free [63].
of intravenous dihydroergotamine (DHE). A
retrospective review of CDH patients showed at Other Agents
least temporary improvement in some cases of In a small series of four patients, clonazepam was
NDPH [57]. A second retrospective review of IV found to be effective at dose of 0.5 mg nightly up
DHE use in 31 NDPH patients with migrainous to 1 mg twice a day with an extra 0.5–1 mg as
phenotype demonstrated medium-term head- needed for breakthrough pain [64]. A single case
ache benefit in two-thirds of patients [58]. Nagy report suggests using nimodipine for NDPH with
et al. found that in 11 patients with NDPH, only thunderclap onset [65]. There is a case report on
those with migrainous symptoms responded the utility of mirtazapine for NDPH-associated
to IV DHE and that response was less robust chronic nausea at a dose of 15 mg nightly. Though
when compared to those patients with chronic there was complete remission in chronic nausea,
migraine [59]. no improvement in headache was seen (Table 7.3).
Table 7.3 Literature review of NDPH therapies

Medication Dosage Evidence
Oral therapy
Topiramate 75 mg twice a day Two case reports
Gabapentin No consistent dose Two case reports
Consider 1800–1700 mg/day
Venlafaxine 75 mg/day One case report
Nortriptyline 100 mg/day One case report
Doxycycline 100 mg twice a day for 3 months One abstract
Montelukast 10 mg twice a day, used concurrently with Anecdotal only, not actually
doxycycline documented in literature
Mexiletine 1050–1200 mg/day One case report
Clonazepam 0.5 mg nightly up to 1 mg twice daily + 0.5–1 mg as One case report
needed for breakthrough pain
IV therapy
Methylprednisolone 1 g IV for 5 days ± 60 mg prednisone daily for One case report, not all
2–3 weeks patients met NDPH criteria
Dihydroergotamine No standardized dose; authors suggest 5-day course Three retrospective reviews
Interventional procedures
0.5% bupivacaine block No standard dose Two case reports
onabotulinumtoxinA 100–195 units every 3 months Three case reports
Emerging Therapies to have episodic headache [66]. These findings

were further supported by a prospective pilot
Naltrexone study with 30 intractable CDH patients treated
Joshi et al. proposed the potential of naltrexone with naratriptan 2.5 mg BID for 3 months.
as a therapeutic agent for NDPH. The use of nal- There was a reduction in mean headache fre-
trexone in fibromyalgia (FM) has been shown to quency at 3 months from 27.1 to 19.0 days. Of
be effective. Fibromyalgia is a chronic pain dis- the 22 patients who completed the protocol,
order due to chronic central sensitization of the 54% converted to an episodic headache pattern
nervous system. In a placebo crossover study, [67]. Gallagher and Mueller documented excel-
ten patients with FM were given low-dose nal- lent response to daily naratriptan, especially a
trexone, 4.5 mg/day for 9 weeks. The patients 1-year treatment, in intractable migraine patients
showed a 30% reduction in pain scores compared [68]. These findings, though documented for the
with 23% reduction in the placebo group [60]. treatment of CDH (some cases might have been
Another small trial of low-dose naltrexone in 27 NDPH) may suggest naratriptan as a potentially
FM patients showed an almost 50% reduction in useful agent for NDPH.
pain scored compared to placebo [62].
Prazosin
Naratriptan Prazosin is an alpha-adrenergic antagonist typi-
Naratriptan 2.5 mg twice daily has been proposed cally used to manage hypertension. It has been
as treatment of refractory CDH. Rapoport et al. used by psychiatrists to treat anxiety, insomnia,
retrospectively reviewed 27 cases of patients and posttraumatic stress disorder. In a study by
with CDH (many of whom may have had NDPH Ruff et al., treatment with prazosin resulted in
[62]) who had received 2.5 mg naratriptan BID long-term improvement of headache in 126 vet-
for more than 2 consecutive months. Sixty-five erans with mild traumatic head injury caused by
percent of 20 patients who took naratriptan for a blast injury [69]. Both peak headache pain and
6 months transformed to an episodic headache the number of headaches per month decreased.
pattern. At 12-month follow-up, 55% continued The authors speculated that prazosin, through
alpha-adrenergic antagonism, may decrease Table 7.4 Treatment suggestions for NDPH based on
triggering event
sympathetically maintained pain, the postulated
cause of chronification of posttraumatic head- Postinfectious If caught early: IV
methylprednisolone up to 1 g/day for
ache. Thus, prazosin could also potentially be 2–3 days
effective for the treatment of NDPH [62]. If believed to be post-viral with high
serum viral titers: IV acyclovir for
3–5 days ± IV
methylprednisolone ± IV
Diet and Lifestyle doxycycline for several days then
oral doxycycline
Given similarities in phenotype with migraine, If no elevated viral titers: tetracycline
NDPH patients should be counseled about simi- derivative (minocycline or
doxycycline) 100 mg twice
lar lifestyle adjustments that have been beneficial daily ± montelukast 10 mg for
in decreasing migraine frequency including regu- 3 months
lar sleep, exercise, and meal schedules. Post-stressful Tetracycline derivative ± montelukast
life event for 3 months
Evaluate for cervical hypermobility
syndrome and cervical irritation on
Treatment Approach exam. If present, suggest physical
therapy for neck-strengthening
Rozen outlined a treatment approach based on exercises and possibly anesthetic
symptom duration, triggering factors, and the blockade
Postsurgical Evaluate neck for upper cervical
available literature. He found that the success facet inflammation and greater
with intravenous therapy was highest in the occipital nerve irritation; consider
1 year following onset of NDPH and dropped off nerve block
precipitously after that. Thus, he suggested treat- Medications: Muscle
relaxant + NSAID or tetracycline
ing early onset NDPH with intravenous therapy derivative ± montelukast or
similar to that used in treating chronic migraine. antiepileptic (topiramate or
Suggestions for treatment based on trigger- gabapentin)
ing factors can be seen in Table 7.4 [53]. In all Unknown Tetracycline derivative ± montelukast
subgroups, if outpatient therapy fails, it is rec- trigger or antiepileptic (topiramate or
gabapentin)
ommended to consider use of daily mexiletine, If cervical issues consider nerve
according to that author. blockage and/or combination of
muscle relaxant + NSAID
Prognosis
headaches for longer than 2 years. Of those patients
Vanast first described NDPH as a benign chronic who remitted, 63.6% did so within 24 months.
daily headache that spontaneously regressed In the relapsing-remitting subgroup, all patients
within 2 years without any treatment in 86% of remitted for the first time within 24 months; how-
19 male patients and 73% of 26 female patients ever relapses inevitably occurred [10].
[1]. However, in headache specialty clinics, As previously stated, only two subforms of
NDPH is not benign and is recognized as one of NDPH have been included in the ICHD-3: a self-
the most difficult headache syndromes to treat. limiting subform that typically resolves within
Robbins et al. proposed categorizing NDPH several months without therapy and a refractory
patients into three prognostic categories. Out of 71 form that is resistant to aggressive treatment regi-
patients, 76.1% had persisting form with continu- mens [2]. The self-limiting form of NDPH has
ous headache from onset, 15% had remitting form, a good prognosis, as patients appear to improve
and 8% had relapsing-remitting form. Over half of without any intervention. In patients who have
the patients with the persisting subform had daily the refractory form of NDPH, their symptoms can
go on for years to decades even with aggressive 6. Koenig MA, Gladstein J, McCarter RJ, Hershey AD,
Wasiewski W. Pediatric Committee of the American
treatment. A 5-year study of 30 patients found a Headache Society. Chronic daily headache in children
poor prognosis for recovery when patients had and adolescents presenting to tertiary headache clin-
headache for a longer duration of time with a ics. Headache. 2002;42(6):491–500.
mean of 3.3 years and up to 27 years [47]. Chil- 7. Bigal ME, Lipton RB, Tepper SJ, Rapoport AM,
Sheftell FD. Primary chronic daily headache and
dren and adolescents seem to have more disabil- its subtypes in adolescents and adults. Neurology.
ity from NDPH. In a study of 28 children and 2004;63(5):843–7.
adolescents, 20 out of 28 continued to have head- 8. Li D, Rozen TD. The clinical characteristics
ache 6 months to 2 years later. Only 8 out of 28 of new daily persistent headache. Cephalalgia.
2002;22(1):66–9.
were headache-free within 1–2 years [70]. 9. Evans RW. New daily persistent headache. Headache.
2012;52(Suppl 1):40–4.
10. Robbins MS, Grosberg BM, Napchan U, Crys-

Conclusion tal SC, Lipton RB. Clinical and prognostic sub-
forms of new daily-persistent headache. Neurology.
New daily persistent headache is a unique
2010;74(17):1358–64.
form of primary chronic daily headache. 11. Rozen TD. New daily persistent headache: a lack
NDPH is marked by headache that is continu- of an association with white matter abnormali-
ous from onset with patients often being able ties on neuroimaging. Cephalalgia. 2016;36(10):
987–92.
to recall the exact date their headache started. 12. Siberstein SD, Lipton RB, Solomon S, Mathew

The first step in managing a patient with sus- NT. Classification of daily and near-daily headaches:
pected NDPH is to rule out secondary causes. proposed revisions to the IHS criteria. Headache.
Once a diagnosis of primary NDPH is made, 1994;34(1):1–7.
13. Headache Classification Subcommittee of the Interna-
we recommend initiating treatment based on tional Headache Society. The international classifica-
(1) time course of symptom onset and (2) trig- tion of headache disorders: 2nd edition. Cephalalgia.
gering event. Prognosis of NDPH is poor with 2004;24(Suppl 1):9–160.
most patients failing to improve despite 14. Kung E, Tepper SJ, Rapoport AM, Sheftell FD, Bigal
ME. New daily persistent headache in the paediatric
aggressive medication therapy. Further population. Cephalalgia. 2009;29(1):17–22.
research is needed given the increasing preva- 15.
Robbins MS, Evans RW. The heterogene-
lence of NDPH and its refractory nature. ity of new daily persistent headache. Headache.
2012;52(10):1579–89.
16. Young WB. New daily persistent headache: contro-
versy in the diagnostic criteria. Curr Pain Headache
Rep. 2011;15(1):47–50.
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Chronic Secondary Headaches
8
Robert Kaniecki
Overview and Clinical Assessment

Secondary Headache Disorders
Post-traumatic headache
Headache may result from intrinsic biological
Head injury
dysfunction of the nervous system or from acti-
Whiplash injury
vation of nociceptors from an identifiable organic
Headache attributed to cranial or cer-
process. These nociceptors may be found in
vical vascular disorder
intracranial structures or extracranial tissues of
Ischemic stroke or transient ischemic
the head and neck. Intracranial pain may result
attack
from irritation of nociceptive neurons arising
Parenchymal or subarachnoid hemor-
largely from the ophthalmic branch of the trigem-
rhage
inal nerve and terminating in the dura, meningeal
Unruptured vascular malformation or
or proximal cerebral arteries, dural sinuses, or
aneurysm
periosteum. Additional innervation is seen from
Intracranial or extracranial arteritis
cranial nerves IX and X and the second cervical
Arterial dissection
root. Extracranial tissues are innervated by all
Venous or sinus thrombosis
three branches of the trigeminal nerve; cranial
Headache attributed to nonvascular
nerves VII, IX, and X (largely the auricle); and
intracranial disorders
the second and third cervical roots. The Interna-
Intracranial hypertension or hypotension
tional Classification of Headache Disorders 3rd
Brain neoplasia
edition beta version (ICHD-3 beta) recognizes
Noninfectious inflammatory disorders
three headache subtypes: primary headaches,
(sarcoidosis)
secondary headaches, and painful cranial neu-
Chiari malformation
ralgias [1]. Primary headaches are organized by
Headache attributed to substance use
clinical criteria, while secondary headaches are
or withdrawal
categorized on the basis of contributory pathol-
Medication adverse event (nitrates)
ogy. Suspicion for secondary headache should be
Alcohol
heightened in the setting of clinical “red flags.”
Caffeine withdrawal
Medication overuse headache
R. Kaniecki Headache attributed to infection
Headache Division, Department of Neurology,
UPMC Headache Center, University of Pittsburgh
Intracranial infection (meningitis,
School of Medicine, Pittsburgh, PA, USA encephalitis, brain abscess)
e-mail: kanieckirg@upmc.edu

114 R. Kaniecki
is imperative. Recent changes in headache quan-

Extracranial infection (systemic bacte- tity or quality must always be explored. General
rial infection, viral syndrome) physical and complete neurological examinations
Headache attributed to disorder of with detailed cranial nerve and fundoscopic eval-
homeostasis uation are essential.
Hypertensive crisis, dialysis, hypoxia, Diagnostic studies are typically necessary
hypercapnia, hypothyroidism in the evaluation of patients with chronic head-
Headache attributed to disorder of ache. Brain imaging is the most valuable diag-
the neck, eyes, ears, nose, sinuses, teeth, nostic study despite yielding abnormalities in
or mouth only 1–3% of those with chronic headaches [2,
Headache attributed to psychiatric 3]. Guidelines recommend head CT scan when
disorder headache is acute and severe and brain MRI
Data from: Headache Classification when headaches are subacute or chronic [4].
Committee of the International Headache Noninvasive and occasionally invasive vascu-
Society (IHS). The International Classifi- lar imaging modalities are required in the set-
cation of Headache Disorders, 3rd edition ting of potential vascular etiologies. Lumbar
(beta version). Cephalalgia. 2013;33:683. puncture with opening pressure assessment may
be helpful in the workup of intracranial pres-
sure disorders and suspected meningitis. Serum
chemistries, erythrocyte sedimentation rate and
Red Flags for Secondary Headache C-reactive protein, and thyroid function stud-
Disorders ies are sometimes helpful. Tissue biopsy (brain
First or worst severe headache mass lesion, temporal artery) may be required
Abrupt or thunderclap-onset headache in select circumstances. Electroencephalogra-
Progressive or fundamental change in phy has no role in the assessment of headache
headache pattern disorders unless suspicion for seizure activity is
Abnormal physical examination find- also present.
ings
Neurologic symptoms lasting greater
than 1 h econdary Chronic Headache
S
New headache in persons younger than Disorders
5 years or older than 50 years
New headache in patients with cancer, eadache Attributed to Trauma or
H
immunosuppression, or pregnancy Injury to the Head and/or Neck
Headache associated with alteration in
or loss of consciousness Trauma to the head and neck frequently results in
Headache triggered by exertion, sexual acute headache and sometimes chronic headache.
activity, or Valsalva maneuvers ICHD classification applies the term “acute” to
those subjects reporting headache within the first
3 months following the injury and “persistent” to
those extending beyond that time point. Criteria
A detailed headache history outlining the tem- require development of headache within 7 days
poral pattern of past and present headache occur- of one of the following: trauma, regaining con-
rences is essential. Age of onset, attack frequency sciousness following the injury, or discontinua-
and duration, and associated features should be tion of medications that might impair headache
documented. Identification of the timing and cir- recognition. Diagnostic subcategories include
cumstances of transition into a daily or near-daily headaches from head trauma, whiplash injuries,
headache pattern in those with chronic headache and craniotomy procedures [1].
8 Chronic Secondary Headaches 115
Headaches Following Head Injury disruption of blood-brain barrier, and release of

migraine-associated neuropeptides such as cal-
Traumatic brain injury (TBI) may result from citonin gene-related peptide (CGRP) and pitu-
nervous system exposure to either blunt or pen- itary adenylate cyclase-activating polypeptide
etrating trauma. Fractures of the skull or facial (PACAP) [10]. Headache is reported by over
bones and intracranial hemorrhages are potential 90% of athletes after sports-related concussion,
complications. Most patients with serious intra- with the majority improving within several days
cranial structural lesions, such as epidural or to several weeks [11]. From 8 to 35% may expe-
parenchymal hemorrhages, will present acutely. rience persistent headaches at 1 year and perhaps
Subdural hematomas (SDH) may present either 25% at 4 years [12]. Nearly 80% of those with
acutely or with more chronic complaints [5]. The combat-related TBI will report episodic head-
elderly, those with a history of alcohol abuse, and ache and 20% chronic daily headache following
those receiving anticoagulation may be at partic- return from military theater [13]. Risk factors
ular risk. SDH may occur in the setting of rela- for the development of PTH include preexisting
tively insignificant trauma and are occasionally headaches, family history of headache disorder,
spontaneous. The interval between trauma and female sex, and, in the military population, the
symptom development may extend from hours to presence of post-traumatic stress disorder [14].
weeks. Headaches are typically global, progres- Age under 60 was recently shown to be an addi-
sive, and with variable intensity. Other common tional risk factor [15]. The presence of a con-
symptoms include somnolence, confusion, dizzi- tinuous headache appears to be associated with
ness, hemiparesis, and seizure. Diagnosis is typi- negative occupational outcomes in the military
cally made following brain MRI. Blood under population [16].
venous pressure accumulates between the dura Additional complaints of those with post-
and meninges, resulting in a crescent-shaped concussion syndrome include cognitive impair-
extracerebral imaging abnormality. Small subdu- ment, fatigue, dizziness, blurred vision, and
ral hematomas are often followed conservatively. disturbances of sleep or mood. Management of
Indications for surgical drainage include hema- the assorted symptoms of the post-concussion
toma thickness greater than 10 mm, a midline syndrome is largely rehabilitative and symptom-
shift greater than 5 mm, and significant neuro- atic and extends beyond PTH. Visual therapy
logical compromise [6]. may help address convergence insufficiency,
The terms concussion and mild TBI are often which commonly provokes or aggravates head-
used interchangeably. Approximately 75% of aches. Vestibular-balance therapy is also a
TBI is classified as mild. The most common valuable ally in the management of dizziness fol-
causes of mild TBI in the civilian population are lowing TBI. Specific therapies for insomnia or
motor vehicle or recreational accidents, falls, depression may be necessary. Cognitive impair-
competitive athletics, occupational hazards, and ment may require specific attention, and it often
assaults [7]. The incidence in the US military affects therapeutic choices aimed at other post-
population has increased dramatically in the past concussion complaints. Nonpharmacological
two decades, primarily through blast exposure steps such as regulation of sleep, nutrition, and
during conflicts in the Middle East [8]. hydration, combined with a graduated exercise
Post-traumatic headache (PTH) is the most program, are essential in recovery [17]. There
common symptom after mild TBI, and it is often are no large-scale studies on the management
the most lasting and most disabling complaint. of headaches following TBI [18]. The majority
There is no direct correlation between the degree of patients rely on nonprescription analgesics,
of trauma and either the duration or severity of but many presenting to clinical attention will
the subsequent headache condition [9]. The require prescription medication [19]. Pharma-
pathophysiology of PTH likely involves mul- cologic management is typically tailored to the
tiple mechanisms including neuroinflammation, phenotype of the headache disorder. The most
116 R. Kaniecki
common headache subtype appears to possess Occipital nerve blocks or cervical trigger point
migraine characteristics, but many possess traits injections may be helpful and are usually well
similar to tension-type headaches and trigeminal tolerated. No specific guidelines for manage-
autonomic cephalalgias (TACs) or are unclassi- ment are available, with controlled clinical trials
fiable [20]. Acetaminophen, aspirin, NSAIDs, failing to show benefit of any active treatment
and triptans are effective acute therapies for over conservative care [22]. Recovery is seen
severe breakthrough headaches, while opioids in the majority of patients over several weeks
and butalbital products should be avoided. to months, with only 12% reporting persistent
Certain β-blockers, antidepressants (tricyclic symptoms at 6 months. Risk factors for a more
antidepressants and venlafaxine), and antiepi- prolonged course include advanced age, female
leptic drugs (sodium valproate and topiramate) sex, pain or numbness in the upper extremities,
may be useful for headache prevention in those severe headaches, or prior history of concussion
with persistent post-traumatic migraines. Only or mental health disorder [23]. Ongoing legal
topiramate and onabotulinumtoxin A have sub- issues may contribute to delayed recovery in
stantial data in the setting of chronic migraine. some cases.
Those with chronic tension-type or TAC phe-
notypes should be managed like their primary
headache counterparts. Headaches Following Craniotomy
Persistent headache attributed to craniotomy is

Headaches Following Neck Injury defined as >3 months of headache discomfort
following a craniotomy performed for non-
Whiplash is defined as a sudden acceleration/ traumatic reasons. Like other forms of post-trau-
deceleration movement of the head, typically matic headache, ICHD-3 beta criteria require
with extension and then flexion of the cervical the headache develop within 7 days of the pro-
spine. This may involve either high- or low- cedure or either the restoration of consciousness
impact forces. Similar to TBI, whiplash injuries or elimination of pain-modifying medication [1].
are most commonly classified as mild to moder- At least 50% of patients experience acute head-
ate, and no correlation is apparent between the ache, while 25–30% appear to develop the per-
degree of injury and the extent of post-traumatic sistent form [24]. Larger craniotomies and those
symptomatology. Persistent headache attributed performed in the posterior fossa appear more
to whiplash is defined by ICHD-3 beta crite- likely to result in persistent headaches [25].
ria requiring development of headache within Pathophysiology of persistent post-craniotomy
7 days of the injury and persistence of discom- headache may involve a number of mechanisms
fort for >3 months [1]. Neck and shoulder pain including pericranial nerve injury or neuroma
are common. Many report features of the post- development, scar tissue adhering muscular tis-
concussion syndrome such as dizziness, fatigue, sue to dura mater, or central sensitization [26].
and disturbances of sleep or mood. Exam may be Although postoperative headaches often exhibit
normal or reveal tightness or spasm of the para- features of migraine, the most frequent pheno-
spinal cervical muscles [21]. Imaging is typi- typical description of persistent post-craniotomy
cally only indicated in the presence of signs of headache is a tension-type pattern [27]. Local
cervical radiculopathy or myelopathy. Cervical tenderness or allodynia at the scar site tends to
MRI may be normal or reveal loss of cervical persist for up to 1 year [28]. In the absence of
lordosis or occasionally a disc bulge or hernia- empiric data, most use the headache character-
tion. Management is typically symptomatic and istics as a guide to preventive and symptomatic
usually involves a combination of NSAID anal- medications. Pericranial nerve blocks may also
gesics, muscle relaxants, and physiotherapy. be of some utility.
eadache Attributed to Cranial or

H MRV are inconclusive [35]. Management steps
Cervical Vascular Disorder include symptomatic care and heparin in the
acute setting, followed by oral anticoagulation
I schemic or Hemorrhagic Stroke for 3–6 months. Those with identified hereditary
Headaches of cerebrovascular origin will most hypercoagulable states receive long-term antico-
often present acutely. Headache may be a tran- agulation [36]. Management of headache is gen-
sient symptom of ischemic or hemorrhagic erally symptomatic.
stroke, while some may continue to experience
chronic headaches [29]. Studies indicate 10–23% Cerebral Aneurysm
will continue report headaches at 2 years [30]. The most well-known headache associated with
One report at 3 years of follow-up documented cerebral aneurysm is the severe thunderclap
new headaches following prior stroke persisting attack associated with leak or rupture. Chronic
in over 7%, with the majority displaying tension- headaches may persist following subarachnoid
type features. Approximately 20% described hemorrhage, may follow interventional proce-
chronic headaches occurring 15 or more days dures for aneurysm, or may be associated with
per month [31]. A minority present with a con- unruptured cerebral aneurysms [37]. Cerebral
stant, unrelenting headache that is refractory to aneurysms are present in 0.4–3.6% of the pop-
treatment and may continue for months or years. ulation. Headache has been reported in up to
Management of poststroke headache is symp- 20% but is not well defined. In one trial 68% of
tomatic and based on phenotype. Triptans are patients experienced headache frequency reduc-
contraindicated in the presence of known isch- tion, while 9% of patients had new or worsened
emic cerebrovascular disease. headaches following aneurysm treatment [38].
Cerebral Venous Thrombosis Vascular Malformation

Thrombosis of the cerebral veins or sinuses Vascular malformations of the brain or dura may
may present acutely or with a pattern of chronic be linked with recurrent headaches. Develop-
head discomfort. Headache is the most common mental venous anomalies (DVAs), also known
symptom, seen in 80–90%, and is the most com- as venous angiomas, account for 60% of cerebral
mon presenting symptom. The pain is frequently vascular malformations. DVAs are best visual-
unrelenting from onset and exhibits mixed ten- ized on contrast-enhanced T1-weighted brain
sion-type and migraine features. The majority of MRI scans. Acute or chronic headache may result
cases are associated with papilledema or focal from a complication of DVA such as ischemic
neurological findings. The triad of findings of infarction or hemorrhage. Annual risk of hemor-
increased intracranial pressure, focal neurologi- rhage is approximately 0.2% and most are fol-
cal deficits, and encephalopathy is characteristic, lowed conservatively. Any link between chronic
at least early in the course [32]. Focal symptoms headaches and uncomplicated DVA is uncertain
and signs are highly variable and dependent on [39]. Arteriovenous malformations (AVMs) may
the location of thrombosis. Seizures occur in present with headaches in approximately 15% of
up to 40% [33]. Those with isolated headache cases. Headache may be persistent but is often
often go undetected. Suspicion should be raised episodic. Atypical presentations of migraine and
in the presence of certain prothrombotic condi- cluster have been reported. Side-locked headache
tions such as the use of oral contraceptives, preg- with contralateral neurological symptoms is com-
nancy, or malignancy. Imaging with brain MRI mon in symptomatic cases [40]. Diagnosis may
and MRV is more sensitive than head CT [34]. be made by head CT angiography or brain MR
Catheter-based angiography is the gold stan- angiography, but digital subtraction angiography
dard, but due to the risks of this invasive pro- remains the gold standard imaging technique. Risk
cedure, it is reserved for cases where MRI and of hemorrhage is 2–4% in those with unruptured
118 R. Kaniecki
and 4.5% ruptured AVMs. Older patients, those and an abnormal temporal artery biopsy [47].
with asymptomatic or unruptured AVMs, and Headache is classically subacute in onset, tem-
those with low risk of rupture (absence of deep poral in location, with focal scalp tenderness, but
location/drainage or associated aneurysm) are is highly variable [48]. Persistent pain is more
treated conservatively [41]. Observation is also common than episodic, and pain may extend
recommended for very large lesions or those from mild to severe. Jaw claudication, pain in the
located in surgically challenging areas. Headache muscles of mastication after a period of chew-
management typically follows migraine proto- ing, is nearly pathognomonic but present in only
cols. Cavernous malformations or angiomas are 25% of cases. Polymyalgia rheumatica is seen in
present in 0.5% of the population and may be nearly 50%, and other symptoms such as fatigue,
associated with headache in up to 40% of cases. malaise, fevers, anorexia, and weight loss are not
Most may mimic but will not meet diagnostic cri- uncommon. Cranial nerve palsies and stroke are
teria for any specific primary headache disorder additional potential complications. Visual loss
[42]. Many only become symptomatic at the time from anterior ischemic optic neuropathy is the
of hemorrhage. Conservative management may most common serious outcome and is typically
be superior to surgical excision or radiosurgical permanent. It may occur in up to 20% of patients
procedures in most settings [43]. Headache treat- [49]. ESR is elevated in 95% of biopsy-proven
ment is symptomatic. Dural or pial arteriovenous GCA cases, with a mean value of 85 millimeters
fistulas may also mimic any of the primary head- per hour. Diagnosis may require bilateral tem-
ache disorders. Risk of hemorrhage varies widely poral artery biopsies of at least 2 cm in length.
with the type of venous drainage pattern [44]. Prednisone at a daily dose of 1 mg/kg is the ini-
tial treatment of choice, and corticosteroids may
ervicocephalic Artery Dissection
C be necessary for a period of 6–24 months. Head-
Dissections of the intracranial and extracranial aches typically respond rapidly and completely.
cervicocephalic arteries commonly present with Guidelines also recommend addition of low-dose
acute head or neck pain. Onset may be thunder- aspirin in the absence of contraindications. Those
clap. Focal neurological findings such as cranial presenting with visual compromise or neurologic
nerve abnormalities or Horner syndrome are often findings are best managed initially with intra-
noted. These are seen in younger individuals and venous methylprednisolone [50]. Introduction
sometimes are a consequence of trauma. A vari- of alternate immunosuppressive agents such as
ety of headache phenotypes have been described, methotrexate should be considered in patients
including migraine and trigeminal autonomic with resistant disease or steroid-related compli-
cephalalgia [45]. Diagnosis may be confirmed cations. Both clinical and laboratory values are
by MRA, CTA, or catheter-based angiography. helpful in assessing improvement or relapse [51].
Most are treated with aspirin. Evidence suggests
some patients may develop long-term headaches,
which are treated symptomatically [46]. Nonvascular Intracranial Disorders
iant Cell Arteritis

G Intracranial Hypertension
Headache is the most common presenting symp- Idiopathic intracranial hypertension (IIH), previ-
tom of giant cell arteritis (GCA). Incidence is ously pseudotumor cerebri, involves CSF pressure
nearly always after age 50 and peaks between 70 elevation in the absence of an identifiable struc-
and 80 years of age. American College of Rheu- tural cause such as an intracranial mass lesion or
matology criteria require fulfillment of three of hydrocephalus. Potential pathophysiologic mech-
the following five clinical attributes for diagnosis: anisms include excess CSF production, reduced
a new headache, onset age 50 or older, elevated CSF absorption, increased brain water content,
erythrocyte sedimentation rate (ESR) of >50 mm and increased back pressure in the cerebral venous
per hour, a clinical temporal artery abnormality, sinus drainage system [52]. Approximately 90%
of subjects are female, 90% of childbearing age, Diagnostic evaluation should include brain
and 90% with elevations in body mass index. MRI with magnetic resonance venography and
The main risk factor appears to be obesity [53]. lumbar puncture. Imaging may be normal or
Headache is present in the vast majority at time reveal distention of optic nerve sheaths, flatten-
of diagnosis. It presents heterogeneously but ing of the posterior globe, empty sella, or trans-
tends to be daily and constant with fluctuations verse sinus stenosis [55]. Elevated CSF opening
in pain intensity. Headache may be aggravated pressure (>250 mm H2O in adults) in the absence
by Valsalva maneuvers. Migrainous features are of intracranial lesions confirms the diagnosis
not uncommon, while autonomic symptoms are [1]. Visual perimetry is essential initially and is
rare. Blurring or episodic darkening of vision the most valuable test in the course of disease
(visual obscurations), diplopia, pulsatile tinnitus, management. Enlargement of the blind spot and
and neck pain are other frequent complaints. The loss of peripheral fields are noted in 75–80% at
hallmark finding of increased intracranial pres- diagnosis [56]. The focus of treatment is preser-
sure, papilledema, is nearly universal [54]. Other vation of vision, with headache reduction a sec-
potential causes of increased ICP must be consid- ondary goal. Lumbar puncture acutely reduces
ered in the history and examination. intracranial pressure. It is immediately and usu-
ally transiently helpful and at times may need
to be repeated. Acetazolamide has been shown
Possible Causes of Increased Intracranial to improve visual field function and is the drug
Pressure of choice [57]. Many now prescribe topiramate
Intracranial mass lesion for the added benefit of weight loss. Weight
Neoplasm, abscess, hemorrhage reduction is an essential management step in
Intracranial venous or sinus pressure those with elevated BMI. A program involving
elevation diet and exercise should be instituted and bar-
Venous or sinus thrombosis iatric surgery considered when those steps have
Sinus stenosis failed. Optic nerve fenestration or shunt proce-
Dural fistula dures (ventriculoperitoneal or lumboperitoneal)
Extracranial obstruction—jugular may be required in refractory cases [58]. Any
vein occlusion, pulmonary hyperten- role of cerebral venous sinus stenting remains
sion, right heart failure controversial.
Cerebrospinal fluid pressure eleva-
tion Intracranial Hypotension
Hydrocephalus Headache from intracranial hypotension is most
CSF shunt obstruction commonly seen in the setting of recent lumbar
Meningeal inflammation—malig- puncture. Risk factors for post-dural puncture
nant, infectious, autoimmune, granu- headache include age under 60 years, female sex,
lomatous low BMI, history of prior low-pressure headache,
Colloid cyst of 3rd ventricle and use of a large-diameter traumatic needle
Other causes [59]. Although 90% of patients develop head-
Idiopathic intracranial hypertension ache within 72 h of the procedure, some may
Hypervitaminosis A develop low-pressure headaches several weeks
Drug effect—tetracycline or similar later. The headache may be generalized or focal
antibiotics, isotretinoin and develops within 15 min upon assuming an
Uremia upright posture. It may be worsened by physi-
Other—obstructive sleep apnea, car- cal activity or Valsalva maneuvers. Resolution of
bon monoxide poisoning, hypopara- discomfort is typically within minutes of return-
thyroidism, Addison disease ing to the supine position. Neck pain or stiffness,
nausea, vertigo, muffled hearing, and tinnitus
120 R. Kaniecki
are other common complaints. Neurological Brain Tumor

examination may show a 6th nerve palsy but is Headache from intracranial neoplasm is highly
typically normal. Contrast-enhanced brain MRI variable. It may arise from mass effect or paren-
may show diffuse non-nodular pachymeningeal chymal hemorrhage in those with solid tumors
enhancement and occasionally cerebellar tonsil- or from disruption of cerebrospinal fluid flow in
lar descent or subdural fluid collections. Sponta- those with malignant meningitis. Brain tumors
neous recovery is common, but 15% will still be may aggravate an underlying primary headache
symptomatic at 6 weeks. Bedrest and hydration condition or provoke a new headache profile.
are the first steps in management. Both caffeine Only 2% will experience isolated headache on
and theophylline have data in headache reduction presentation. Approximately 20% of patients
[60]. The use of an epidural blood patch is often will present and 60% eventually develop head-
curative in patients with symptoms persisting ache linked to the malignancy [68]. Those with
beyond the first several days [61]. Surgical inter- prior headache history and those with evidence
vention is rarely necessary. of increased intracranial pressure, supratentorial
Intracranial hypotension may also occur in mass location, and large tumor size are all asso-
the settings of mild or no trauma. Spontane- ciated with greater likelihood of headache devel-
ous intracranial hypotension (SIH) may pres- opment [69]. Patients at extremes of age appear
ent with the same clinical features and brain to be less likely to develop headache. Symptoms
imaging findings seen with post-dural puncture typically arise from increased intracranial pres-
headache [62]. Some with a prolonged course sure from the mass lesion, associated edema, or
may develop non-orthostatic or reverse-ortho- obstructive hydrocephalus. The textbook presen-
static headache. Predisposing conditions for tation of headache worse in the morning with asso-
SIH include Marfan or Ehlers-Danlos syn- ciated vomiting is present in approximately 10%
dromes, joint hypermobility, and neurofibro- of cases [70]. Instead the majority will describe
matosis. Microtrauma from osteophytes or disc headaches phenotypically similar to tension-type
herniations may be responsible in some cases headache, while others may report migraine-like
of ventral dural leaks [63]. Identification of events [71]. Treatment strategies are aimed at
the presence and site of CSF leak in cases of tumor management and symptom control.
SIH can be challenging. Normal CSF pressure
may actually be noted on rare occasions [64]. Chiari Malformation
CT myelography of the entire spine has been Chiari I malformations involve downward dis-
considered the gold standard technique, but placement of the cerebellar tonsils through the
spinal MRI is less invasive and may identify foramen magnum. The majority are diagnosed fol-
many patients with CSF leaks [65]. Radioiso- lowing brain or cervical spine MRI. Present crite-
tope cisternography may be useful in patients ria require cerebellar tonsillar descent of >5 mm
with suspected CSF leaks without MRI or CT (below the line connecting the internal occipital
abnormalities [66]. Conservative and medical protuberance to the basion) or descent of >3 mm
management is similar to that with post-dural with crowding of the subarachnoid space at the
puncture headache. Single or serial epidural craniocervical junction [72]. Syringomyelia of the
blood patch procedures are associated with cervical cord may be seen in up to 40% of cases.
resolution of symptoms in 90% of cases. Blood Population prevalence of Chiari I malformation
patch “targeting” the defined site of CSF leak is nearly 1%, the majority apparently asymptom-
is more effective than empiric “blind” lumbar atic. It is congenital but may be acquired, with
procedures [67]. Efficacy is approximately cerebellar tonsillar descent also seen in the set-
90%, while rate of recurrence is approximately ting of intracranial hypotension. Women are more
10%. Additional invasive procedures such as often affected than men, and time of presentation
direct surgical repair may be required in refrac- seemingly extends from early childhood to mid-
tory cases. adulthood. Headache may be the sole symptom,
part of a complicated symptom complex, or acute or subacute in onset and the history brief.
absent. In children it is the most common symp- Intracranial infection is a rare cause of chronic
tom [73]. An occipital or suboccipital location is headache. Chronic meningitis is arbitrarily defined
most common [74]. By definition headache has as meningitis lasting more than 4 weeks. It may
at least one of the following three characteristics: have infectious and noninfectious causes, and the
triggered by cough or other Valsalva-like maneu- treatment depends upon the etiology. Headache
ver, occipital or suboccipital location, and duration management is otherwise symptomatic.
<5 min [1]. Dizziness, ataxia, changes in hearing,
and diplopia or transient visual phenomena are
not unusual. Conversion from an asymptomatic Possible Causes of Chronic Infectious Meningitis
to a symptomatic state has been reported to occur Mycobacterium
following minor head or neck trauma [75]. Neu- Mycobacterium tuberculosis
Spirochete
rological examinations are typically normal but Borrelia burgdorferi
may show brainstem or cerebellar findings. Cer- Treponema pallidum
vical spine abnormalities may be seen when the Leptospira
Chiari is complicated by a syrinx or when there is Bacteria
Listeria
cord compression from the tonsillar ectopia. There Brucella
appears to be some correlation between obstructed Actinomyces
CSF and occipital headaches, but the precise role Francisella tularensis
of cine MRI CSF flow study is unclear [76]. Sur- Other: Erlichia, Nocardia, Whipple disease
Virus
gery should be reserved for those patients exhibit- Human immunodeficiency virus
ing abnormalities on physical exam or for those Cytomegalovirus
with refractory headaches meeting the previously Epstein-Barr virus
outlined diagnostic criteria. Other: Enterovirus, Herpes simplex, Varicella
zoster, HTLV I and II
Fungus
Substances Cryptococcus
Headache may be associated with the use of mul- Histoplasma
tiple substances or their withdrawal. In most cases Blastomyces
Other: Sporothrix, Coccidioides
the headaches are acute and transient. Chronic Parasite
headaches are less common but may arise with Toxoplasma
continued exposure to certain medications or Schistosoma
substances administered on a regular basis. Food Other: Taenia solium (cysticercosis),
Acanthamoeba, Angiostrongylus
additives or preservatives, nitrates, phosphodies-
terase inhibitors, alcohol, antidepressants, neuro-
stimulants, endogenous hormones, and excessive
caffeine are the agents most commonly indicted. Miscellaneous
A high index of suspicion is required. Treatment Disorders of homeostasis may occasionally pro-
involves discontinuation of the offending agent voke chronic headaches. Hypothyroidism and
when possible. Headaches linked to overtreat- sleep apnea are two of the more common eti-
ment with acute medication, now termed “medi- ologies to consider [77]. Headaches respond to
cation overuse” headache (previously “rebound” treatment of the underlying disorder. Structural
headache), are covered separately. disease of specific extracerebral structures may
result in chronic head, neck, or face pain. Head-
Intracranial Infection ache may be a symptom of conditions primar-
Headache may be a symptom of intracranial or ily affecting the eye, ear, or paranasal sinuses,
systemic infection. Meningitis, encephalitis, and bit it rarely is seen in isolation. In such settings
focal abscess or empyema are potential intracra- referral to an ophthalmologist or otolaryngolo-
nial causes. In most settings these headaches are gist is indicated [78]. Cervicogenic headache
122 R. Kaniecki
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Chronic Facial Pain and Other
Chronic Neuralgias 9
Salman Farooq and Fallon C. Schloemer
The International Association for Study of Pain pain which are abrupt in onset and termination
defines neuralgia as pain in the distribution of a (lasting seconds to minutes). The painful parox-
nerve or nerves which are otherwise normal in ysms are limited to the distribution of one or
function. Neuropathy is defined as a disturbance more divisions of the trigeminal nerve which can
of function or pathologic change in a nerve or arise spontaneously or triggered by trivial stim-
nerves. Neuropathic pain can be caused by a uli, including light touching, cold air, eating,
lesion or disease of the central or peripheral drinking, washing, shaving, brushing the hair or
somatosensory system. teeth, and applying make-up [1–4].
Facial pain is usually caused by a stimulation
of afferent fibers in the trigeminal nerve (cranial
nerve V), nervus intermedius (cranial nerve VII), Epidemiology
glossopharyngeal nerve (cranial nerve IX), vagus
nerve (cranial nerve X), and upper cervical spinal Trigeminal neuralgia is a rare condition but is
cord roots [1]. also the most common and the most severe of all
cranial neuralgias. The annual incidence of tri-
geminal neuralgia is 5–30 per 100,000 people
Trigeminal Neuralgia [3, 5–7]. Peak age of onset is after 50 and the
incidence increases with age. Women are 1.7
Introduction times more likely to be affected compared to
men [3, 4, 6, 8–10].
The International Classification of Headache
Disorders (ICHD), 3rd edition defines trigeminal
neuralgia (also known as tic douloureux) as a Etiology
facial pain disorder characterized by paroxysms
of recurrent, brief electric shock-like or stabbing Most cases of trigeminal neuralgia are caused by
compression of the trigeminal nerve root [3]. The
compression is usually located within a few mil-
S. Farooq (*) limeters of entry into the pons and can extend
Neurology, Medical College of Wisconsin, several millimeters along the root without involv-
Wauwatosa, WI, USA
e-mail: sfarooq@mcw.edu ing the peripheral trigeminal nerve [3, 8].
The compression is most commonly caused
F. C. Schloemer
Neurology, Froedtert and the Medical College by an aberrant loop of an artery or vein (80–90%
of Wisconsin, Milwaukee, WI, USA of cases) [3, 8, 11] but can also result from a

126 S. Farooq and F. C. Schloemer
vestibular schwannoma, meningioma, epider- wise, and the superior cerebellar artery is most
moid cyst, saccular aneurysm, arteriovenous frequently the cause of compression. The pain
malformation, or rarely an osteoma [7, 12–18]. most commonly involves the second or third
Trigeminal neuralgia can also be seen as a divisions of the trigeminal nerve and is typi-
complication of multiple sclerosis where demye- cally unilateral, and the right side of the face is
lination involves the root entry zone of the tri- affected more commonly than the left side [4, 8,
geminal nerve in the pons [3, 19]. This rarely (in 10, 30]. Following a painful paroxysm, there is
1% of cases) can be the initial manifestation of usually a refractory period during which pain
multiple sclerosis [20, 21]. Trigeminal neuralgia cannot be triggered and patients are mostly
can also be seen in patients with peripheral demy- asymptomatic in between the paroxysms.
elinating neuropathies such as Charcot-Marie- Severe attacks may cause ipsilateral contraction
Tooth disease [22]. of facial muscles (hence the term tic doulou-
Other uncommonly reported causes of trigem- reux) and also can be associated with mild auto-
inal neuralgia include infiltrative carcinomatous nomic symptoms such as lacrimation and/or
or amyloid deposits within the nerve root, conjunctival injection [4, 9]. The duration and
Gasserian ganglion and/or the nerve itself [23, intensity of these painful attacks can increase
24], as well as infarcts or angiomas involving the over time, significantly affecting patients’ qual-
brainstem [25–27]. Some cases may even be idio- ity of life.
pathic for which no identifiable cause is found. The ICHD-3 has defined the following criteria
for the clinical diagnosis of classical trigeminal
neuralgia [1]:
Pathogenesis
Compression of trigeminal nerve from above-

mentioned etiologies results in focal demyelin- ICHD Criteria for Classical Trigeminal
ation around the site of compression [28]. This Neuralgia
focal demyelination then creates abnormal cir- Classical Trigeminal Neuralgia
cuits between the exposed axons, resulting in
generation of abnormal sensory impulses (termed A. At least three attacks of unilateral facial
“ephaptic transmission”) which are carried along pain fulfilling criteria B and C.
the pathways involved in the perception of pain B. Occurring in one or more divisions of
and light touch from specific areas of face. This is the trigeminal nerve, with no radiation
the proposed mechanism resulting in generation beyond the trigeminal distribution.
of the painful paroxysms by touching the trigger C. Pain has at least three of the following
areas on the face [3, 29]. The same mechanism of four characteristics:
ephaptic transmission also applies to trigeminal 1. Recurring in paroxysmal attacks

neuralgia resulting from demyelinating disorders lasting from a fraction of a second to
described above. 2 min.
2. Severe intensity.
3. Electric shock-like, shooting, stab-
Classification and Clinical bing, or sharp in quality.
Presentation: 4. Precipitated by innocuous stimuli to
the affected side of the face.
The ICHD-3 has broadly divided trigeminal neu- D. No clinically evident neurological

ralgia into classical trigeminal neuralgia and deficit.
painful trigeminal neuropathy [1]. E. Not better accounted for by another
Classical trigeminal neuralgia is caused by ICHD-3 diagnosis.
neurovascular compression until proven other-
9 Chronic Facial Pain and Other Chronic Neuralgias 127
Classical trigeminal neuralgia is further subdi- at least 3 months in the distribution of the
vided into: same trigeminal nerve branch or branches
affected by herpes zoster eruptions [31]. It is
a) Purely paroxysmal classical trigeminal neu- more prevalent in the elderly and ophthalmic
ralgia which is defined as recurrent parox- division of trigeminal nerve is the most com-
ysms of unilateral facial pain fulfilling criteria monly involved.
for classical trigeminal neuralgia but without c) Painful post-traumatic trigeminal neuropathy
persistent facial pain between attacks. This is defined as constant unilateral facial or oral
subtype is usually responsive to severe burning/aching pain that develops
pharmacotherapy. within 3–6 months following trauma to the
b) Classical trigeminal neuralgia with concomi- trigeminal nerve. The pain is located in the
tant persistent facial pain (aka atypical tri- distribution of the same trigeminal nerve
geminal neuralgia or trigeminal neuralgia branch or branches affected by trauma. The
type 2) which is defined as recurrent parox- trauma can be mechanical, chemical, and
ysms of unilateral facial pain fulfilling criteria thermal or caused by radiation [32].
for classical trigeminal neuralgia with persis- d) Painful trigeminal neuropathy attributed to
tent facial pain of moderate intensity in the multiple sclerosis (MS) plaque is defined as
affected area. Unlike the former subtype, this unilateral or bilateral head and/or facial pain
subtype is less likely to respond to medical or in the distribution of trigeminal nerve in a
surgical therapy and is usually not triggered patient who has been diagnosed with MS and
by innocuous stimuli. with MRI evidence of an MS plaque affecting
the trigeminal nerve root [18, 19]. This sub-
Painful trigeminal neuropathy (previously type of trigeminal neuralgia is less likely to
known as secondary trigeminal neuralgia) is respond to pharmacotherapy.
head, facial, and/or oral pain in the distribution of e) Painful trigeminal neuropathy attributed to
one or more branches of the trigeminal nerve that space-occupying lesion is defined as unilat-
fulfills criterion C of classical trigeminal neural- eral head and/or facial pain in the distribution
gia but is caused by lesions other than vascular of a trigeminal nerve in a patient with radio-
compression [1]. logic evidence of a space-occupying lesion
affecting the trigeminal nerve [15, 17].
a) Painful trigeminal neuropathy attributed to f) Painful trigeminal neuropathy attributed to
acute herpes zoster usually precedes the her- other disorders is defined as unilateral or
petic eruptions by <7 days, lasts for less than bilateral head, facial, and/or oral pain with the
3 months, and is localized to the territory of characteristics of trigeminal neuralgia caused
the same trigeminal nerve branch or branches by disorders other than those described above.
affected by such eruptions/rash [31].
Ophthalmic division is the most commonly An important differential diagnosis: Short-
involved (80% of cases). Rarely, however, the lasting unilateral neuralgiform headache attacks,
pain is not followed by the eruption or rash because of their overlapping clinical presenta-
and diagnosis in such cases is confirmed by tion, can often be misdiagnosed as trigeminal
polymerase chain reaction (PCR) detection of neuralgia or vice versa [33]. ICHD-3 have classi-
varicella zoster virus DNA in the cerebrospi- fied them separately under the category of tri-
nal fluid (CSF). geminal autonomic cephalalgias and established
b) Postherpetic trigeminal neuralgia is defined the following criteria for their diagnosis and dif-
as unilateral head and/or facial pain following ferentiation from trigeminal neuralgia and other
acute herpes zoster that persists or recurs for headache disorders [1]:
them apart. It is important to note that these too can

ICHD Criteria for Short-Lasting Unilateral become chronic defined by occurring without a
Neuralgiform Headache remission period or with remissions lasting
Short-Lasting Unilateral Neuralgiform <1 month for at least 1 year [Table 9.1] [1].
Headache
A. At least 20 attacks fulfilling criteria

Medical Management
B–D.
B. Moderate or severe unilateral head The best and initial approach for the management
pain, with orbital, supraorbital, tempo- of trigeminal neuralgia is pharmacotherapy.
ral, and/or other trigeminal distribution, Various classes of medication have been used,
lasting for 1–600 s and occurring as most commonly the antiepileptics, for the treat-
single stabs, series of stabs, or in a saw- ment of trigeminal neuralgia. We will individu-
tooth pattern. ally discuss the commonly used drugs and their
C. At least one of the following cranial efficacy for the treatment of this disorder.
autonomic symptoms or signs, ipsilat- Carbamazepine is the most studied drug for
eral to the pain: the management of trigeminal neuralgia (Class I
1.
Conjunctival injection and/or and II evidence from four randomized, controlled
lacrimation. trials including a total of 147 patients), making it
2. Nasal congestion and/or rhinorrhea. the drug of choice for the management of this
3. Eyelid edema. condition [34–42]. The commonly reported side
4. Forehead and facial sweating. effects include drowsiness, dizziness, and nausea
5. Forehead and facial flushing. which can be controlled by slow titration of the
6. Sensation of fullness in the ear. drug. Leukopenia and in rare cases aplastic ane-
7. Miosis and/or ptosis. mia can be seen as a complication of trigeminal
D. Attacks have a frequency of at least neuralgia. Another serious side effect, however,
1 day for more than half of the time is the development Stevens-Johnson syndrome
when the disorder is active. (SJS) which should be an indication for stopping
E. Not better accounted for by another the drug. Asian patients who are positive for
ICHD-3 diagnosis. HLA-B 15:02 allele are more prone to the devel-
opment of SJS secondary to carbamazepine [43].
Dosing (orally):
Short-lasting unilateral neuralgiform headache Initial: 200 mg daily in two divided doses,
attacks are further subclassified by ICHD-3 as gradually increasing by 200 mg/day as needed.
short-lasting unilateral neuralgiform headache Maintenance: 400–800 mg daily in two
attacks with conjunctival injection and tearing divided doses.
(SUNCT) and short-lasting unilateral neuralgiform Maximum dose: 1200 mg daily in two divided
headache attacks with cranial autonomic symptoms doses.
(SUNA).The two subtypes are clinically differenti- Oxcarbazepine has shown to be equally
ated by the presence (SUNCT) or absence (SUNA) effective to carbamazepine for the management
of conjunctival injection and/or lacrimation [1, 33]. trigeminal neuralgia (Class II evidence from two
Chronic cluster headache, which was covered in randomized, controlled trials including a total of
chapter 6 also falls under the umbrella of the tri- 130 patients) [37, 40, 42]. Unfortunately, it car-
geminal autonomic cephalalgias. Others in this cat- ries the same risk as carbamazepine for the devel-
egory that are often confused with cluster headache opment of rash in Asian patients who are positive
include paroxysmal hemicrania and hemicrania for HLA-B 15:02 allele [43].
continua. While each is very similar, frequency and Dosing (orally):
duration of attacks, circadian periodicity, and Initial: 600 mg daily in two divided doses; grad-
responsiveness to indomethacin are what separates ually increasing by 300 mg every 5 days as needed.
Table 9.1 Characteristics of the trigeminal autonomic cephalalgias

Paroxysmal SUNCT/
Characteristic Cluster hemicrania SUNA Hemicrania continua
Similarities Pain quality Stabbing Throbbing, stabbing Burning, Baseline steady ache
stabbing with stabbing attacks
Pain severity Severe Severe Severe Baseline mild-to-
moderate pain with
moderate-to-severe
attacks
Typical site of Orbit, temple Orbit, temple Orbit, Orbit, temple
pain temple
Autonomic Yes Yes Yes Present with attacks
features
Response to Occasionally Yes No Yes
indomethacin
Distinguishing Duration of 15–180 min 2–30 min 1–600 s Constant pain with
features attacks variable attack duration
Correlation with Yes No No No
circadian rhythm
Nocturnal attacks Yes No No No
Triggers Alcohol Alcohol, cervical Cutaneous No specific triggers
nerve root pressure/ pressure
neck movement
Maximum dose: 1200–1800 mg daily in two at week 3, 200 mg once daily at week 5, 300 mg
divided doses. once daily at week 6, and 400 mg once daily at
Baclofen has limited evidence in the manage- week 7.
ment of trigeminal neuralgia (Class II evidence For patients taking valproate (Depakote): ini-
from a single double-blind crossover study tial dose of 12.5–25 mg every other day, gradu-
including a total of ten patients) [37, 44]. ally increasing by 25 mg every 2 weeks as needed
Drowsiness, dizziness, and dyspepsia are the to a maximum of 400 mg daily.
commonly reported side effects. Pimozide has been shown to be more effec-
Dosing (orally): tive than carbamazepine (Class II evidence from
Initial: 15–30 mg daily in three divided doses, a double-blind crossover trial including a total of
gradually increasing by 10 mg every other day 48 patients). However, because of limited evi-
over 1–2 weeks. dence of its efficacy and safety compared to car-
Maximum dose: 50–60 mg daily in three bamazepine, pimozide is rarely used for
divided doses. trigeminal neuralgia [7, 37, 47].
Lamotrigine has been studied as an adjuvant Tizanidine was found to be more effective
therapy to carbamazepine for trigeminal neuralgia than placebo in a small 3-week double-blind
(Class II evidence from a double-blind crossover crossover trial including 12 patients (Class III
study including a total of 14 patients) [7, 37, 45, 46]. evidence), but because of limited evidence and
Dosing (orally): short-term benefits, it is not commonly used for
For patients not taking other anticonvulsants: the treatment of trigeminal neuralgia [7, 37, 48].
initial dose of 25 mg daily for the first 2 weeks, Tocainide was found to be as effective as car-
gradually increasing as needed to 50 mg daily for bamazepine in a small 2-week double-blind
weeks 3 and 4 and then by 50 mg daily every crossover study including 12 patients (Class III
2 weeks to a maximum dose of 400 mg daily. evidence), but because of limited evidence and
For patients taking carbamazepine, phenyt- side effect profile (nausea, distal paresthesias and
oin, or primidone (CYP450 enzymes, enzyme skin rash), it is rarely used [7, 37, 49].
inducers): initial dose of 50 mg once daily, grad- Topical ophthalmic anesthesia
ually increasing as needed to 100 mg once daily (Proparacaine hydrochloride 0.5%) was found
to ineffective in a randomized double-blind pla- Rhizotomy is also an invasive procedure that

cebo-controlled trial including 47 patients (Class involves penetration of the foramen ovale with a
I evidence) [7, 37, 50]. cannula, followed by controlled lesion of the tri-
Phenytoin, clonazepam, gabapentin, and geminal ganglion or root by following means:
valproate have shown therapeutic benefits in
small open-label studies (Class IV evidence), but (a) Radiofrequency thermocoagulation: uses
because of lack of controlled trials, their role is heat to lesion trigeminal root.
limited in the management of trigeminal neural- (b) Mechanical balloon compression: uses bal-
gia [37, 51]. loon inflated into Meckel’s cave to compress
Botulinum toxin injections which are com- the trigeminal nerve root.
monly used for chronic migraine prevention have
(c) Chemical rhizolysis: produces chemical
shown limited evidence (two double-blind, pla- lesion of trigeminal nerve root by injection of
cebo-controlled trials and five prospective case 0.1–0.4 mL of glycerol.
series) for the treatment of trigeminal neuralgia in
patients who have either failed or are intolerant of The efficacy of these rhizotomy procedure is
oral medications [52, 53]. Techniques and dose of demonstrated by only four uncontrolled case
the neurotoxins varied in these studies. Some series (Class III evidence) which showed an ini-
authors mapped out a grid of the painful area and tial relief following the procedure in 90% of
injected at various cross points, while others patients which then decreased to 68–85% at
injected trigger points. Often the same technique 1 year, 54–64% at 3 years, and 50% at 5 years
was done bilaterally to achieve facial asymmetry. [37, 40]. Aseptic meningitis was reported in 0.2%
While the exact mechanism of how botulinum of patients, trigeminal-distribution sensory loss
toxin injections work for trigeminal neuralgia is was reported in almost half of patients, 12%
unknown, it is thought to be due to inhibition of developed dysesthesias, 4% developed anesthe-
the release of pain-related mediators [42]. sia dolorosa, and 4% developed corneal numb-
ness. Transient jaw weakness was reported in
50% of patients undergoing balloon compres-
Surgical Management sion. No procedure-related deaths were reported
[36, 37].
Surgical management is usually reserved for Gamma knife surgery is a noninvasive
patients who are refractory to medical manage- procedure which uses a stereotactic frame and
ment. The commonly used surgical techniques MRI to target a focused beam of radiation at
for the management of trigeminal neuralgia the trigeminal root in the posterior fossa [36,
include microvascular decompression and abla- 55]. The efficacy of this procedure is demon-
tive therapy. strated by three case series (Class III evidence)
Microvascular decompression is an invasive which showed a complete relief at 1 year fol-
neurosurgical procedure that involves separation lowing the procedure in 90% of patient which
of compressing vascular structures away from the then dropped to 52% at 3 years. Pain relief fol-
trigeminal nerve through craniotomy to reach the lowing this procedure can be delayed by
posterior fossa [8]. The efficacy of this procedure 1 month at an average. The most commonly
has been demonstrated by five major prospective reported complication was facial numbness
studies (Class III evidence) which showed an ini- (9–37% of patients) [37, 40].
tial relief following the procedure in 90% of Peripheral denervation techniques involve
patient which then decreased to 80% at 1 year, focal destruction of trigeminal nerve distal to
75% at 3 years, and 73% at 5 years [36, 37, 40]. the Gasserian ganglia and include cryotherapy,
The most commonly reported complication was neurectomies, alcohol injection, phenol injec-
aseptic meningitis, followed by severe hearing tion, peripheral acupuncture, radiofrequency,
loss, CSF leak, and trigeminal distribution sen- and thermocoagulation, but the evidence sup-
sory loss. Only two procedure-related deaths porting these techniques is very weak (Class
were reported in these studies [54]. IV) [37, 40].
Glossopharyngeal Neuralgia ryngeal neuralgia occurs in the distribution of the

auricular and pharyngeal branches of the vagus
Introduction nerve (X) as well as branches of the glossopha-
ryngeal nerve (IX). The development of overt
The ICHD-3 defines glossopharyngeal neuralgia glossopharyngeal neuralgic pain attacks can
(previously known as vagoglossopharyngeal neu- often be preceded by an aura consisting of an
ralgia) as a facial pain disorder characterized by uncomfortable sensation in the affected area,
paroxysms of severe, stabbing pain in the ear, base lasting for weeks to months [1].
of the tongue, tonsillar fossa, and/or underneath Paroxysms of pain can rarely be associated
the angle of the jaw. It is commonly triggered by with vagal symptoms such as cough, hoarseness,
innocuous stimuli, including swallowing, talking, syncope, and/or bradycardia (hence the old term
yawning, coughing, or manipulation of external vagoglossopharyngeal neuralgia), likely because
auditory canal and usually lasts seconds or min- of close connections between the vagus nerve
utes [1]. The pain is unilateral in most of the cases, and glossopharyngeal nerve. The afferent
but bilateral involvement has been reported more impulses from glossopharyngeal nerve may reach
often than in trigeminal neuralgia [56, 57]. the dorsal nucleus of the vagus nerve (via collat-
erals from the tractus solitarius nucleus of the
midbrain) which supplies parasympathetic fibers
Epidemiology to the heart, bronchi, and abdominal nerve [59].
The ICHD-3 has defined the following criteria
Glossopharyngeal neuralgia is a rare disease; for the clinical diagnosis of glossopharyngeal
annual incidence is 0.4–0.8 per 100,000 popula- neuralgia [1]:
tions. It affects both sexes almost equally and the
risk increase with age [5, 6, 56, 57].
ICHD Criteria for Glossopharyngeal
Neuralgia
Etiology Glossopharyngeal Neuralgia
Most of the cases of glossopharyngeal neuralgia A. At least three attacks of unilateral pain
are idiopathic, but it can be caused by compres- fulfilling criteria B and C.
sion of cranial nerves IX and X at the nerve root B. Pain is located in the posterior part of
entry zone, commonly by the vertebral artery or the tongue, tonsillar fossa, pharynx,
posterior inferior cerebellar artery [58]. Other beneath the angle of the lower jaw, and/
secondary causes of glossopharyngeal neuralgia or in the ear.
include neck trauma, demyelinating diseases, C. Pain has at least three of the following
tonsillar or regional abscesses/tumors, cerebello- four characteristics:
pontine angle tumors, Arnold-Chiari malforma- 1. Recurring in paroxysmal attacks

tion, and Eagle syndrome (an elongated or lasting from a few seconds to 2 min.
calcified stylohyoid ligament compressing the 2. Severe intensity.
cranial nerve IX) [1, 5, 59]. 3. Shooting, stabbing, or sharp in

quality.
4. Precipitated by swallowing, cough-
Clinical Presentation ing, talking, or yawning.
and Diagnostic Criteria D. No clinically evident neurological

deficit.
Glossopharyngeal neuralgia is less severe than E. Not better accounted for by another
the classical trigeminal neuralgia, but the two ICHD-3 diagnosis.
disorders can often coexist. Pain from glossopha-
Pain attacks from glossopharyngeal neuralgia ralgia) as a rare facial pain disorder characterized
can occur in clusters lasting weeks to months, by brief paroxysms of unilateral pain felt deeply
alternating with longer periods of remission, in the auditory canal which can sometimes radi-
ranging from months to years [59]. ate to the parieto-occipital region [1]. It is occa-
sionally associated with a trigger zone in the
posterior wall of auditory canal; however, pres-
Medical Management ence of trigger is not a characteristic feature of
nervus intermedius neuralgia [61].
Like trigeminal neuralgia, the best and initial
approach for the management of glossopharyn-
geal neuralgia is medical management with drugs. Classification
The medical management is essentially the same
as for trigeminal neuralgia and has been discussed The ICHD-3 classifies trigeminal neuralgia into
in detail in the section of trigeminal neuralgia. classical nervus intermedius neuralgia and sec-
ondary nervus intermedius neuropathy.
Surgical Management
pidemiology, Etiology, and Clinical
E
Surgical management is usually reserved for patients Diagnostic Criteria
who are refractory to medical management. The
commonly used surgical techniques for the manage- Classical nervus intermedius neuralgia is ner-
ment of glossopharyngeal neuralgia include micro- vus intermedius neuralgia developing without an
vascular decompression and intracranial suctioning. apparent cause. Most of the cases are idiopathic,
Microvascular decompression of the cranial but like other cranial neuralgias, possible vascu-
nerve IX and cranial nerve X is an effective treat- lar compression has been proposed as a possible
ment strategy for patients refractory to maximal etiology, although evidence is limited and contro-
medical therapy and had shown to provide complete versial. Classical nervus intermedius neuralgia is
and long-lasting relief ~80% of patients treated an extremely rare condition. It affects women
[58]. Although this is an invasive procedure, only a more commonly than men and the average age of
small percentage of complications have been onset is ~40 years [61].
reported from the procedure, including cerebrospi- The ICHD-3 has defined the following criteria
nal fluid leaks (<2% of patients) and postoperative for the clinical diagnosis of classical nervus
cranial nerve palsies (<3% of patients) [58, 60]. intermedius neuralgia [1]:
Intracranial sectioning of cranial nerve IX and
the upper three to four rootlets of cranial nerve X at
the jugular foramen has also been used for the man- ICHD Criteria for Nervus Intermedius
agement of glossopharyngeal neuralgia. Because Neuralgia
of comparatively more risk of complications and Nervus Intermedius Neuralgia
less long-term benefits, microvascular decompres-
sion is the procedure of choice for the management A. At least three attacks of unilateral pain
of refractory glossopharyngeal neuralgia [57, 58]. fulfilling criteria B and C.
B. Pain is located in the auditory canal,
sometimes radiating to the parieto-
Nervus Intermedius Neuralgia occipital region.
C. Pain has at least three of the following
Introduction four characteristics:
1. Recurring in paroxysmal attacks last-
The ICHD-3 defines nervus intermedius neural- ing from a few seconds to minutes.
gia (also known as facial nerve or geniculate neu-
2. Severe intensity. 2. Pain is localized to the distribution

3. Shooting, stabbing, or sharp in
of the nervus intermedius.
quality. D. Clinical features of peripheral facial

4. Precipitated by stimulation of a trig- paresis.
ger area in the posterior wall of the E. Not better accounted for by another
auditory canal and/or periauricular ICHD-3 diagnosis.
region.
D. No clinically evident neurological

deficit. Medical Management
E. Not better accounted for by another
ICHD-3 diagnosis. The best and initial approach for the management
of nervus intermedius neuralgia is pharmacother-
apy. The medical management is essentially the
Secondary nervus intermedius neuropathy same as for trigeminal neuralgia with carbamaze-
(also known as Ramsay Hunt syndrome) is nervus pine being the initial drug of choice and has been
intermedius neuralgia attributed to acute herpes discussed in detail in the section of trigeminal
zoster of the nervus intermedius. It is associated neuralgia. However, in secondary nervus inter-
with facial paresis and zoster lesions in the ear or medius neuropathy attributed to Herpes zoster,
oral mucosa. Additionally reported associated treatment should be initiated with steroids and
symptoms in this disorder include taste, lacrima- acyclovir as early as possible.
tion/salivation, and acoustic disturbances [61].
Secondary nervus intermedius neuralgia is also a
rare disease but more common compared to clas- Surgical Management
sic nerve intermedius neuralgia and also affects
women more commonly than men, and the aver- Surgical management is reserved as the last resort
age age of onset is ~50 years [5, 62]. when medical management fails. The commonly
The ICHD-3 has defined the following crite- used surgical techniques for the management of
ria for the clinical diagnosis of nervus interme- nervus intermedius neuralgia include microvas-
dius neuralgia attributed to herpes zoster cular decompression and excision of involved
neuralgia [1]: nerve and its ganglion.
Excision of the nervus intermedius and
geniculate ganglion is an invasive neurosurgical
procedure that involves exposing the motor com-
ICHD Criteria for Nervus Intermedius ponent of the facial nerve, geniculate ganglion,
Neuropathy Attributed to Herpes Zoster greater superficial petrosal nerve, and nervus
Nervus Intermedius Neuropathy intermedius from the cochleariformis process to
Attributed to Herpes Zoster the cerebellopontine angle and then excising the
segment of nervus intermedius at the internal
A. Unilateral facial pain fulfilling criterion C. auditory canal before it joins the facial nerve. The
B. Herpetic eruption has occurred in the geniculate ganglion is also excised from the inter-
ear and/or oral mucosa, in the territory nal genu of the facial nerve along with a segment
of the nervus intermedius. of the greater superficial petrosal nerve. The effi-
C. Evidence of causation demonstrated by cacy of this procedure has been demonstrated by
both of the following: a case series of 64 patients which showed an
1. Pain has preceded the herpetic erup- excellent relief following the procedure in 98% of
tion by <7 days. patients. The most commonly reported complica-
tion was permanent ipsilateral xerophthalmia in
all the patients (100%), followed by temporary Etiology

partial facial paralysis in 11 patients (17%) [63].
The procedure can also involve exploration Most of the cases are idiopathic. Uncommonly
and/or transection of multiple cranial nerves as reported etiologies include posterior head trauma
well as microvascular vascular decompression (if and whiplash injuries, chronic entrapment of the
a potential offending vessel is seen during explo- occipital nerves by the posterior neck and scalp
ration) as demonstrated by Rupa et al. in a series muscles, and vascular compression of the nerve
of 18 patients which showed pain relief following by the occipital artery, posterior inferior cerebel-
the procedure in 72% of the patient. Post-op lar artery, and arteriovenous fistulas [67].
complications included sensorineural hearing
loss (two patients), CSF leak (one patient), asep-
tic meningitis (one patient), and transient facial Clinical Presentation
paresis (one patient) [64]. and Diagnostic Criteria
Microvascular decompression of cranial
nerves V, IX, and X with or without section of Pain from occipital neuralgia occurs in the distri-
the nervus intermedius is also an invasive pro- bution of the greater, lesser, or third occipital
cedure used in patients with medically refractory nerves which are branches off of the upper cervi-
nervus intermedius neuralgia. Its efficacy was cal nerve roots. Each episode is sudden in onset,
demonstrated in a series of 14 patients (and a few originates in the nuchal region, and immediately
other case reports) with long-term relief in 90% spreads toward the vertex, lasting for seconds to
of the patients. Post-op complications were simi- minutes. Pain from the lesser occipital nerve is
lar to those reported by Rupa et al. [64–66]. felt laterally, while pain from the greater and third
Extracranial intratemporal division of the occipital nerves is felt medially. In some cases the
cutaneous branches of the facial nerve has pain may radiate to the ipsilateral fronto-orbital
shown to offer a safer treatment (no complication region. The paroxysms can start spontaneously or
reported over 1 year) with similar effectiveness in be provoked by specific maneuvers such as brush-
a series of three cases. Because of small sample ing the hair or moving the neck. The pain is uni-
sizes, relatively short follow-up, and poor study lateral in 85% of the cases, but bilateral
design, further research is needed to confirm the involvement had also been reported. Physical
effectiveness and safety of this procedure [66]. examination of affected area reveals tenderness
and might trigger a painful paroxysm [67].
The ICHD-3 has defined the following criteria
Occipital Neuralgia for the diagnosis of occipital neuralgia [1]:
Introduction
ICHD Criteria for Occipital Neuralgia
The ICHD-3 defines occipital neuralgia as a head- Occipital Neuralgia
ache disorder characterized by unilateral or bilat-
eral paroxysmal, shooting or stabbing pain in the A. Unilateral or bilateral pain fulfilling

posterior part of the scalp. It is sometimes accom- criteria B-E.
panied by diminished sensation or dysesthesia in B. Pain is located in the distribution of the
the affected area and is commonly associated with greater, lesser, and/or third occipital
tenderness over the involved nerve(s) [1]. nerves.
C. Pain has two of the following three
characteristics:
Epidemiology 1. Recurring in paroxysmal attacks

lasting from a few seconds to
The actual incidence and prevalence of occipital minutes.
neuralgia are unknown.
It provides immediate relief which may last for

2. Severe intensity. several weeks to a couple of months and can be
3. Shooting, stabbing, or sharp in quality. repeated as it is a relatively safe procedure with
D. Pain is associated with both of the
fewer, if any, complications. Knowing the anatom-
following: ical landmarks and course of the nerves helps
1. Dysesthesia and/or allodynia appar- guide where to perform the injections. Various
ent during innocuous stimulation of local anesthetics such as lidocaine, and bupiva-
the scalp and/or hair. caine have been used alone and in combination
2. Either or both of the following: with each other (often in a 1:1 ratio) or with a cor-
(a) Tenderness over the affected ticosteroid such as methylprednisolone or triam-
nerve branches. cinolone to achieve the blockade [67, 68].
(b) Trigger points at the emergence Alternate strategies: Carbamazepine, gaba-
of the greater occipital nerve or pentin, nonsteroidal anti-inflammatory medica-
in the area of distribution of C2. tions, or tricyclic antidepressants may be used if
E. Pain is eased temporarily by local anes- the pain is paroxysmal in nature or the patient is
thetic block of the affected nerve. not tolerant/hesitant of repeated nerve blocks.
F. Not better accounted for by another Limited evidence suggests that neuromodula-
ICHD-3 diagnosis. tion with pulsed radiofrequency and implanted
occipital nerve stimulators may be effective in
refractory cases [67, 69]. This will be discussed
Management in detail in Chapter 25.
Conservative management, including rest, peri-

odic application of warm or cold compresses, Optic Neuritis
massage, and physical therapy directed at
improving posture, may improve symptoms in Introduction
some patients and should be tried initially [67].
Block of the greater or lesser occipital nerves Optic neuritis is an acute inflammatory, demye-
is often the treatment of choice for occipital neu- linating condition that is characterized by pain
ralgia as it also has diagnostic potential (Fig. 9.1). behind one or both eyes and is accompanied by
impairment of central vision.
Epidemiology
Neuralgia
and headache pain
The annual incidence of acute demyelinating
optic neuritis is ~6 per 100,000 people and is
more common in the northern United States and
Greater occipital Western Europe. The age of onset is between the
nerve 20 and 40 and two-thirds of the cases occur in
Nerve block women compared to men [70, 71].
Lesser
occipital
nerve
Etiology
The most etiology for optic neuritis is immune-

mediated inflammatory demyelination of the
Fig. 9.1 Block of the greater occipital nerve. From
Anesthesia Key with permission from Lucas Clelemo. optic nerve, but the specific mechanism and tar-
[Accessed at: https://aneskey.com/occipital-nerve-block/] get antigens are unknown [72].
Clinical Presentation Management

and Diagnostic Criteria
Visual recovery from optic neuritis usually begins
Optic neuritis usually presents with retro-orbital within the first 2–4 weeks of symptom onset and
pain which worsens with movement and is asso- usually reaches 20/20 or better in 75% of patients
ciated with progressively worsening visual loss who have normal vision at baseline. Thirty percent
over a period of hours to days and peaking of adults will eventually develop multiple sclerosis
within 1 to 2 weeks. Visual loss is usually mon- (MS) at 5 years; however, children are less likely
ocular and bilateral involvement is more com- than adults to develop MS. Treatment with intrave-
mon in children. The clinical features of optic nous methylprednisolone hastens recovery of
neuritis have been systematically characterized vision and delays onset of MS but does not impact
in the Optic Neuritis Treatment Trial (ONTT), long-term visual function (Class I evidence from
and the most commonly reported symptoms are several studies including ONTT) [73–75].
visual loss and eye pain [73, 74]. One-third of
patients have visible optic nerve inflammation
on funduscopic examination, while in the eadache Attributed to Ischemic
H
remainder, the inflammation is retrobulbar. Ocular Motor Nerve Palsy
Optic neuritis can present as an isolated syn-
drome or as a manifestation of multiple sclero- Introduction
sis or neuromyelitis optica. Diagnosis of optic
neuritis is based on history and clinical features, The ICHD-3 defines this disorder as unilateral
but an MRI of the brain and orbit and CSF eval- frontal and/or periorbital pain caused by ischemic
uation are commonly used to aide in diagnosis paresis of the ipsilateral third, fourth or sixth cra-
when in doubt [72, 74, 75]. nial nerve and associated with other symptoms
The ICHD-3 has defined the following criteria and/or clinical signs of cranial nerve paresis [1, 76].
for the diagnosis of optic neuritis [1]:
Etiology
The most common risk factor for ischemic ocular

ICHD Criteria for Optic Neuritis motor nerve palsy is diabetes mellitus. Other risk
Optic Neuritis factors include left ventricular hypertrophy, ele-
vated hematocrit, hypercholesterolemia, coro-
A. Unilateral or bilateral headache fulfill- nary artery disease, and smoking. Cranial nerve
ing criterion C. III is affected more commonly followed in order
B. Clinical, electrophysiological, imaging, by cranial nerves IV and VI [77, 78].
and/or laboratory evidence confirming
the presence of optic neuritis.
C. Evidence of causation demonstrated by Clinical Presentation
both of the following: and Diagnostic Criteria
1. Headache has developed in tempo-
ral relationship to optic neuritis. Most cases of ischemic ocular motor nerve palsy
2. Headache has either or both of the are associated with pain, regardless of the etiology,
following features: but pain is more frequently seen with CN III palsies
(a) Localized in retro-orbital, orbital, followed by cranial nerves VI and IV palsies. The
frontal, and/or temporal regions. pain is mostly unilateral and is mainly localized to
(b) Aggravated by eye movement. ipsilateral brow and eye (presenting as unilateral
D. Not better accounted for by another
frontal headache). The pain usually precedes the
ICHD-3 diagnosis. onset of visual symptoms by a few weeks but can
occur concurrently with diplopia [76].
The ICHD-3 has defined the following criteria Epidemiology

for the diagnosis of headache attributed to isch-
emic ocular motor nerve palsy [1]: Recurrent painful ophthalmoplegic neuropathy is
a rarely encountered headache syndrome; annual
incidence is estimated at 0.7 per million popula-
ICHD Criteria for Headache Attributed to tions. It most commonly affects the children and
Ischemic Ocular Motor Nerve Palsy young adults with a mean age of onset at ~4–5.
Headache Attributed to Ischemic Ocular Females are affected more commonly [81, 82].
Motor Nerve Palsy
A. Unilateral headache fulfilling criterion C. Etiology

B. Clinical and imaging findings confirming
an ischemic ocular motor nerve palsy. Although the exact etiology of this disorder is
C. Evidence of causation demonstrated by controversial, MRI of the brain demonstrates
both of the following: gadolinium enhancement or thickening of the
1. Headache has developed in tempo- cisternal segment of the affected cranial nerve (in
ral relation to the motor nerve palsy. a ~75% of cases) suggesting a demyelinating or
2. Headache is localized around the
inflammatory etiology [81, 82].
ipsilateral brow and eye.

ICHD-3 diagnosis. Clinical Presentation
Management It was previously known as ophthalmoplegic

migraine, but ICHD reclassified the syndrome as a
Treatment is aimed at modifying the risk factors and cranial neuralgia by ICHD because of its non-
treating the underlying etiologies (antiplatelet ther- migrainous character and associated MRI findings.
apy is usually recommended). Patients with isch- The onset of headache can precede ophthalmople-
emic ocular motor nerve palsies frequently recover, gia by up to 2 weeks [80, 81]. The third cranial
regardless of nerve affected. The pain usually nerve is most commonly affected, in which case
resolves within a few days to a few months depend- mydriasis and ptosis can also be observed [80].
ing on the intensity of pain. The visual symptoms The ICHD-3 has defined the following criteria
also recover over several weeks to months; how- for the diagnosis of recurrent painful ophthalmo-
ever, if they persist beyond 6 months, prism therapy plegic neuropathy [1]:
or surgical interventions are indicated to alleviate
disabling diplopia and/or ptosis [76, 78, 79].
ICHD Criteria for Other Causes of Painful
Ophthalmoplegia
ecurrent Painful Ophthalmoplegic
R Recurrent Painful Ophthalmoplegic
Neuropathy Neuropathy
Introduction A. At least two attacks fulfilling criterion B.

B. Unilateral headache accompanied by
Recurrent painful ophthalmoplegic neuropathy ipsilateral paresis of one, two, or all
(previously known as ophthalmoplegic migraine) three ocular motor nerves.
is a rare condition, characterized by recurrent C. Orbital, parasellar, or posterior fossa
attacks of paresis of one or more ocular cranial lesion has been excluded by appropri-
nerves (commonly the cranial nerve III), with ate investigation.
associated ipsilateral headache [1, 80].

. Ipsilateral Horner’s syndrome.
D
ICHD-3 diagnosis. E. Not better accounted for by another
Tolosa-Hunt Syndrome ICHD-3 diagnosis.
A. Unilateral headache fulfilling criterion C.

B. Both of the following:
1. Granulomatous inflammation of the Similar causes of painful ophthalmoplegias
cavernous sinus, superior orbital fis- are included for comparison and should be con-
sure, or orbit, demonstrated by MRI sidered on the differential diagnosis. Tolosa-Hunt
or biopsy. and Raeder’s syndrome are further discussed in
2. Paresis of one or more of the ipsilat- detail below.
eral third, fourth and/or sixth cranial
nerves.
C. Evidence of causation demonstrated by Management
both of the following:
Treatment with corticosteroids has shown to be
1. Headache has preceded paresis of the beneficial in some patients; however, the evi-
third, fourth and/or sixth nerves by less dence is limited, and further trials are indicated
than or equal to 2 weeks or developed to confirm the efficacy of steroids in this syn-
with it. drome [1, 80].
2. Headache is localized around the ipsi-
lateral brow and eye.
Tolosa-Hunt Syndrome

ICHD-3 diagnosis. Introduction
Paratrigeminal Oculosympathetic
(Raeder’s) Syndrome Tolosa-Hunt syndrome is an extremely rare facial
pain syndrome which consists of unilateral
A. Constant, unilateral headache fulfilling orbital pain associated with ophthalmoplegia
criterion C. caused by a granulomatous inflammation in the
B. Imaging evidence of underlying dis- cavernous sinus, superior orbital fissure, or orbit
ease of either the middle cranial fossa [1, 83, 84].
or of the ipsilateral carotid artery.
C. Evidence of causation demonstrated by
both of the following: Epidemiology
1. Headache has developed in temporal
Annual incidence is estimated at one to two per
relation to the onset of the underlying million populations. Any age group can be
disorder. affected from the first to eighth decade of life,
2. Headache has either or both of the fol- and men and women are equally affected [85].
lowing features:
(a) Localized to the distribution of the
ophthalmic division of the trigemi- Etiology
nal nerve, with or without spread to
the maxillary division. The Tolosa-Hunt syndrome is caused by granulo-
(b) Aggravated by eye movement. matous inflammatory process of unknown etiol-
ogy in the region of the cavernous sinus, superior
orbital fissure, or orbit which may spread intra- months or years. However, follow-up is indi-
cranially in rare cases [83, 85]. cated to exclude other causes of persistent pain-
ful ophthalmoplegia such as tumors, vasculitis,
basal meningitis, sarcoidosis, or diabetes melli-
Clinical Presentation tus [1, 84, 85].
It is characterized by episodic, unilateral orbital Paratrigeminal Oculosympathetic

pain associated with paresis of one or more of the (Raeder’s) Syndrome
third (most common), fourth, and/or sixth cranial
nerves (see ICHD Criteria above). Additional Introduction
involvement of the cranial nerves II, V1, V2, VII,
or VIII has also been uncommonly reported, sug- Paratrigeminal oculosympathetic syndrome (also
gesting that inflammation can extend beyond the known as Raeder’s syndrome) is characterized by
cavernous sinus in some cases [83, 85]. The pain constant, unilateral pain in the distribution of the
is usually constant and retro-orbital with frequent ophthalmic division of the trigeminal nerve,
extension to frontal and temporal regions. The along with ipsilateral Horner’s syndrome [1].
onset of pain usually precedes the ophthalmople-
gia by several days, but their onset can also coin-
cide. Bilateral involvement has also been reported Epidemiology
although it is less common. There can also be
associated sympathetic/parasympathetic involve- Paratrigeminal oculosympathetic syndrome is a
ment of pupil and sensory loss in the division of rare facial pain syndrome. Males are affected more
cranial nerve V1 [85]. Tolosa-Hunt syndrome is commonly then females, and onset is usually
diagnosed on the basis of clinical presentation in between the fourth and fifth decade of life [86].
conjunction with neuroimaging findings
(enlarged cavernous sinus, isointense on
T1-weighted images with marked enhancement Etiology
with gadolinium) and also a clinical response to
corticosteroids [84]. It is commonly caused by lesions involving the
middle cranial fossa (particularly neoplasm) or
the carotid artery (particularly dissection) [86].
Management
Tolosa-Hunt syndrome is a benign syndrome. Clinical Presentation

Pain and paresis usually resolve within 72 h of and Diagnostic Criteria
adequate treatment with systemic corticosteroids
[85] but may take up to 8 weeks in some cases Patients mostly complain of constant, unilateral,
[83]. The steroid regimens for treatment of burning pain (often with hypesthesia and/or dys-
Tolosa-Hunt syndrome vary with institutions and esthesia) in the distribution of the ophthalmic
providers, but we recommend an additional dose division of the trigeminal nerve which may some-
of prednisone 80 mg for 3 days and if the symp- times extend to the maxillary division of the tri-
toms have resolved, then a slow taper over geminal nerve (see ICHD Criteria above).
8 weeks. Associated ptosis and miosis are seen in almost
Even if untreated, the episode usually all the cases; however, anhidrosis is not a com-
resolves spontaneously after a couple of months, mon association (seen in lesions involving com-
but recurrences are common at an interval of mon carotid artery). Some authors also use the
term “painful Horner’s syndrome” as a diagnosti- Clinical Presentation

cally useful indication of a middle cranial fossa and Diagnostic Criteria
lesion or of carotid artery dissection. An MRI of
the brain and angiogram of carotid vessels are The pain of burning mouth syndrome is usually
indicated to rule out/confirm carotid or middle bilateral, recurring daily for more than 2 h per day
cranial fossa lesions and also to confirm the clini- over more than 3 months. The most common site
cal diagnosis [1, 86]. for pain is the tip of the tongue, and it may be asso-
ciated with dysesthesia, altered taste sensation,
and/or subjective dryness of the mouth. Comorbid
Management psychosocial and psychiatric disorders have been
commonly reported in these patients [88, 89].
Treatment is aimed at treating the underlying eti- Oral mucosal diseases, such as herpes sim-
ology. Systemic steroids have been occasionally plex and aphthous stomatitis, can often be asso-
used to hasten the recovery [87]. The headache ciated with burning mouth pain. Other
usually resolves spontaneously in 1–3 months, commonly associated conditions include psy-
but the residual features of Horner’s syndrome chiatric disorders, xerostomia (drug, connective
may persist. Recurrences are uncommon [86]. tissue disease, or age related), nutritional defi-
ciencies (vitamin B12, iron, folate, zinc, vita-
min B6), allergic contact stomatitis, candidiasis,
Burning Mouth Syndrome diabetes, denture-related pain, thyroid abnor-
malities, and menopause. These secondarily
Introduction associated conditions should be ruled out before
making the diagnosis of idiopathic burning
Burning mouth syndrome (previously known as mouth syndrome [90, 91].
stomatodynia, or glossodynia when confined to The ICHD-3 has defined the following criteria
the tongue) is characterized by recurrent intraoral for the clinical diagnosis of burning mouth syn-
burning or dysesthetic sensation without clini- drome [1]:
cally evident causative lesions [1].
Epidemiology ICHD Criteria for Burning Mouth Syndrome

Burning Mouth Syndrome
The prevalence of burning mouth syndrome in
US population is estimated at 0.7% of all adults . Oral pain fulfilling criteria B and C.
A
(0.8% of women and 0.6% of men). It most com- B. Recurring daily for >2 h per day for
monly affects middle-aged women, and the inci- >3 months.
dence increases with age in both sexes [88, 89]. C. Pain has both of the following
characteristics:
Etiology 1. Burning quality.

2. Felt superficially in the oral mucosa.
Although the exact etiology of burning mouth
syndrome is unclear, trigeminal small-fiber sen- D. Oral mucosa is of normal appearance
sory neuropathy, presynaptic dysfunction of the and clinical examination including sen-
nigrostriatal dopaminergic pathway of central sory testing is normal.
pain modulation, salivary gland dysfunction, and E. Not better accounted for by another
alteration of oral mucosal blood flow have been ICHD-3 diagnosis.
proposed as possible etiologies [89, 90].
Management maxillae, teeth, or gums from minor procedures

or trauma may trigger the pain; the symptoms
In cases of burning mouth pain secondary to above- usually persist even after healing of the presumed
mentioned etiologies, treating the underlying cause initial noxious trigger and without any demon-
usually results in the remission of the symptoms strable local cause. Psychogenic factors and
[91]. However, when no secondary cause of symp- peripheral nerve dysfunction have been proposed
toms is found, the condition is considered idiopathic as possible etiologies, but such hypothesis lacks
burning mouth syndrome. Research evidence pro- sufficient evidence at this time [92].
viding guidance for the treatment of idiopathic
burning mouth syndrome is limited. Based on the
systematic review of several clinical trials, three Clinical Presentation
interventions have shown a reduction in symptoms and Diagnostic Criteria
compared with placebo, including alpha-lipoic acid,
clonazepam, and cognitive behavioral therapy. The pain is commonly described as dull, nagging,
However, credibility of most these trials is limited or aching and is usually located in the nasolabial
by methodological errors, low quality, and greater fold or upper jaw and may spread to region of the
bias risk; hence, caution and clinical judgment are eyes, nose, cheek, and temple. Patients experience
warranted while interpreting results of these treat- daily recurrences, lasting more than 2 hours, over
ment trials [90]. On the basis of available date and more than 3 months. It is often associated with
our clinical practice, we recommend tricyclic anti- comorbid chronic pain syndromes, irritable bowel
depressants as first-line agents for the treatment of syndrome, and various psychiatric and psychoso-
idiopathic burning mouth syndrome. Gabapentin, cial disorders. Persistent idiopathic facial pain is
pregabalin, clonazepam, and alpha-lipoic acid are mainly a diagnosis of exclusion [1, 92].
suitable alternatives for those intolerant/unrespon- The ICHD-3 has defined the following criteria
sive to tricyclic antidepressants [89]. for the diagnosis of persistent idiopathic facial
pain [1]:
Pain
ICHD Criteria for Persistent Idiopathic Facial
Introduction Pain
Persistent Idiopathic Facial Pain
Persistent idiopathic facial pain (previously
known as atypical facial pain) is defined as per- A. Facial and/or oral pain fulfilling criteria
sistent and recurrent facial and/or oral pain in the B and C.
absence of clinical neurological deficit [1]. B. Recurring daily for >2 h per day for
>3 months.
C. Pain has both of the following
Epidemiology characteristics:
The actual incidence and prevalence of persistent 1. Poorly localized and not following the
idiopathic facial pain are unknown, but the preva- distribution of a peripheral nerve.
lence of orofacial pain has been estimated at 25% 2. Dull, aching, or nagging quality.
of the general population. Women are affected
more commonly then men [92, 93]. D. Clinical neurological examination is

normal.
E. A dental cause has been excluded by
Etiology appropriate investigations.
F. Not better accounted for by another
The exact etiology of persistent idiopathic facial ICHD-3 diagnosis.
pain is unknown. Although injury to the face,
Management craniocervical pain with variable presentation,

attributed to a demyelinating lesion in the brain
On the basis of available date and our clinical stem or ascending projections of the trigeminal
practice, we recommend tricyclic antidepressants nuclei in a person with multiple sclerosis. Its prev-
as first-line agents for the treatment of persistent alence is estimated between 12% and 28% in mul-
idiopathic facial pain. Gabapentin, pregabalin, tiple sclerosis patients; however, it rarely is the
and topiramate, with or without behavioral ther- presenting symptoms of multiple sclerosis. The
apy, are suitable alternatives; however, clinicians pain commonly remits and relapses, with or with-
should be aware of the fact that no Class I or out sensory changes (usually dysesthesia but also
Class II evidence is available for any of these hypoesthesia, anesthesia, hypoalgesia, paresthe-
treatments and further randomized controlled tri- sia) but may be continuous in some cases [1, 97].
als are needed [92]. The ICHD-3 has defined the following criteria
for the diagnosis of central neuropathic pain
attributed to multiple sclerosis [1]:
Central Neuropathic Pain
Introduction
ICHD Criteria for Central Neuropathic Pain
Central neuropathic pain is defined as unilateral Attributed to Multiple Sclerosis
or bilateral craniocervical pain, caused by lesions Central Neuropathic Pain Attributed to
involving the central nervous system. The pain Multiple Sclerosis
can have a variable presentation, depending on
the cause; it may be constant or remitting and A. Facial and/or head pain fulfilling crite-
relapsing [1, 94]. rion C.
B. Multiple sclerosis (MS) has been diag-
nosed, with MRI demonstration of a
Pathogenesis demyelinating lesion in the brain stem
or ascending projections of the trigemi-
The exact pathophysiology of central neuropathic nal nuclei.
pain is not entirely understood but may multiple C. Pain has developed in temporal relation
mechanisms including central neuronal hyperex- to the demyelinating lesion or led to its
citability, loss of inhibition, and alterations in the discovery.
processing of incoming noxious and non-noxious D. Not better accounted for by another

stimuli [94–96]. ICHD-3 diagnosis.
Classification
Central poststroke pain is defined as facial
The ICHD-3 classifies central neuropathic pain, and/or head pain with varying presentations
on the basis of etiology, as central neuropathic involving parts or the entire craniocervical region
pain attributed to multiple sclerosis or central and associated with impaired sensation which
poststroke pain [1]. occurs within 6 months of an ischemic or hemor-
rhagic stroke and is not explicable by a lesion
involving peripheral trigeminal or other cranial
pidemiology, Etiology, and Clinical
E or cervical nerves. The pain is unilateral and per-
Presentation and Diagnostic Criteria sistent in most of the cases and is seen in approxi-
mately 8% of poststroke patients. Central
Central neuropathic pain attributed to multi- poststroke pain has varying characteristics, and
ple sclerosis is defined as a unilateral or bilateral the most commonly reported characters of pain
include cramping, dysesthetic, hyperpathic Dosing (orally):

(heightened response to noxious stimuli), allo- Amitriptyline: Initial 25 mg daily may increase
dynic, shooting/lancinating, and jabbing (pin/ as tolerated to 75 mg daily.
needles sensation) [94, 95]. Lamotrigine: Initial 25 mg daily may increase
Central poststroke pain is attributed to a lesion as tolerated to 200 mg daily.
of the ascending projections of the trigeminal Carbamazepine has been evaluated to be
nuclei. Symptoms may also involve the trunk and ineffective as monotherapy (Class II, level B evi-
limbs of the affected side, indicating possible dence from a placebo-controlled crossover
involvement of cervical spinothalamic pathways study); however, it may be used as adjuvant ther-
and their cortical processing. The pain develops apy if desired response is not achieved from rec-
in about 8% of poststroke patients [1, 94]. ommended agents. Other alternative/adjuvant
The ICHD-3 has defined the following criteria agents for the treatment of central neuropathic
for the diagnosis of central poststroke pain [1]: pain include gabapentin, pregabalin, and fluvox-
amine; however, their efficacy has not been
proven in clinical trials [95–97].
ICHD Criteria for Central Poststroke Pain
Central Poststroke Pain Conclusion
Cranial neuralgias are characterized by cra-
A. Facial and/or head pain fulfilling crite- niofacial pain of varying character and distri-
rion C. bution and are usually associated with, at
B. Ischemic or hemorrhagic stroke has least, some neurologic symptoms/deficits.
occurred. Trigeminal neuralgia is the most common
C. Evidence of causation demonstrated by of all cranial neuralgias, and most cases are
both of the following: caused by compression of the trigeminal nerve
root. The best initial approach for the manage-
1. Pain has developed within 6 months
ment of trigeminal neuralgia is pharmacother-
after the stroke. apy with carbamazepine being the most
2. Imaging (usually MRI) has demon-
effective initial therapy. Most cases of glosso-
strated a vascular lesion in an appropri- pharyngeal neuralgia are idiopathic, but it can
ate site. be caused by vascular compression of cranial
nerves IX and X at the nerve root entry zone.
Nervus intermedius neuralgia is classified into
ICHD-3 diagnosis. classic (mostly idiopathic) and secondary
(caused by acute herpes zoster) types.
The medical management of glossopharyn-
geal and nervus intermedius neuralgias is
Management essentially the same as for trigeminal neural-
gia with carbamazepine being the initial drug
Amitriptyline (Class II, level B evidence from a of choice.
double-blind, placebo-controlled crossover study) Greater or lesser occipital nerve block is
and lamotrigine (Class I, level B evidence from a the treatment (and also diagnostic test) of
double-blind, randomized, placebo-controlled choice for occipital neuralgias. In patients
crossover study and two case series) are first-line with optic neuritis, treatment with intravenous
drugs for the treatment of central neuropathic steroids hastens recovery of vision and delays
pain. However, the prophylactic role of amitripty- onset of MS but does not impact long-term
line has been evaluated to be ineffective in pre- visual function. For ischemic ocular motor
venting central poststroke pain in a double-blind, nerve palsy, risk factor modification and treat-
placebo-controlled study [94–96]. ing the underlying etiologies is recommended.
Tricyclic antidepressants are the recom- nal neuralgia secondary to tumors. Neurology.
mended first-line agents for treatment of idio- 1993;43(11):2298–302.
13. Ildan F, et al. Isolated trigeminal neuralgia secondary
pathic burning mouth syndrome. to distal anterior inferior cerebellar artery aneurysm.
Other rare chronic facial pain disorders and Neurosurg Rev. 1996;19(1):43–6.
their initial treatments include recurrent pain- 14. Figueiredo PC, et al. Arteriovenous malformation in
the cerebellopontine angle presenting as trigeminal
ful ophthalmoplegic neuropathy (corticoste- neuralgia. Arq Neuropsiquiatr. 1989;47(1):61–71.
roids may be beneficial), Tolosa-Hunt 15. Matthies C, Samii M. Management of 1000 vestibular
syndrome (systemic corticosteroids), Raeder’s schwannomas (acoustic neuromas): clinical presenta-
syndrome (treating the underlying etiology), tion. Neurosurgery. 1997;40(1):1–9. discussion 9-10
16. Haddad FS, Taha JM. An unusual cause for trigeminal
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depressants), and central neuropathic pain fossa. Neurosurgery. 1990;26(6):1033–8.
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discussion 29-30
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multiple sclerosis: demonstration of the plaque in an
operative case. Neurosurgery. 1979;5(6):711–7.
20.
Jensen TS, Rasmussen P, Reske-Nielsen
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CDH in Pediatric and Adolescent
Patients 10
Andrew D. Hershey and Shannon Babineau
Introduction of the International Classification of Headache

Disorders (ICHD) [8] specifies that all headache
Headache is a common complaint in children. It is types should be classified but that if a diagnosis
one of the primary reasons for visits to the pedia- of migraine is suspected for any of the headaches,
trician and emergency room as either a problem the migraine diagnosis should trump classification
by itself or as a symptomatic feature of another as tension-type headache. Historically, this varia-
disease process. Headache is often a symptom of tion in nomenclature has made comparisons and
infection and usually resolves with effective treat- conclusions difficult, and this chapter will include
ment [1, 2]. However, a significant portion of the the original authors’ nomenclature but in general
pediatric population suffers with recurrent head- chronic headaches and chronic daily headaches
ache. These episodic, recurrent headaches and its (CDH) can be equated to chronic migraine (CM),
associated features should then be considered a although it can sometimes include chronic ten-
primary headache disorder. Primary headache dis- sion-type headaches (CTTH).
orders, like migraine and tension-type headache, When headaches become frequent, they have
occur in all ages but increase in frequency as chil- been generically called “chronic daily headaches”
dren age. Epidemiologic data shows that migraine (CDH). CDH are broadly defined as 15 headache
occurs in 1.2–3.2% of 3–7-year-olds, 4–11% of days per month for at least 3 months. It should
7–11-year-olds, and in 8–23% of those aged 15 be defined by the predominant primary headache
[3]. The epidemiology of tension-type headache semiology. Although CDH may only occur in 1%
is more variable, secondary to differences in of children and adolescents, they make up a large
populations, study design methods, and inclu- portion of patients seen in specialty clinics [5].
sion of migraine, but studies show it to be pres- Chronic pain in children causes significant dis-
ent in 10–72% of the pediatric population [4]. To ability and not only impacts their lives but the
address some of these variations, the latest version lives of their caregivers [6, 7]. In addition, it is
very challenging to treat chronic pain, and while
A. D. Hershey (*) there have been some recent high-quality studies
Department of Pediatrics, Division of Neurology, on treatment methods, evidence-based data and
Cincinnati Children’s Hospital Medical Center, guidance are lacking for these patients.
University of Cincinnati College of Medicine,
Cincinnati, OH, USA
CDH in children and adolescents is divided
e-mail: andrew.hershey@cchmc.org into the same categories as adults with the pri-
S. Babineau
mary headache driving the nosology (i.e., when
Pediatrics, Goryeb Children’s Hospital, the headaches have a migraine phenotype at least
Morristown, NJ, USA some of the time, they should be called chronic

148 A. D. Hershey and S. Babineau
migraine (CM), while if they lack this phenotype be associated with medication overuse than other
completely and meet the features of tension-type types [16], although MOH is less likely to be an
headache, they should be called chronic tension- issue in adolescents than in the adult population.
type headache (CTTH)). In addition to CM and Rates of CTTH have been identified as
CTTH, children may have new daily persistent around 0.1–5.9% [4]. There are no large popu-
headache (NDPH) and hemicrania continua. lation studies for NDPH. In studies that look at
Hemicrania continua is rare in children and will the percent of each subtype in children/adoles-
not be reviewed in this chapter. The ICHD-3 sug- cents with CDH, CM is shown to be the most
gests that migraine in children and adolescents common. However, a relatively higher percent
may differ slightly from adults, headaches may of the adolescent population versus the adult
be of shorter duration, and location may be more population has CTTH or NDPH. NDPH is the
likely frontotemporal. The onset of an attack is second most common CDH type in adoles-
often more rapid. In addition, parental observa- cents [17–19]. NDPH occurs in 1.7–10.8% of
tion may play a role in identifying associated adults with daily headaches, and in those under
features [8]. At this time there is insufficient data 18 years, it occurs in 13–35% of those with
to support that there is need for a different classi- daily headaches [19].
fication syndrome. Although knowing that there
are some differences in presentation in children,
it would be interesting to continue to pursue the isk Factors for Chronification/
R
possible need for modifications to the criteria for Progression
CM, CTTH, and NDPH for children.
Most children with CDH (80%) have transformed
from episodic headache [20]. This happens, on
Epidemiology average, over about 2 years from onset of head-
aches [21]. With any progression of headache fre-
The prevalence of CDH in two population-based quency, secondary causes certainly need to be
studies of adolescents was shown to be 1.5–1.7% ruled out. There are also some conditions that
[9, 10]. There is less known about CDH in those increase the risk of the transformation from epi-
younger than 12 years. One large headache cen- sodic to chronic. Lu showed in 63 kids with CDH
ter reported that over a 6-year period, 4.8% of independent risk factors for CDH including
their patients were children under 6 years with female gender, family financial distress, obesity,
daily headache [11]. Arruda et al. also looked higher-frequency headache at baseline, and base-
specifically at a population-based sample of chil- line diagnosis of migraine [22].
dren between 5 and 12 years and identified that Medication overuse is one reason adults with
1.68% had CDH [12]. episodic headaches, particularly migraine, prog-
The adult prevalence of CM is about 2–3% ress to CM. MOH is less common in children
of the population. In a large population survey and adolescents than adults, but it still repre-
of adolescents, CM was identified in 0.79% not sents an issue and a risk factor for progression
including those with medication-overuse head- to CM [9]. In a patient with CDH, particularly
aches (MOH) and 1.75% if MOH was included relatively new onset, it is important to ask about
[13]. This data has been supported by other pop- frequency of use of pain relieving medication
ulation-based studies showing rates of 1.5% [14] including over-the-counter agents and dietary
in Turkish adolescents and a slightly lower rate caffeine. Identifying overuse of medication and
in a Norwegian population of 0.8% [15]. CM, counseling about MOH can result in a significant
like in adults, is more likely to be an issue for decrease in headache frequency. Hering-Hanit
girls than boys than the other subtypes of CDH et al. showed that cessation of overused medica-
[16]. CM also carries the highest disability of all tions completely stopped headaches in 20 out of
the subtypes of CDH [15] and is more likely to 26 pediatric patients with CDH and MOH and
10 CDH in Pediatric and Adolescent Patients 149
reduced the frequency significantly in another 5 under 18 years. A limited set of a long-term
children [23]. longitudinal study on children of abuse did not
Family history of headaches seems to be asso- see an increased risk of CM. Conversely, in
ciated with CM and less likely to be a factor in one study of children and adolescents, the rate
those with NDPH [16]. Frequency of headaches of child abuse was 6.5% which is significantly
in the mother can predict the frequency of head- higher than the rate in the general population
aches in her children; when a mother has CDH, (0.012%) [29, 30].
the risk of CDH in her children increases by Mild traumatic brain injury and its short- and
almost 13-fold [24]. It is unknown if this is a long-term effects on brain health are increas-
genetic contribution of frequency, shared envi- ingly being recognized in the lay and medical
ronment, or co-dependence. population. The majority of children who suffer a
The relationship between psychiatric comor- concussion will recover in a few weeks, but a sig-
bidities and CDH in children is less clear, with nificant minority will have symptoms persisting
some studies showing rates that are equal to the beyond 3 months. Headache is the most common
general population and other showing rates that symptom of concussion, and in one longitudinal
are much higher. In a study of children under study of children presenting with concussion,
6 years of age with CDH, authors identified psy- 7.8% had persisting headaches after 3 months
chiatric comorbidity in 80% of the kids including with about 50% of those patients having daily
anxiety, adjustment disorder, sleep disorders, and headache [31].
hyperactivity [11]. In Taiwanese adolescents with
CDH, not followed at a headache clinic, 47%
were identified as having at least one psychiatric Impact
comorbidity. The two most common comorbidi-
ties were depression (21%) and panic disorder Daily headache impacts not only the child but
(19%). Interestingly, there was a stronger asso- also the family. The Pediatric Migraine Disability
ciation with depression and suicidal risk in those Assessment (PedMIDAS) is a validated question-
with migraine with aura [25]. In a separate study naire for children and adolescents to help assess
in a pediatric headache clinic population, of those disability from migraine. PedMIDAS has three
with daily headache, about 30% met criteria for significant domains—impact on school, home,
a psychiatric disorder. This number was similar and social functioning – and is helpful for track-
to general population rate of 36% in children and ing success/worsening over time in a clinic popu-
adolescents [26], although those with psychiatric lation [5]. It is important to focus beyond just
comorbidity did have increased disability from school days missed because of headache but also
migraine. A different study also looking at pedi- on days present at school with pain where the
atric patients from a headache center showed that child cannot function optimally. Children that
there was a higher percentage of CDH sufferers attend school with pain often struggle with focus
with clinically significant anxiety than popula- and attention. In a study of functional ability at
tion norms (11% vs. 5%), but this did not occur school, children with CM were shown to have
with depression. Most children/adolescents with significantly increased struggles compared to
CDH did not have clinically significant depres- healthy children [7], and in a study of children
sion (93%) or anxiety (88.7%) [27]. In a study with CDH, half reported that school performance
of children with migraine, CM, and controls, the was influenced moderately (48%) or severely
children with CM had significantly higher scores (21%) by their headaches [9].
on social anxiety inventories [28]. Often during periods of more intense pain,
Adult data shows that childhood abuse and the child or adolescent will miss school, which
PTSD are risk factors for CM; however it is leads to a disruption in their education. The
unclear if this is a later effect or if the onset of missed school can also cause a vicious cycle of
daily headache occurs while the child is still falling behind and increased stress about catch-
ing up, all leading to amplification of symptoms nosis through appropriate history and any test-
and worsened disability from the headaches. ing to ensure there isn’t a secondary cause of the
There are some children whose headaches, and headaches. This may be accomplished through
the subsequent disruption they cause, make them a detailed explanation of the differences among
stop attending school altogether. This withdrawal common etiologies of chronic and acute pain.
from the regular schedule of the day as well as They should be educated that pain is a signal that
socialization with peers leads to further disability, usually identifies when something is wrong with
depression, and worsening of lifestyle habits. The the body, but in chronic pain the body has started
impact in these circumstances extends beyond the to misinterpret those pain signals making it think
child to impact caregivers as well, who not only there is something causing pain even when there
have to watch the child suffer with pain but have is not. Caregivers and patients should be prepared
to cope with disruption in their own lives as they that many of the treatment methods are going to
have to stay home from work to attend to the child ask them to work with some degree of discom-
and accompany him/her to doctor’s visits. fort. It’s also important to ensure them that they
will not have to go through this process alone
and that the goal is to manage and function with
Treatment the pain, rather than eliminate it. They need to
feel that they can control how they perceive the
The majority of patients suffering with CDH do pain and how they let the pain affect their lives.
not seek treatment right away, and when they do And, rather than feeling that there is nothing that
seek treatment, they often do not see a neurolo- can be done to cure the pain, they should learn to
gist [32], meaning that this population of patients focus on the power of positive, active, and inter-
is tremendously underserved. nally motivated solutions to live, despite the pain.
Treatment of chronic pain has to have a differ- The beginning goal of CDH management is
ent focus than treatment of episodic pain. When to help a child or adolescent assume some sem-
headache is only a few days a month, it is helpful blance of normalcy in their daily life. Chronic
to keep track of the circumstances under which pain is exhausting, and while it is best for a child
the headache occurs. While triggers are notori- to maintain a normal schedule attending school
ously inaccurate and inconsistent, awareness of and participating in activities after school, they
possible triggers can help modify certain daily are unlikely to be able to maintain the breakneck
activities and focus on adoption of healthy life- pace that many children keep up. They may be
style habits including adequate hydration, exer- able to participate in one after school activity, but
cise, healthy eating, and regular, adequate sleep. not multiple ones. This is further complicated by
Patients with migraine are encouraged to be the observation that many of these children and
treated early in the attack. However, when pain is adolescents are overachievers with a degree of
daily, it may be difficult to identify a beginning, anxiety about their immediate and long-term suc-
especially when continuous. In these instances, cess. Taking care of one’s body and mental health
advice to treat at the beginning of an attack or at become priorities. Sleep needs to be emphasized
the onset of worsening on three specific school as does making time to relax/destress, includ-
days (Monday, Wednesday, and Friday) can ing unstructured time as well as fitting in some
simplify the treatment regimen and improve physical exercise. It is also helpful to establish
compliance while avoiding medication-overuse a relationship with the school, making sure they
headache. understand the child’s needs. It is helpful to work
It is important that the child and caregivers with the school and caregivers to create reason-
are ready to treat the child for the pain, rather able accommodations, particularly in those chil-
than continue to spend efforts finding a “cause” dren with high-frequency absences, to help the
or overly worry about specific triggers. Patients child be successful academically.
and caregivers should be confident of the diag-
As with most conditions in pediatrics, there Disease Control (CDC) but remains inadequately
is insufficient research done on interventional addressed by states and school systems. Also,
treatments for migraine, let alone CM and other there is frequent practice of sacrificing sleep to
subtypes of CDH. There have been a few papers allow more time to do homework or extracurricu-
in the past 10 years that have started to work on lar activities. It is often unfathomable to teenag-
identifying approaches, but there is still a lack ers, and their caregivers, that sleep may need to
of guidance, although the inclusion of cognitive take priority over after school activities including
behavioral therapy (CBT) should be considered homework. It may be helpful to review that stud-
an essential component of treatment. In general, it ies show those with more sleep do better in ath-
is best to break treatment modalities into lifestyle letic competitions and academically than those
modifications, non-medication-based therapies, with less sleep [34, 35]. In addition, it is helpful
and medications. The children that do the best to emphasize that those with chronic pain often
employ treatments from all categories. It is help- need more sleep to feel rested and the quality of
ful to think of all components of treatment to be sleep with chronic pain can be lower, meaning
part of a multidisciplinary, multimodality treat- longer nighttime stretches and dedicated sleep
ment plan with no one treatment or therapy that is are important [36]. It is helpful to review the
going to be 100% effective. Also, it is important sleep requirements based on age with the family,
to emphasize that therapies will need to be tried as there are many young children who are getting
for an adequate time period. Often it has taken insufficient sleep (National Sleep Foundation
at least a year to reach a point of daily pain and Sleep Poll 2014 [37]). Then, some time spent on
longer still to seek the advice of a physician, so sleep hygiene with take home resources can help
the pain is not going to resolve overnight. Setting start the family in the right direction. Also, if
expectations with the family and patient of a slow sleep is a big struggle for the patient, you may
steady improvement will help avoid giving up on need to look into sleep disorders, like sleep
effective therapies too soon. It is also helpful apnea, which occur more commonly in migraine
not to be prescriptive, because there is not over- sufferers [38–40].
whelming evidence that any one method of treat- It is important for chronic pain sufferers to
ment is the best and having the family and older ensure that they are eating regularly, as skipping
children/adolescents help guide which therapies meals is one of the more reproducible triggers
they want to start with will improve compliance. for migraine. Patients with CDH should not be
skipping meals and should try to eat regular pro-
tein with each meal. Caregivers should ensure
Lifestyle Modifications that the child/adolescent is actually eating the
lunch provided to them and that they have access
There is only a modest amount of data about use to a snack if needed. Also, children should have
of lifestyle measures in treatment of CDH, but adequate hydration, particularly in children that
the general consensus in reports on CDH in chil- are also suffering with dizziness. Intake should
dren and adolescents is that there are certain approximate one cup of liquid for each year of
behaviors that are better for chronic pain than age with additional cups when the child par-
others. One of the biggest areas of focus is on ticipates in physical activity. It is important to
sleep and sleep hygiene. There is often a signifi- review caffeine use in all children. Often people
cant issue with sleep deprivation in children and do not realize that the iced tea or the soda they
adolescents. About 70% of adolescents do not get are drinking contains caffeine, and subsequently
the recommended 8–10 h of sleep that is needed there are some children who intake a fair amount
[33]. This is because of the teenager’s natural ten- of daily caffeine. This high rate of caffeine
dency to phase shift to later bedtimes/later wake intake can lead to medication-overuse headache
times compounded by early school start times. [41] and worsen dehydration, as caffeine is a
This has been recognized by the Center for natural diuretic.
In addition to these lifestyle measures, high- ety issues that amplify or trigger headaches [42].
frequency exercise is also helpful. Exercise is Powers et al. randomized children between 10
excellent as a stress reliever and can help with and 17 years old with CM to amitriptyline plus
mood and sleep difficulties. The tendency in CBT or amitriptyline with regular headache edu-
children with chronic pain is to stop moving cation. There was a significant reduction in head-
because it can make pain worse; however this ache days (average decrease of 11 days in CBT
will only lead to deconditioning and worsening group vs. 6 days in medication alone group) and
of the pain as well as amplify mood symptoms disability in the children provided with CBT and
and worsen symptoms of fatigue and dizziness. amitriptyline [43].
CDH is a pain amplification syndrome, and There are many barriers to the use of
other pain amplification syndromes like fibro- CBT. There is often a negative perception associ-
myalgia and amplified musculoskeletal pain ated with going to see a therapist. Emphasizing
respond very well to physical activity. In the that this is behavioral medicine and not a men-
beginning, patients may not be able to work to tal health issue in which the child or adolescent
a full aerobic level and may need to use lower is using their own brain power to control their
impact activities to avoid aggravating head pain behavioral response to pain can be quite success-
with bouncing. Activities that combine some ful in persuading the family of its usefulness.
posture and core strengthening as well as low CBT can be thought of as a method of coping
impact aerobics can be very helpful. Physical with pain and the impact of chronic pain on one’s
therapy may be beneficial to get people started, life regardless of whether it has affected men-
particularly those who are very disabled or who tal health or not [44]. Many patients struggle to
have not done a lot of sports/activities in the find a practitioner that is familiar with CBT that
past. Physical therapy can help them feel safe accepts insurance or who can see new patients in
in an observed environment, but the goal should a timely fashion. In addition, there are even fewer
be to help set up a home regimen that can be available CBT practitioners that are familiar with
continued long term [36]. the use of CBT for pain management. However,
many CBT practitioners are open to the use of
CBT for pain after a conversation with the treat-
Non-medication Therapies ing practitioner who can familiarize them with
the concept of using it for pain. Some programs
Addressing stress as well as identifying and man- have designed online−/computer-based CBT,
aging the mood comorbidities in CDH is very and while this certainly needs further study and
important. It is helpful to have a mental health standardization, this option would likely greatly
professional assess the patient with CDH at least improve compliance and provide a more readily
once to help identify comorbid psychiatric issues accessible service.
and screen for PTSD and trauma. Although this Other less rigorously studied non-medication
rarely reaches the level of a disease state, it may options that can also be helpful in the manage-
be a contributing comorbidity. Many of the non- ment of CDH include biofeedback, mindfulness
medication-based therapies do focus on both pain meditation, and acupuncture [45–49].
and stress reduction. These methods are some of
the best studied, with the best evidence. However,
they are significantly underused. Medication
One of the most effective treatments for
CDH in children is cognitive behavioral therapy The use of medication can be effective in the
(CBT). CBT is helpful in teaching the patient to management of CM, although the effect may be
take control over and stop catastrophizing the largely driven by the placebo response and the
pain. It can also be effective in helping with anxi- expectation of benefit. The management of
CTTH and NDPH has a true dearth of i nformation ages of children for other indications, with cau-
in the pediatric literature. Many of the same med- tion in those under 2 years of age and with stud-
ications used for migraine are used in these con- ies for episodic migraine to guide dosing. There
ditions, but there are not specific recommendations is not high utility of the tricyclic antidepressants
in management, so the below discussion will in those under the age of 5, so typically this is
focus on CM. In addition, a recent seminal paper listed as a lower age cut point; however this has
of randomized 361 children and adolescents with also been studied widely in migraine, so dosing
migraine (a portion of which had CM, but not is available for those over that age [5]. If preven-
continuous headache) to treatment with either tive medicine is deemed appropriate, a review of
amitriptyline, topiramate, or placebo showed no the side effect profile, with attention to a child’s
difference in outcomes between the three groups, comorbid conditions that may be made worse/
and those treated with medication had more better, should be taken into consideration. Also,
adverse events, leading to early termination of in younger children, the method of administra-
the study [50]. It is important to note that this was tion should also be taken into account, as some
not due to a lack of efficacy; it was due to the fact medications come in a liquid or sprinkle, mak-
that all arms, including the placebo arm, were ing it easier to take if pills cannot be swallowed.
very effective. This called into question whether OnabotulinumtoxinA, in a single study for CM
there is a role for medication at all in treatment of in 45 children, showed a change from severe to
CM. Most practitioners would agree this study moderate disability, a statistical drop in headache
highlighted that medication should not be the frequency from 27 days to 21 days/month. It was
sole or go-to treatment, but likely there is still well tolerated [51]. There was one other series
benefit in some patients. It is also very likely that of ten patients aged 11–17 years with medically
the method of presentation and allowing the child refractory daily headache. Forty percent had sub-
or adolescent to choose can enhance the expecta- jective but meaningful relief (decreased inten-
tion of response and ultimately a superior out- sity and some had decrease in frequency) and
come. Trying to understand what type of patient, improved quality of life after repeated adminis-
and at what point in the course of treatment medi- tration of onabotulinumtoxinA [52]. While there
cation should be offered, is certainly a large ques- certainly needs to be more research in this popu-
tion that needs to be answered. lation, if a patient can tolerate the injections, it is
Medication can be broken down into rescue worth considering.
and preventive. Typically, most of the focus in The supplements such as magnesium, butter-
CDH is placed on preventive therapy. The medi- bur, coenzyme q10, vitamin B2, and melatonin do
cations used for adults, topiramate, propranolol, not have any studies for use in CDHs in children.
valproate, and amitriptyline, are the medications However, they are safe and are often well toler-
also typically used in children. None of these ated. It is reasonable to try them either as a first-
medications have US FDA approval for use in line treatment while other lifestyle habits and/or
pediatrics for CM; however topiramate does biobehavioral methods are being established or as
have FDA approval for use in episodic migraine an add-on to the medication to help with overall
in teenagers (age 12–17 years old). Propranolol percent reduction in pain and severity [53].
and topiramate are used in very young children Rescue medicine can provide some benefit
for other conditions, and there are studies in epi- for breakthrough pain. NSAIDS and acetamino-
sodic migraine, so there are dosing guidelines phen are used frequently in the pediatric popula-
for a variety of weights. Propranolol must be tion and can be used in this setting. Guidance on
used with caution as it can exacerbate asthma appropriate dosing should be reviewed, recogniz-
and oftentimes can make children and adoles- ing that over-the-counter directions often under-
cents feel depressed, worsening this anxiety and dose children. Some of the triptans have US FDA
depression of CM. Valproate is also used in all approval for episodic migraine in the pediatric
population including rizatriptan for those older Prognosis

than 6 years and zolmitriptan/almotriptan and
combined sumatriptan/naproxen for those over There are some long-term follow-up studies of
12 years. There are a few ways to use rescue med- children with CDH that in general are positive. In
icine in those with daily headache. Many patients most studies over time, the headaches become
with CDH will have days where the pain is more less frequent, and the percentage of children/ado-
intense. In this instance, they can be instructed to lescents/young adults still suffering with high-
use the rescue medication as soon as the escalation frequency or chronic pain dramatically improves
of pain can be recognized. Or, if it is related to a over a 5–10-year period.
certain environmental factor that can be predicted In a study of 103 children/adolescents with
(a menstrual period or change in the weather) as daily headaches followed over 8 years, 12% still
associated with more intense headache, when that met criteria for CDH, with CM as the most com-
trigger has occurred, the patient is instructed to mon subtype. The presence of migraine at base-
use the rescue medicine as soon as pain begins. line predicted poorer outcome as well as CDH
The patient can use the medication on days where onset at <13 years, duration of more than 2 years,
the pain is likely to be disruptive, like a day when and presence of medication overuse. While only
there is a test at school or an anticipated social 11% had no headaches at the long-term follow-
event. Continued counseling on avoiding MOH up point, the majority only had episodic head-
should be provided at every visit. aches [32].
Another study with a 4-year follow-up of chil-
dren with CDH showed that 29% were headache-
Additional Interventions free. The others still had headaches, but 60% had
improvement in frequency of attacks. The pres-
Nerve blocks have been used in children with ence of a psychiatric disorder at the first-time
CDH and can be used in different ways. They point was related to persistence of headaches as
can help as a bridge therapy to mitigate pain as a was the total number of psychiatric disorders per
person is trying to discontinue an overused med- patient [57].
ication. In addition, during periods of worsen-
ing, they can help more immediately than Conclusion
preventive therapies to mitigate an attack. CDH affects those of all ages, including those
Gelfand et al. found that on a retrospective chart in their preschool years. CDH causes disabil-
review of 46 patients under 18 with a CDH syn- ity and impacts families in the same way it
drome and tenderness over the greater occipital does for the adult population. There is signifi-
nerve (CM, NDPH) who received a onetime cant overlap in the treatments used for this
treatment of greater occipital nerve blockade, population and the adult CDH population
53% benefitted from it, of which those 52% ben- partly because the lack of specific studies in
efitted significantly. The treatment typically children has led to extrapolation from adult
helped for about 5.4 weeks and seemed to be data and also because many of the adult mea-
more effective in CM [54]. Some people do use sures seem to work in pediatrics. Of note, the
repetitive nerve blocks over time as management data that is specific to childhood CDH points
for CDH [55]. away from use of medication and encourages
Hospitalizations for repetitive dihydroergota- practitioners to emphasize non-medication
mine have been used for migraine in children, approaches. With the advent of newer,
typically to help periods of status migrainosus or migraine-specific drugs, this will need to be
also to help in bridging off overused medications reevaluated.
[56]. It can be considered as an option, particu- These youngest patients may represent
larly for children that are severely disabled and those with the highest penetrance of a genetic
missing school secondary to CM. predisposition to headache, and it is helpful to
identify them and involve them in research 12. Arruda MA, et al. Frequent headaches in the preado-
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Imaging in CDH
11
Danielle D. DeSouza and Anton Rogachov
Introduction MRI Approaches to Study CDH
Over the past few decades, our understanding of MRI uses strong magnets and radiofrequency
brain abnormalities in headache syndromes has pulses to collect information about atomic nuclei
greatly improved with the use of advanced neuro- within tissues of the body [5]. Unlike other forms
imaging methods. Neuroimaging allows for the of imaging, it does not require the use of ionizing
noninvasive examination of brain structure and radiation to obtain images. MRI approaches can
function using modalities such as magnetic reso- largely be divided into two broad categories: (1)
nance imaging (MRI), positron emission tomog- structural (to assess brain gray matter (GM) and
raphy (PET), magnetoencephalography (MEG), white matter (WM)) and (2) functional (to assess
and magnetic resonance spectroscopy (MRS), activity in the brain associated with hemody-
among others. While the majority of studies in the namic and metabolic changes).
headache literature have examined episodic head- Multiple structural approaches are available to
ache disorders, the most common being migraine assess brain GM and WM structure in CDH
(for reviews on this topic, see [1–4]), there has patients using T1-weighted MRI and diffusion
been a recent push toward understanding neuro- tensor imaging (DTI), respectively. For these
imaging-based brain abnormalities associated approaches, data are first preprocessed to distin-
with chronic headache, with the goals of gaining guish and classify brain tissues into GM, WM,
insight into its pathophysiological underpinnings and cerebrospinal fluid (CSF) components. To
and improving treatment strategies. measure GM, a number of automated and semi-
In this chapter, we will discuss studies focused automated techniques are available, with the two
on MRI methods to assess structural and functional most common methods being voxel-based mor-
brain abnormalities in chronic daily headache phometry (VBM) [6] and cortical thickness anal-
(CDH). We will end with a discussion on future ysis (CTA) [7]. VBM can assess both subcortical
directions for neuroimaging research in CDH. and cortical GM density and volume; however,
CTA was developed to measure the thickness of
D. D. DeSouza (*) cortical GM on a submillimeter scale [7]. This
Neurology and Neurological Sciences, Stanford precision is important since the cortex is highly
University, Palo Alto, CA, USA convoluted and measuring thickness based on
e-mail: desouzad@stanford.edu volume measurements can result in overestima-
A. Rogachov tions of GM [7]. Since many disease processes
Institute of Medical Science, Krembil Research involve subtle cortical changes, the submillime-
Institute, Toronto Western Hospital,
Toronto, ON, Canada ter accuracy of CTA is advantageous.

158 D. D. DeSouza and A. Rogachov
For WM methods, analyses are typically based globin in the blood [13]. Physiological events
on MR-diffusion-weighted imaging (DWI), (e.g., changes in neural activity) that change the
which is sensitized to the random Brownian oxy- to deoxy-hemoglobin ratio can be detected
motion of hydrogen protons, mainly in water noninvasively as a change in BOLD response
molecules [8, 9]. DWI requires the acquisition of [13]. Recently, fMRI studies of functional con-
multiple images so that the signal can be sensi- nectivity, which refers to the examination of tem-
tized to diffusion in many directions, allowing porally correlated activity of remote brain
multiple measurements for each voxel compris- regions, have become increasingly popular to
ing the brain images [8]. The diffusion of water in study headache disorders [14]. Connectivity can
body tissues occurs inside, outside, around, and be assessed in both task-based and resting-state
through cellular structures [10]. Some structural fMRI experimental conditions.
barriers can hinder diffusion. For example, diffu- In the following sections, recent literature
sion in WM is more restricted across an axon using these described MRI methods to examine
than along it due to structural barriers such as brain structure and function in patients with CDH
myelin, axonal membranes, microtubules, and will be reviewed.
neurofilaments [11]. Importantly, regional diffu-
sion may be lessened or exacerbated by certain
pathological conditions [10, 12]. To obtain mean- tructural MRI Reveals Abnormalities
S
ingful measures from diffusion scans, mathemat- in the Brain Structure of CDH Patients
ical models can be fit to each voxel to derive
information about the directionality of the diffu- CDH is a descriptive term whereby headaches
sion and presumably underlying tissue micro- occur on 15 days or more per month for at least
structure within that voxel. The most common 3 months [15]. Given the incessant and disabling
model is the diffusion tensor model. DTI involves nature of CDH, there has been a recent push
fitting a tensor, which is an ellipsoid-shaped toward understanding structural brain abnormali-
mathematical model, at each brain voxel of a ties that may be associated with these conditions
DWI scan. In general, the shape of the tensor car- to both understand CDH pathophysiology and
ries information about the three-dimensional develop and improve treatment strategies. CDH
character of the water molecules’ diffusion [8]. encompasses several types of headache including
For example, diffusion is isotropic, with the ten- chronic migraine (CM), chronic tension-type
sor model being roughly spherical in shape, when headache (CTTH), new daily persistent headache
it is not hindered and molecules can flow equally (NDPH), and hemicrania continua. Medication
in all directions (e.g., within CSF). In contrast, overuse can often be a key contributing factor to
diffusion is anisotropic when there are barriers to the transformation of EM into chronic daily
diffusion (e.g., within WM), making diffusion headache, a phenomenon known as “medication
along the length of the axis greater than across it. overuse headache” (MOH) [16]. Most studies in
Using the tensor model, the degree of anisotropy the CDH literature have focused on patients with
can be captured by the parameter fractional CM (with or without MOH); however, in some
anisotropy (FA), which ranges from zero (com- cases, mixed groups were included. In this sec-
pletely isotropic) to one (completely anisotro- tion, the main findings from these studies will be
pic). However, FA alone does not fully capture reviewed in the context of other pain and neuro-
the tensor shape. Measuring FA in combination imaging studies.
with other DTI metrics such as mean, axial, and In general, pain is a multidimensional experi-
radial diffusivity can provide more information ence involving many brain structures as revealed
about the tensor shape and potentially reflect cer- by MRI among other methods. Neuroimaging
tain pathophysiological processes [10–12]. has revealed that many of the brain regions are
Functional MRI methods rely on blood oxy- involved in acute pain function abnormally and/
gen level-dependent (BOLD) signals that are or have abnormal structure in patients with
related to the proportion of oxy- to deoxy-hemo- chronic pain disorders. Nociceptive stimuli can
11 Imaging in CDH 159
evoke changes in brain activity associated with amygdala, prefrontal cortex (PFC), primary and
the sensory-discriminative, affective, motor, and/ supplementary motor areas (M1, SMA), thala-
or pain modulatory dimensions of pain. These mus, basal ganglia, cerebellum, and brainstem
brain regions include the primary and secondary structures such as the periaqueductal gray (PAG)
somatosensory cortices (S1, S2), the anterior and [17–21] (Fig. 11.1). In studies of episodic
midcingulate cortices (ACC, MCC), insula, migraine (EM), structural abnormalities have
Fig. 11.1 Schematic
representation of gray
matter regions
contributing to the
multidimensional
experience of pain. DLPFC
Several cortical and
subcortical brain areas
contribute to the M1
multidimensional
experience of pain.
These regions include S1
the dorsolateral
prefrontal cortex
(DLPFC), primary
motor and
somatosensory cortices
(M1, S1), brainstem
periaqueductal gray
(PAG), anterior and
midcingulate cortices
(ACC, MCC),
supplementary motor
area (SMA), insula, PAG
basal ganglia, and
thalamus. Other gray
matter regions ACC
frequently implicated in
pain perception but not
MCC
pictured here include the
amygdala and
cerebellum SMA
Insula
Basal ganglia
Thalamus
been reported in many of these regions [1, 4]. group of patients with CDH, including two with
Likewise, the WM connecting these brain regions CM, one with CTTH, and eight with medication
may also present with gross or microstructural overuse headache (MOH), was compared to
abnormalities [4]. In CDH, structural abnormali- patients with EM (n = 10) with or without aura
ties are also evident in these areas; however, there and to controls with or without infrequent epi-
is some evidence to support a greater severity of sodic tension-type headaches (n = 12). They used
abnormality compared to their episodic counter- T2-weighted MRI to assess local iron concentra-
parts. This may be indicative of disease progres- tions, as done previously in patients with episodic
sion, as epidemiological studies report that migraine [24, 27]. Tissue iron levels have been
approximately 14% of individuals with migraine shown to be associated with cellular function,
may progress to CDH [22] and/or differentiate and as such, measures of tissue iron may provide
CDH pathophysiological mechanisms. The shift insight into disease pathophysiology [23]. They
from episodic to chronic headache has been pro- restricted their analyses to the basal ganglia and
posed to involve progressive changes in the cen- red nucleus, structures previously shown to have
tral nociceptive system; however for some types decreased T2 signal intensity, consistent with
of CDH, additional mechanisms are likely [23]. increased iron, in patients with migraine with
One of the major brain regions implicated in longer migraine histories [27]. The results of the
pain disorders, including headache, is the PAG, a study by Tepper and group showed that when all
brainstem structure known for its role in pain mod- migraine patients were compared to controls,
ulation, among other functions. Some evidence patients had significantly lower T2 values in the
suggests that repeated migraine attacks result in globus pallidus of the basal ganglia and in the red
free radical formation in the PAG, resulting in a nucleus, in line with the results of Kruit and col-
lowered threshold for additional migraine attacks leagues. However, when episodic migraine
[24]. In one study, Welch and colleagues com- patients were compared to CDH patients, only T2
pared mean values of specific MRI relaxation time values in the globus pallidus were significantly
ratios, indicative of iron levels, in the PAG, red different. Therefore, this study provides evidence
nucleus, and substantia nigra of patients with EM, that T2-weighted MRI can differentiate structural
CDH (patients with near daily headaches due to differences in the globus pallidus between
medication overuse), and healthy controls [24]. patients who have episodic migraine and those
Each group consisted of 17 participants. The who have CDH [26]. The authors suggest this
results indicated that both the EM and CDH groups finding may reflect differences in headache fre-
had higher levels of iron in the PAG compared to quency and/or pathophysiology between episodic
controls, and for both groups, these levels increased and chronic headache groups.
with illness duration. It has been previously In a recent paper with a larger sample size
described that elevations in tissue iron are markers (n = 63), a VBM approach was used to compare
of disturbed neuronal function [25]. Since this GM in groups of patients with EM, CM (includ-
finding was ubiquitous across headache groups, ing MOH), and healthy controls without any his-
the authors suggested a role for the PAG as a tory of primary or secondary headache [28].
potential “generator” of migraine. Interestingly, Patients who had migraine diagnoses were
when comparing the intercept values of the corre- excluded if they had aura. Participants were age-
lations with disease duration, tissue iron values and sex-matched between groups. The results of
were higher than normal at the outset in migraine- the whole-brain analyses revealed that compared
susceptible individuals. This suggests that in addi- to controls, patients with CM had significantly
tion to iron levels rising as a consequence of larger right amygdala and right putamen vol-
migraine, it may also contribute to its etiology. umes. In contrast, patients with EM did not dem-
Tepper and colleagues conducted another onstrate any significant volume differences
study aimed at evaluating structural differences compared to controls. Additionally, regression
in patients with CDH [26]. In this study, a mixed analyses of GM volume and headache frequency
(headache days/month) showed significant posi- provide additional insight into the putative neu-
tive correlations in the temporal gyrus bilater- robiological underpinnings involved in MOH,
ally, right putamen, and inferior frontal gyrus specifically.
and a significant negative correlation with the In a study combining cortical thickness and
left cuneus and headache frequency. These pro- volume measures of GM, Schwedt et al. used
gressive changes suggest that at least some machine learning to classify CM patients com-
observed structural GM abnormalities may be pared to controls, with approximately 86%
the consequence of repetitive attacks over time. accuracy [32]. The GM regions that contributed
Interestingly, all associations with headache fre- to this classification included most of the cingu-
quency did not overlap with the areas of signifi- late gyrus, the lateral and medial prefrontal
cant differences compared to controls. This regions, the superior temporal lobe, the parahip-
corroborates another recent VBM study demon- pocampal cortex, the entorhinal cortex, and the
strating significant interactions between affec- insula. Average classifier accuracies were only
tive measures and amygdala volume in CM in 67% for EM patients versus controls. When
the absence of group volumetric differences [29] classifying EM versus CM patients directly, GM
and highlights the importance of examining regions that contributed to the classification
abnormal associations in CDH in addition to accuracy of 84% included the S1, cingulate
group differences. gyrus, lateral and medial PFC, insula, and tem-
Since many of the previous neuroimaging poral pole, among other regions. These results
studies described included patients with MOH in provide further support that subtle differences in
their CDH cohorts, Lai and colleagues [30] MRI-derived structural GM measures can reflect
sought to specifically compare GM volumes in headache chronicity and potentially CDH
CM patients with medication overuse (MO) and pathophysiology.
those without. The results of their whole-brain Others have shown that abnormalities in WM
VBM analysis revealed that CM patients with microstructure may be predominant in individu-
MO had decreased GM volumes in the orbito- als with long-term CM. In a recent study, Gomez-
frontal cortex and left middle occipital gyrus and Beldarrain and colleagues [33] examined
increased GM volumes in the left temporal pole structural abnormalities in WM using tract-based
and parahippocampal gyrus. These GM volume spatial statistics (TBSS), an automated method
differences explained approximately 31% of that allows for the comparison of WM tracts
variance in analgesics use frequency and orbito- between groups [34]. They used a region of inter-
frontal GM volume was predictive of MO treat- est (ROI) approach to specifically examine FA in
ment response. These results suggest that CM WM underlying the cingulate and insular gyri, in
with MO and CM without MO are reflected dif- addition to the uncinate fasciculus. Patients with
ferently in brain GM and provide insight into a CM (n = 18) and EM (n = − 19) were assessed at
potential source of variation between brain imag- baseline compared to controls (n = 15), and
ing studies that have mixed CM cohorts. patients were again assessed at a 3-month and
Cortical thickness has also been assessed in 6-month post-baseline. At the 3-month time
patients with MOH. In a study by Riederer et al. point, patients maintained the same diagnoses,
[31], 29 patients with MOH who had on average and no differences in FA were evident. However,
approximately 25 headache days per month at the 6-month time point, only nine patients still
were compared to 29 sex-matched healthy con- met diagnostic criteria for CM (i.e., more than
trol participants. Compared to controls, MOH 15 days of migraine pain per month) and were
patients had thinner cortex in the left PFC and labeled the long-term CM group. Only this group
higher local gyrification in a region encompass- demonstrated significantly lower FA values in the
ing the fusiform cortex and in the right occipital regions examined, which were also more pro-
pole. Since cortical thickness better estimates nounced on the right side and associated with
cortical GM compared to VBM, these findings headache frequency. The authors discussed that
these structural WM abnormalities may reflect In a study by Chen and colleagues [37], rest-
migraine pain chronification and as they were ing-state fMRI scans were acquired for 18
only evident in patients that maintained a CM patients with EM, 16 patients with CM, 44
diagnosis over time. These results contrast earlier patients with CM and MOH, and 32 normal con-
work by Neeb and colleagues [35] that found no trol participants. The authors were specifically
WM microstructural abnormalities in patients interested in examining functional connectivity
with EM and CM using a whole-brain TBSS of the marginal division of neostriatum, a flat,
approach. The differences between study results pan-shaped zone between the neostriatum and
may reflect methodological considerations such the globus pallidus, which has been implicated in
as using an ROI versus a whole-brain approach to learning, memory, and pain modulation. They
examine WM microstructure, differences in employed an ROI approach to examine marginal
patient sampling, medication use, and/or other division connectivity with the rest of the brain.
factors. The results of their study indicated that func-
Taken together, these findings support a role tional connectivity of the marginal division of
for structural abnormalities in the progression of neostriatum could not only differentiate patients
CDH and, in some cases, may even predispose from controls but also patient subtypes.
individuals to developing CDH. Specifically, when compared to controls, EM
patients showed altered connectivity between the
marginal division and the right insula, right pre-
unctional Brain Abnormalities
F central gyrus, and ACC. For the CM group,
in CDH as Assessed by fMRI altered connectivity occurred between the mar-
ginal division and brain regions including the
Functional activity in the brain can be associated right cuneus, left MCC, bilateral middle frontal
with electromagnetic, hemodynamic, and meta- gyri, and left hippocampus. The patients that had
bolic changes [14]. fMRI methods are most com- CM and MOH demonstrated altered connectivity
monly used capture brain hemodynamics, which only between the marginal division and the left
serves as a proxy for functional activity and con- parahippocampus, right middle frontal gyrus, and
nectivity measures in the brain. There are numer- inferior temporal gyrus. The authors concluded
ous ways to assess brain function using that the marginal division of neostriatum is an
fMRI. One option is to use a hypothesis-driven important structure to understand pain modula-
approach (e.g., general linear model regression), tion and migraine chronification, as connectivity
whereby signal time courses are extracted from of this structure could differentiate headache sub-
specific seeds or ROIs based on a priori hypoth- types [37].
eses. Alternately, a whole-brain approach may be Chen and colleagues again used an ROI rest-
used when hypotheses about specific brain area ing-state fMRI approach to study amygdala
involvement are lacking. Data-driven approaches connectivity in patients with EM, CM, and con-
(e.g., independent component analysis) can addi- trols [38]. Patients with EM had increased func-
tionally identify networks of activity (e.g., default tional connectivity between the left amygdala
mode network, salience network, central execu- and the left MCC and left precuneus, compared
tive network, sensorimotor network) (Fig. 11.2) to controls. No functional connectivity differ-
that may not have been predicted [14, 36]. While ences were observed for the right amygdala in
these options allow for flexibility when designing EM patients. In contrast, patients with CM had
a study, they can also be the source of heteroge- significantly lower functional connectivity
neity between study results. In recent years, there between the right amygdala and regions of the
have been important advances in our understand- occipital lobe, compared to controls, but no con-
ing of brain activity in CDH. Some of these nectivity differences of the left amygdala. This
prominent findings will be discussed. right lateralized amygdala finding in CDH
Fig. 11.2 Brain a Default mode network (DMN)

networks implicated in
chronic pain. (a) DMN:
medial prefrontal cortex
(mPFC), left and right
lateral parietal cortex,
left and right lateral
temporal cortex, and
posterior cingulate
cortex. (b) SN: right and
left temporoparietal
junction, midcingulate
cortex, left and right
anterior insula, and left
and right dorsolateral
prefrontal cortex b Salience network (SN)
(dlPFC). (c) Central
executive network:
mPFC, dlPFC, and
posterior parietal cortex.
(d) Sensorimotor cortex:
left and right primary
motor cortex and left
and right primary
somatosensory cortex
c Central executive network (CEN)
d Sensorimotor network (SM)

patients has also been demonstrated using struc- posterior hypothalamus appears to play a role in
tural MRI [29, 39]. The animal literature has the acute stage pain, while the anterior hypothal-
shown right lateralized pain-related activity in amus seems to be more involved in attack genera-
animal models of inflammatory pain [40, 41]. tion and migraine chronification.
Moreover, transient increases in amygdala A recent study carried out by Androulakis
activity were observed only acutely in the left et al. [45] sought to evaluate resting-state func-
amygdala in a neuropathic pain model, whereas tional connectivity of women with CM (includ-
activity in the right amygdala became predomi- ing those with MOH) in three major intrinsic
nant at 2 weeks post-surgery and persisted [42]. brain networks: the default mode network
While these amygdala findings may not be spe- (DMN), salience network (SN), and the central
cific to CDH, they may serve as a useful bio- executive network (CEN) (Fig. 11.2a–c).
marker of pain chronicity and the heavy affective Previous work on patients with EM demonstrated
burden it imparts, in general. abnormal connectivity within these networks
In another study, Schulte and colleagues [43] [46–48]; however, their connectivity patterns in
used a standardized trigeminal nociceptive stim- CM had not previously been characterized.
ulation task to examine brainstem activity of Compared to controls, all three networks were
patients with EM (n = 20), CM (n = 22), and less coherent in CM patients compared to age-
healthy controls (n = 21). Typically, the spatial and sex-matched controls. When CM patients
resolution of conventional whole-brain fMRI were stratified based on MOH status, each group
protocols does not allow for the detailed differen- remained less coherent in the resting-state net-
tiation of brainstem structures. As such, the works examined compared to controls. No sig-
authors used a specialized fMRI sequence to spe- nificant differences in network connectivity were
cifically examine the brainstem, as they have found between the patient subtypes. Importantly,
done previously [44]. The fMRI task involved the significant associations were also found for the
application of either gaseous ammonia, an activa- SN and clinical variables such that decreased SN
tor of nociceptive fibers, or air to the left nostril activity was associated with the frequency of
of participants using an olfactometer with a moderate and severe headache days and increased
Teflon tube. The results showed that in patients SN activity was associated with cutaneous allo-
with CM, activity within the right anterior hypo- dynia, providing potential pathophysiologic
thalamus was higher compared to controls when underpinnings for these findings.
the ammonia and air conditions were compared. As discussed in the structural imaging section,
Additionally, it was demonstrated that this ante- machine learning has been used to classify CM
rior hypothalamus region showed greater activity from EM patients and controls using GM thick-
in patients with CM who had a headache at the ness and volume measures with high accuracy. In
time of scanning compared to EMs with head- their recent paper, Chong et al. demonstrated that
aches at the time of scanning. Because a larger resting-state functional connectivity could also
subgroup of CM patients had headache at the discriminate patients with migraine from healthy
time of scanning, a secondary analysis was con- controls [32]. Connectivity of the right middle
ducted to exclude headache chronicity as a vari- temporal, posterior insula, MCC, left ventrome-
able. This time, significant activity in the posterior dial PFC, and amygdala bilaterally contributed to
hypothalamus in migraineurs with headache at this discrimination. While this analysis combined
the time of the scan was observed, compared to patients with EM and CM, it was demonstrated
migraineurs without headache and controls. that classification accuracy was higher (~97%
These findings suggest an important role for the accuracy) for migraineurs with longer disease
hypothalamus in the pathophysiology of migraine duration (>14 years) compared to migraineurs
chronification and provide evidence for differen- with shorter disease duration (~82% accuracy),
tial roles of the anterior and posterior hypothala- suggesting that greater functional reorganization
mus in migraine. The authors concluded that the occurs over time in patients with migraine.
Several recent studies have started to employ dependence, to normal levels of function could
fMRI methods to elucidate CDH pathophysiol- predispose these patients to recurring analgesic
ogy; however, differences between imaging overuse. Nevertheless, because MOH appears to
methods and participant samples make it difficult be largely reversible following medication with-
to generalize findings. These studies nonetheless drawal, a failure to halt medication overuse is
provide significant insight into how brain activity believed to contribute to the chronification of
and connectivity differs in patients with CDH headaches.
compared to episodic headache and controls and Another common modality used to study
set the foundation for future studies to build pathological brain function is MEG, a highly sen-
upon. sitive brain imaging tool capable of recording the
magnetic fields produced by neural activity and
has greater temporal resolution than fMRI meth-
hat Other Neuroimaging
W ods. Its noninvasive nature permits its utility in
Modalities Reveal About CDH many different patient populations, including
pediatric populations. A study by Leiken and col-
In addition to structural and functional MRI, leagues [51] used MEG to assess the spatial and
other neuroimaging modalities, such as PET, temporal properties of brain activity during a fin-
have been used to investigate functional abnor- ger tapping motor task in a pediatric cohort of
malities in CDH patients. Unlike MRI, PET is an patients suffering from acute (n = 27) and chronic
invasive procedure that involves the administra- (n = 27) migraine. While healthy subjects (n = 27)
tion of a biologically active molecule tagged with displayed the expected activation of primary
a radioactive tracer into the bloodstream. Using motor region contralateral to the finger perform-
advanced kinetic modeling, the decay of the ing the tapping motion, this pattern of activity
radioactive tracer can be used to image synaptic extended beyond the primary motor regions in
activity or the tissue concentration of a molecule acute migraine patients into sensorimotor regions,
of interest (i.e., membrane-bound receptors). SMA, premotor regions, and occipital cortex.
Given its invasive nature, PET represents a sensi- This effect was even more prominent in the CM
tive technique for assessing in vivo changes in group, suggesting that cortical excitability is ele-
cerebral blood flow (CBF) during pathological vated in migraine and the degree of excitability
conditions in humans [49]. tracks the severity of the migraine (i.e., greater
Many patients suffering from EM often resort excitability in chronic migraine than in acute
to a multitude of analgesics to manage their migraine). In addition to heightened cortical
symptoms, which can result in MOH. To investi- excitability, this study also demonstrated that CM
gate patients with MOH, Fumal and colleagues patients were at significantly higher odds for
[50] used PET imaging to examine the functional engaging deep brain (subcortical) areas in com-
properties of the brain in chronic migraineurs parison to acute migraine and controls. Together,
(n = 16) with analgesic overuse before and these findings suggest that pediatric chronic
3 weeks following medication withdrawal. migraine patients experience elevated activation
Before withdrawal, chronic migraineurs exhib- of cortical-subcortical networks and recruit
ited aberrant activity across many pain process- abnormally large neural network to perform a
ing structures, including the thalamus, ACC, basic motor task.
insula, orbitofrontal cortex (OFC), and cerebel- Other neuroimaging modalities can serve as
lum. Interestingly, these aberrations were effec- powerful tools to assess brain function in dif-
tively reversed in all of these regions 3 weeks ferent ways than MRI approaches. The use of
after medication discontinuation, with the excep- alternate imaging modalities in conjunction
tion of the OFC which continued to show abnor- with MRI can provide valuable opportunities to
mal activity. The inability to restore activity in fully characterize brain function associated
the OFC, a region of the brain implicated in drug with CDH.
uture Directions for Neuroimaging

F ity’s specific limitation and cross-validate find-
Research in CDH ings from different sources.
There remains an opportunity for future research
There are several exciting opportunities for future to understand the cellular and molecular underpin-
neuroimaging research in CDH. As previously nings of structural and functional brain abnormali-
mentioned, CDH is a descriptive term encom- ties as detected by neuroimaging. Several candidate
passing several types of chronic headache. To mechanisms exist to account for these findings
date, the neuroimaging literature has primarily including changes in axon sprouting, dendritic
focused on CDH patients with CM or MOH, branching, neurogenesis, glial changes, angiogen-
likely due to their higher prevalence in the popu- esis, fiber organization, myelin remodeling, and
lation. A large literature now exists to suggest astrocyte changes, among others [55]. However,
that structural and functional brain abnormalities their precise roles in CDH neuroimaging findings
may reflect specific clinical features of chronic remain to be determined. Knowing which cellular
pain disorders and/or their underlying pathophys- and molecular processes contribute to alterations in
iology [12, 52]. The ability to differentiate CDH GM thickness and volume, WM microstructure,
subtypes based on neuroimaging-derived bio- and function could potentially allow for the devel-
markers would be highly beneficial toward opment of new therapeutic strategies aimed at lim-
understanding the neural underpinnings of iting or reversing these abnormalities.
chronic headache subtypes and provide insight
into the mechanisms of action of effective treat- Conclusion
ments. Neuroimaging-based biomarkers have In summary, neuroimaging provides a valu-
previously been used to differentiate subtypes of able tool to gain insight into CDH pathophysi-
depression with varying clinical symptoms with ology. There are several modalities available
high accuracy and even predict which patients to assess both brain structure and function in
would benefit from repetitive transcranial mag- CDH patients. While great leaps have been
netic stimulation therapy [53]. Knowing in made in our understanding of CDH, there are
advance which CDH patients would be respon- several opportunities for the future studies to
sive to specific therapeutic strategies could use neuroimaging to develop biomarkers of
greatly decrease both the patient and economic CDH subtypes, cross-validate imaging modal-
burden of these disorders. ities, and determine the cellular and molecular
While recent studies have begun to employ underpinnings of these imaging findings.
individual neuroimaging approaches to advance
our understanding of brain abnormalities in
CDH, multimodal neuroimaging approaches may References
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Laboratory Investigation in CDH
12
Benjamin J. Saunders, Iryna S. Aberkorn,
and Barbara L. Nye
Introduction remembering that just because a patient has a his-

tory of a primary headache disorder, it does not
The chronic daily headache patient will present mean that they cannot develop a new secondary
in two distinct clinical settings: to the outpatient headache disorder.
practitioner and to the emergency department for The laboratory and neuroimaging evaluation
evaluation. The role of the provider in these of the patient is often preformed concurrently,
diverse clinical settings is very different. The role and one can inform the other.
of the emergency practitioner is to stabilize and
exclude conditions that will lead to immediate
morbidity, where the outpatient provider is tasked Serological Testing
with the role of establishing a clear diagnosis and
treating the patient appropriately for the condi- Complete Blood Profile
tion. Both providers have the important task of
evaluating for red flag signs and symptoms that A complete blood count includes white blood
may lead to the diagnosis of a secondary condi- cell count, red blood cell count, platelets, as well
tion causing the patient’s headaches. as a differential.
In the previous chapters, you have read about White blood cell count and differential:
how to take a headache history and about specific Neutrophil count elevation with a left shift would
headache disorders that should be considered. In be indicative of an infectious process. In patients
this chapter we will walk you through available that are immunocompromised, leukopenia and
laboratory testing that should be considered in thrombocytopenia may be present. Elevation in
each of the clinical scenarios. Finally, we will go the neutrophils vs lymphocytes can help differ-
through some special cases and considerations entiate between bacterial and viral etiologies,
that can present to either the inpatient or outpa- respectively.
tient setting. The focus will be to eliminate the Red blood cell, hemoglobin, and hemato-
suspicion for a secondary headache disorder, crit: Relationships between anemia, myelopro-
liferative diseases such as polycythemia vera,
and sickle cell disease with the development of
B. J. Saunders headaches have also been described.
Commonwealth of Massachusetts, Boston, MA, USA
I. S. Aberkorn · B. L. Nye (*)
Dartmouth-Hitchcock Medical Center,
Lebanon, NH, USA
e-mail: Barbara.L.Nye@hitchcock.org

170 B. J. Saunders et al.
Platelets: Thrombocytopenia can be found Table 12.1 List of medications used for the treatment
of headache disorders that cause drug-induced liver
as a result of a medication reaction in headache
injury [2]
patients. Medications that can cause this include
Type of liver
but are not limited to acetaminophen, ibupro- toxicity Medications
fen, naproxen, carbamazepine, and valproic Acute injury Acetaminophen, aspirin,
acid. Drug-induced thrombocytopenia typically bupropion, diclofenac, fluoxetine,
occurs within the first 2 weeks of drug exposure. lisinopril, losartan, NSAID,
Recovery starts 1 to 2 days following the dis- paroxetine, sertraline, trazodone,
valproate, varenicline
continuation of the medication. Recovery to the
Cholestasis Carbamazepine, chlorpromazine,
patient’s normal range typically occurs within diclofenac, phenothiazine
1 week [1]. Mixed liver injury Amitriptyline, carbamazepine,
cyproheptadine, ibuprofen,
phenothiazines, trazadone,
verapamil
Complete Metabolic Profile (CMP) Steatohepatitis Valproic acid
and
This study includes evaluation of liver function, microvesicular
renal function, as well as electrolytes and steatosis
glucose. Granulomas Carbamazepine, diclofenac,
diltiazem
CMP can be useful in the evaluation of the
Autoimmune Diclofenac
chronic daily headache patient for both the initial hepatitis
assessment and continued medical management Chronic hepatitis Diclofenac, Lisinopril, trazodone
and monitoring. Renal failure has been found Neoplasm Carbamazepine
to be a cause of headache. Dehydration is com- Ischemic necrosis Ergot
mon in headache patients who frequently have
associated symptoms of nausea, vomiting, gas-
troparesis, and decreased oral intake. This can Coagulation Studies
lead to prerenal failure especially with the con-
comitant use of nonsteroidal anti-inflammatory Coagulation studies are useful in evaluation of
drugs (NSAIDs). These have been linked to an refractory headache in patients with suspected
increased risk for renal injury, causing parenchy- hypercoagulable disorders such as SLE, an
mal kidney disease. antiphospholipid syndrome.
Hypoglycemia can cause brain dysfunction Current literature points to a connection
and may be associated with headache; however between migraine, especially with aura, and ele-
there is no conclusive evidence to support this vated level of procoagulation factors [4].
association. Current evidence suggests checking:
The combination of the lactic acidosis in
patients with migraine attacks and seizures or 1. Full hypercoagulable profile in patients with
stroke-like episodes could be suspicious for migraine with (1) aura and a personal history
MELAS (mitochondrial encephalopathy, lactic or family history of thrombosis or (2) MRI
acidosis, and stroke-like episodes). In addition to evidence of microvascular ischemia or of
elevated lactate level, there might be an elevated stroke.
level of pyruvate in the serum. However these 2. Screen patients with migraine with aura for
abnormalities are not confirmatory for the diag- markers of endothelial activation (vWF,
nosis. MELAS is covered in more details later in high-sensitivity C-reactive protein and
this chapter. fibrinogen) [3].
Liver function studies are used more for
the monitoring of medication complications Patients taking oral contraceptives are
(Table 12.1). also at risk for secondary headaches due to
12 Laboratory Investigation in CDH 171
hypercoagulable state as estrogen-containing tory of hypertension. The most common tests for
oral contraceptives are associated with elevated detection of this condition are 24-h urine collec-
plasma concentrations of clotting factors II, VII, tion for creatinine, total catecholamines, vanillyl-
VII, X, and prothrombin, fibrinogen, and throm- mandelic acid, and metanephrines. The most
bin-activatable fibrinolysis inhibitor (TAFI), a sensitive test is plasma metanephrine. Be aware
procarboxypeptidase B- like proenzyme which that false-negative results can occur, and it is best
inhibits fibrinolysis [4, 5]. to collect specimens during symptomatic periods
[9, 10].
upus Anticoagulant, Anticardiolipin
L
Antibodies, Protein S, Protein C, Factor
VIII, Antithrombin III, and Factor V Markers of Inflammation
Leiden
Antiphospholipid protein syndrome (APS) can Vasculitis and giant cell arteritis may be causes of
be primary or secondary. The primary syndrome chronic daily headache. Erythrocyte sediment
is present in the absence of other autoimmune rate (ESR) and C-reactive protein (CRP), as well
diseases. Secondary forms include systemic as platelet counts and iron studies, can be benefi-
lupus erythematous (SLE). Chronic headache or cial in identifying systemic inflammation. It
episodes of migraines are the most common neu- should be noted that steroids as well as NSAIDs
rological manifestation of APS [5]. may artificially suppress ESR and CRP.
Patients that have a history of headache,
miscarriages, and venous thrombosis should be ESR
screened for hypercoagulable states. Erythrocyte sediment rate (ESR) is the rate at
which red blood cells sediment in a period of 1 h.
D-Dimer This is a very nonspecific test that requires a level
Cerebral venous thrombosis (CVT) is uncommon of clinical suspicion to help guide the provider. It
but should be suspected in a patient presenting can be elevated in a variety of conditions includ-
with acute worsening headache symptoms. This is ing inflammation, pregnancy, anemia, autoim-
more common in women (3:1, female/male ratio) mune disorders, infections, kidney diseases, and
with some gender-specific risk factors, including some cancers—like lymphoma and multiple
the use of oral contraceptives, pregnancy, puerpe- myeloma.
rium, and hormone replacement therapy [6]. The For patients that are over 50 years old and have
D-dimer study has not been shown to be clinically headache, this can be useful in the identification
helpful in the assessment of CVT in most cases. or ruling out giant cell arteritis (GCA). ICHD-3
Up to 26% of 73 patients in one study with a nega- beta criteria for headache attributed to giant cell
tive D-dimer had radiography-confirmed CVT arteritis (GCA) include the development of head-
[7]. A meta-analysis demonstrated that in low-risk ache in temporal relationship with clinical or bio-
patients (headache patients with normal neurological signs of onset of GCA; this would include
logical examination, normal standard CT head, ESR, CRP, and temporal artery biopsy [11].
and absence of risk factors), d-dimer has a high The American College of Rheumatology GCA
negative predictive value for excluding diagnostic criteria include the elevation of ESR
CVT. Sensitivity was low but comparable to val- above 50 mm/hour by the Westergren method.
ues accepted in pulmonary embolism and deep Sensitivity of ESR alone is 86.5% and a specific-
venous thrombosis assessments [8]. ity of 47.7% [12].
Normal clinical ESR value is anything less
than age divided by 2 in men and age plus 10
Plasma Metanephrines divided by 2 in women [13]. An alternative for-
mula uses a more complex method to determine
Catecholamine-secreting tumors can be consid- a normal ESR based on age: 17.3 + (0.18 ¥ age)
ered with refractory chronic headache and his- for men and 22.1 + (0.18 ¥ age) for women [14].
ESR result depends on multiple factors includ- to test for anti-beta-2- glycoprotein I antibodies
ing age and medication use. Steroids and NSAIDs or clot-based tests for the presence of the lupus
use could suppress the ESR value in GCA. It also anticoagulant [10, 25].
could be normal in cases of biopsy-proven GCA Primary angiitis of the central nervous sys-
[15, 16]. tem (PACNS)—normal serological markers but
abnormal CSF (nonspecific elevation in total pro-
CRP tein or WBC count).
C-reactive protein (CRP) is an acute-phase reac-
tant; levels rise in response to inflammation. CRP
level is stable and does not depend on age or sex. Endocrine Testing
A CRP value of 5 is considered elevated. The
sensitivity of CRP in biopsy-proven GCA is hyroid Function Studies
T
98.6%, and specificity is 75.7% [10, 17]. There are multiple studies investigating the rela-
The combination of both ESR and CRP pro- tionship between headache disorders and thyroid
vides high sensitivity and specificity for a diag- function. The relationship between headache and
nosis of GCA. Per 1 study of 199 patients, only 1 hypothyroidism has not been well established.
patient had both a normal ESR and normal CRP Several small studies have shown a weak rela-
in the presence of biopsy-proven GCA [10, 18]. tionship between hypothyroidism and migraines.
A small case control study published in 2002
ANA suggested an association [26], and a small uncon-
Antinuclear antibodies (ANA) are autoantibodies trolled case series in 1998 showed resolution of
that bind to the contents of the cell nucleus. There headache in 31 of 102 patients treated for hypo-
are many subtypes that can be found in specific thyroidism [27]. A more recent article by
autoimmune disorders including systemic lupus Carvalho et al. described a cross-sectional study
erythematosus (SLE)—both primary and drug of overt hypothyroidism and subclinical hypo-
induced—antiphospholipid syndrome (APS), thyroidism both with and without headache
Sjögren’s syndrome, mixed connective tissue dis- attributed to hypothyroidism [28]. The study
ease, scleroderma, polymyositis, dermatomyosi- showed similar frequencies of headache attrib-
tis, and autoimmune hepatitis. Headache is one of uted to hypothyroidism in both overt and subclin-
the most often described neurologic manifestation ical hypothyroidism. The study did also show
in patients with APS, being presented either as a that a history of migraine was more common in
chronic headache or episodes of migraine [19]. patients presenting with headache attributed to
There some evidence that about 1% of hypothyroidism. After levothyroxine treatment
patients with SLE develop headaches due to the study showed an improvement in 78% of
idiopathic intracranial hypertension (IIH). Also, cases. This study did have some limitations as it
patients with polycystic ovary syndrome (POS) was a relatively small, cross-sectional study.
have shown abnormalities in coagulation cascade There have been some conflicting studies,
associated with IIH. Based on these findings, an which have shown that hypothyroidism is not
ANA test and a lumbar puncture to evaluate an prevalent among patients with chronic head-
opening pressure should be included in an evalu- aches or that there is no association between
ation of patients with chronic refractory head- hypothyroidism and headache [29–31]. However,
ache [20–24]. these studies too have their limitations, as they
A diagnosis of antiphospholipid antibody syn- tend to be older studies and were on a small scale.
drome should be considered in female patients Martin et al. [32] report that patients with pre-
with recurrent pregnancy loss or patients with existing headache disorders had a 21% increased
unexplained vascular thrombosis. It is an autoim- risk of developing new-onset hypothyroidism,
mune syndrome, and diagnosis requires evidence while those with possible migraine showed an
of antiphospholipid antibodies. It is appropriate increased risk of 41%. One of the population-
based studies reported that headache was 50% include but are not limited to headache, myalgia,
less likely in women with no history of thyroid arthralgias, fever, and fatigue, and who have no
dysfunction [31]. other clinical signs or symptoms of Lyme dis-
Based on growing evidence of relation- ease, particularly erythema migrans, and do not
ship between headache disorders and thyroid have a history of exposure to an arthropod vector
abnormalities, we recommend checking serum and do not live or have not recently traveled to an
TSH and a free T4 in all patients with chronic endemic area [34].
migraine to evaluate for hypo- and hyperthyroid- The current CDC recommendation is for a
ism. Diagnostic TSH value for hypothyroidism is two-tiered test for Lyme disease. At the current
10 mU/L with total serum thyroxine (T4) levels time, serologic testing is the only Lyme disease
of 4.8 lg/dL. If TSH levels are elevated, a free T4 test method approved by the US FDA. The first
level should be checked. Some experts suggest test is performed using either an enzyme immu-
checking total T4 level and thyroid-binding glob- noassay (EIA) or immunofluorescence assay
ulin level. Elevation of TSH levels in the setting (IFA) [1]. Most commonly enzyme immunoas-
of a low T4 is specific for primary hypothyroid- says are used, and measured total immunoglobu-
ism diagnosis. Elevated TSH in the presence of lin G (IgG), immunoglobulin M (IgM), and, less
normal T4 levels is defined as subclinical hypo- commonly, immunofluorescence assays are used
thyroidism [33]. [34]. Enzyme immunoassays are quantitative
Hypothalamic or pituitary tumors, lympho- tests, and they are diagnostically sensitive but not
cytic hypophysitis, and traumatic brain injury specific; specificity rates range only about 85%
could present clinically with headache, and cen- [34]. False-positive enzyme immunoassays may
tral hypothyroidism should be suspected when occur in the presence of multiple cross-reactive
TSH levels are inappropriately low in relation to antibodies, some of which include but are not
T4 level. limited to Helicobacter pylori, some autoim-
mune disorders, syphilis, anaplasmosis, and oth-
rolactin, GH, and ACTH
P ers [35]. In the presence of a positive first-tier
Evaluation of pituitary hormonal function for test, a second-tier test should be able to differen-
patients with chronic headache is not recom- tiate Lyme disease from other conditions, since
mended routinely. Headaches secondary to pitu- second-tier testing has a higher diagnostic speci-
itary adenoma are usually diagnosed by ficity [36]. Further testing is not performed if the
radiological methods. Pituitary apoplexy, which is first-tier test is negative, because doing so would
a life-threatening condition, can be diagnosed in reduce the test diagnostic specificity and could
ER based on clinical symptoms. Pituitary function potentially yield a false positive.
tests can be abnormal in cases of pituitary apo- Second-tier testing uses immunoblot tests;
plexy, but they usually do not play a critical role in this consists of a Western blot for IGF and IgG
the diagnosis. which has a very high diagnostic specificity [34,
Although not the part of diagnostic criteria, 37]. Failing to follow the sequence outlined in the
in cases of lymphocytic hypophysitis, prolactin CDC recommendation increases the probability
level could be elevated in 50% of cases, or auto- of a false-positive result, because of decreas-
antibodies against hypophyseal cytosol protein ing test specificity. Negative EIA testing is not
could be detected in 20% [1]. sent for further testing and is considered nega-
tive. A positive or equivocal EIA with a negative
Western blot is reported as negative, while a posi-
Infectious tive or equivocal EIA with a positive Western blot
is reported as positive [38].
Lyme Unfortunately, two-tiered testing is relatively
Testing for Lyme disease is not recommended in insensitive (<40%) during early illness which is
patients with vague complaints, which may characterized by erythema migrans rash; however
it is reasonably sensitive (>87%) and very spe- HIV

cific (99%) when used for diagnostic testing of In patients with acute symptomatic HIV infec-
disseminated Lyme disease [39]. During the first tion, the usual time from exposure to develop-
30 days of the disease, when erythema migrans ment of symptoms is typically 2–4 weeks,
are most notably present, an IgM response is although incubation periods of up to 10 months
present, and an IgG response does not typically have been observed [43]. Initial HIV infections
develop until after 30 days. If the patient has had can present with a variety of symptoms and are
signs and symptoms for less than 30 days, IgM known as acute retroviral syndrome. Typical
and IgG Western blots should be performed; if signs and symptoms include, but are not limited
symptoms are present for more than 30 days, to, fever, sore throat, rash, arthralgias, lymphade-
only IgG Western blot should be performed. nopathy, weight loss, diarrhea, and headaches
Both IgM and IgG can remain elevated for years [44]. The headache is often described as retro-
after successful treatment; therefore IgM is not a orbital exacerbated by eye movement. With the
dependable indicator of reinfection [34]; instead onset of headache, one must be concerned about
the clinician should rely on clinical signs and aseptic meningitis which is typically accompa-
symptoms. nied by photophobia. In addition to HIV testing,
Negative testing during the early stages of a lumbar puncture with cerebrospinal fluid analy-
Lyme disease does not completely eliminate the sis should be obtained [45]. In a study of 41
possibility of Lyme disease. If there is a high patients presenting with acute symptomatic HIV
clinical suspicion of Lyme disease, a second infection, approximately 24% had signs and
specimen may be tested; it is also important keep symptoms that would be suggestive of an aseptic
in mind that antimicrobial therapy may decrease meningitis [46].
the main response and lead to negative testing at Thus, in high-risk populations, we recom-
later dates [40, 41]. mend a very low threshold for HIV testing with
Lyme neuroborreliosis occurs in proximally new-onset chronic headache. High-risk popu-
5–20% of Lyme disease cases in North America. lations include homosexual and bisexual men
Manifestations can include aseptic meningi- who engage in unprotected sex [47]; in par-
tis, encephalopathy, cranial nerve palsies, and ticular, minorities appear to be more affected
peripheral neuropathies [34]. Aseptic meningitis in this demographic. In addition certain minori-
produced by Lyme disease can manifest as head- ties appear to have higher infection rates and
aches and neck pain with possibility of low-grade higher percentage of infected individuals in
fever. Cerebrospinal fluid profile is similar to their communities. These include African
that of viral meningitis, with a mild to moder- Americans and those of Latino descent [47].
ate lymphocytic pleocytosis, normal to slightly Incarcerated individuals have also been shown
decreased glucose level, and a mild increase in to have an infection rate up to five times the rate
protein. Approximately 5% of untreated patients of non-incarcerated individuals [47]. High-risk
went on to develop chronic neuroborreliosis behaviors include but are not limited to IV drug
which can manifest as encephalomyelitis and use and having unprotected sex with multiple
chronic axonal polyneuropathy which can pres- partners.
ent as radicular pain or paresthesias. In cases In patients with newly diagnosed HIV with
of suspected neuroborreliosis, CSF should be signs and symptoms of aseptic meningitis, a
evaluated for the presence of antibodies by EIA lumbar puncture with appropriate CSF fluid
and should have a higher titer in the CSF than studies should certainly be pursued. CSF stud-
in the serum (this seems to have fallen out of ies of patients with later-stage HIV disease
favor). Headache, fatigue, paresthesias, and mild and suspected opportunistic infections will be
stiff neck alone are not criteria for neurological covered in the cerebral spinal fluid analysis
involvement [42]. section.
Lumbar Puncture cases of tuberculosis. Elevated CSF glucose is

more often seen in cases of aseptic meningitis but
Patients with chronic refractory headaches may if not can be <40% in cases of HSV. Cases of sub-
require lumbar puncture as part of the workup; arachnoid hemorrhage often have normal glucose
this may be pursued after imaging has been per- levels. Nucleated cell counts will vary with labo-
formed. Lumbar puncture may be used to evalu- ratory, but elevated cell counts are often indicative
ate for both high and low pressure headaches, as of meningitis or multiple sclerosis. Typically,
well as basic labs which may assess for signs of multiple sclerosis will have a normal to slightly
inflammation and infection. Every lumbar punc- elevated cell count, typically on the order or
ture should have an opening pressure measured; 0–20 cells/microliter with a lymphocyte predomi-
this should be done in the lateral decubitus posi- nance. Bacterial meningitis will typically a have
tion with the patient’s legs extended. Normal cell count of >100 cells/microliter with a poly-
CSF pressure should be 7–18 cm H20 in adults morphonuclear predominance. Typically, aseptic
[48], although some sources do report this as meningitis will have a lymphocyte predominance,
5–25 cm H20 [49, 50]. Certainly an opening pres- and cell counts may range between 10 and
sure of less than 5 cm H20 or greater than or equal 1000 cells/microliter. CSF typically has a clear
to 25 cm H20 is cause for concern (Table 12.2). color, and cloudiness or opacity may clue the cli-
Basic CSF labs should be sent with each lumbar nician into possible infections.
puncture; this should include a cell count and dif-
ferential, protein, and glucose.
Opening Pressure
ell Count and Differential, Protein,

C Obtaining a close opening pressure when pre-
and Glucose forming a lumbar puncture can help guide the
management of a headache patient. An elevated
Typical protein levels in CSF may vary by labora- opening pressure ≥25 cmH2O in adults or
tory, but a typical CSF protein level for an adult is ≥28 cmH2O in children will meet diagnostic cri-
<45 mg/dl. Elevated CSF protein can be a sign of teria for idiopathic intracranial hypertension in
meningitis or tuberculosis, and low levels can be a the setting of a normal cerebrospinal fluid profile
sign of autoimmune disease or multiple sclerosis. [11, 51].
Elevated protein can also raise suspicion of sub-
arachnoid hemorrhage. Normal CSF glucose is
approximately 60% of serum values. CSF glucose ACE
can be low in fungal and bacterial meningitis or in
Neurologic complications can occur in about 5%
Table 12.2 Conditions associated with headache catego- of patients with sarcoidosis [52], and the present-
rized by opening pressure measurements ing manifestation of sarcoid can be neurological
Low- CSF leak, CSF flow obstruction in up to half of those patients with neurosarcoid-
pressure osis. Headache is one of the most common pre-
headaches
senting symptoms of neurosarcoidosis [53]. In
Normal Aseptic meningitis, intracranial masses,
pressure cerebral epidural abscess patients with or without isolated n eurosarcoidosis,
headaches serum angiotensin-converting enzyme (ACE)
High- IIH, meningitis, SAH (acute), abscess, may not always be elevated; in addition CSF
pressure intracranial vasculitis, encephalitis, ACE may either not be consistently elevated or
headaches meningeal carcinomatosis, intracranial
mass, venous sinus thrombosis, GBS, may be falsely elevated. Both infection and carci-
jugular venous compression, choroid nomatosis meningitis can cause elevated
plexus papilloma ACE. The most common CSF abnormalities in
patients with diagnosed neurosarcoidosis were However, the infectious work may vary by
elevated CSF protein and/or pleocytosis, and ele- the time of year. During the spring and sum-
vated CSF ACE is a less common finding [54]. mer months, the clinician should have a higher
CSF ACE concentrations could also potentially suspicion of arthropod-associated diseases and
be elevated if serum ACE elevations exist in addi- test accordingly based upon location and risk
tion to conditions which may cause a leaky factors.
blood-brain barrier. For this reason, CSF ACE
testing should be pursued if there is a clinical sus-
picion of sarcoidosis. TNF-Alpha
Levels of tumor necrosis factor alpha (TNF-α)

Cytology have been shown to be elevated in patients with
new daily persistent headache (NDPH) [57].
Although carcinomatous meningitis is a rare TNF-α is a pro-inflammatory cytokine that is
complication of cancer, it is often devastating. involved in immune and inflammatory activities
Headache is often the most common initial symp- as well as pain initiation. A 2007 study by Rozen
tom and can present in up to 32% of patients [55]. et al. compared CSF TNF-α levels of 36 healthy
CSF findings are typically high protein, low glu- volunteers with 38 patients with chronic daily
cose, and lymphocytic pleocytosis. Cytology is headache [57]. The study evaluated 20 patients
the definitive diagnostic finding with a very high with new daily persistent headache as well as 16
specificity. However the sensitivity has been chronic migraine patients and 2 posttraumatic
reported between 80 and 95 percent. To minimize headache patients. The study did demonstrate
false negatives, a minimum of 10 ml should be elevations and tumor necrosis factor alpha in 19
sent for cytological analysis, specimens should of the 20 new daily persistent headache patients,
be promptly processed, and the lumbar puncture with levels above the upper limit of normal. The
should be repeated if there is high clinical suspi- study did also demonstrate that all 16 chronic
cion. The optimal number of samples is unclear, migraine patients had elevated levels of CSF
but the rates of positive cytology approach 98% tumor necrosis factor alpha above the upper limit
for more than three samples per patient; however of normal as defined by the testing laboratory.
this did vary with the volume of CSF as well as Serum TNF-α levels had also been tested in 14
specimen processing and intervening treatment NDPH patients as well as 5 chronic migraine
[56]. patients, and these levels were only elevated in 3
of the NDPH patients. None of these patients
demonstrated abnormal CSF cell counts, total
Infectious Workup protein, or glucose. Cultures were also done and
negative. Seven patient’s did have elevated spinal
The infectious workup with regard to headache opening pressures (>20 cm H20), but none of
can be broad. Typically, the CSF results may which were deemed to have intracranial hyper-
point the clinician in the proper direction. CSF tension and all had normal funduscopic examina-
results showing meningitis will necessitate Gram tions. It is thought that pro-inflammatory
stains and cultures in the case of bacterial menin- cytokines in the CSF produce and enhance pain
gitis. CSF consistent with aseptic meningitis in animal models [57]. TNF-α has also been
should be sent for cultures, Gram stain, and PCR thought to induce calcitonin gene-related peptide
particularly for herpes simplex virus and vari- production, and elevated levels of TNF-α in the
cella zoster. Cases of fungal meningitis will CSF may explain why a certain percentage of
necessitate India ink stains, CSF, and blood hospitalized patients do not improve with stan-
cultures. dard headache therapy.
The overall role of TNF-α is unclear at this chromosome 19 [64]. This disorder results in a
point, and even the methods used in the initial variety of symptoms, which most commonly
paper describing elevated TNF-α remain contro- include vascular degeneration, progressive cog-
versial [58, 59]. In 2013, Rozen et al. did pub- nitive decline, dementia, and subcortical isch-
lish a case report of a patient with NDPH that did emic strokes, in addition to migraine with aura
respond to nimodipine. The proposed action of [64]. Migraine with aura can occur in nearly one
nimodipine in this case was inhibition of TNF-α half of CADASIL patients [65, 66] and is often
[60]. However, at this time there is very little evi- the initial manifestation of the disease. The aver-
dence to support this. Routinely measuring CSF age age of onset is approximately 30 years, and
TNF-α is not recommended, as there is no signifi- aura symptoms tend to involve the visual and
cant evidence for its use in directing management sensory symptoms [66]. Isolated migraine aura
of such patients. (without headache) may represent up to 20% of
patients with CADASIL [66]. Patients with a
family history or personal history of multi-infarct
IGG Index and Oligoclonal Bands dementia, vascular encephalopathy, or early-
onset dementia in addition to chronic migraine
The majority of studies reviewing the potential with aura should certainly be tested for
association between multiple sclerosis (MS) and CADASIL.
migraine have not supported a definite link [61]. At the current time, there are at least 200
The overall incidence of headache in MS does mutations in the NOTCH3 gene, resulting in an
not appear to be significantly higher than that of odd number of residues which are known to be
the general population. There is an association associated with CADASIL [64]. There are sev-
between MS and trigeminal neuralgia; in addi- eral ways of diagnosing CADASIL; traditionally
tion there may be atypical facial pain syndromes skin biopsy with histological examination has
and neuralgias, associated with multiple sclerosis been used. This evaluates two features which are
which may be referred for evaluation by head- highly specific of the condition: granular osmo-
ache specialist. Typically head imaging will philic material and deposition of the NOTCH3
assist in this diagnosis, if there is a high suspicion receptor in the vascular media. However despite
for a diagnosis of MS, and lumbar puncture might the use of biopsy testing, low sensitivity levels
also be useful, testing for oligoclonal bands [62] have been reported [64]. Genetic sequencing
as well as IgG index. However, we do not recom- using a traditional Sanger sequencing system has
mend routine testing for IgG index and oligoclo- been shown to be expensive and time-consuming
nal bands without a clinical suspicion of multiple because of the large number of axons combined
sclerosis, whether by history or by imaging. with high GC content in the NOTCH3 gene [64].
Although often times done, checking for myelin Current recommendations are for next-genera-
basic protein is not shown to be beneficial for a tion sequencing (NGS) technologies to be used
diagnosis of multiple sclerosis [63]. for genetic testing for NOTCH3 mutations asso-
ciated with CADASIL [64].
Genetic Testing
MTHFR and ACE Polymorphisms
CADASIL
The mechanism of migraine is believed to involve
The stroke syndrome CADASIL (cerebral auto- the trigeminal cervicogenic complex which
somal dominant arteriopathy with subcortical receives nociceptive information via afferent pro-
infarcts and leukoencephalopathy) is thought to jections from the dura matter in large intracranial
be caused by mutations of the NOTCH3 gene on vessels. This information is then in turn passed
up to higher processing centers within the brain. and the MTHFR gene with migraine [67]. This
It is believed that vasoactive neuropeptides are reinforces the idea that migraine is likely the
released leading to neurogenic inflammation result multiple genetic variances. At this time,
[67]. Based on this information, it has been theo- we do not recommend routine testing for ACE
rized that the biochemical molecules disrupt or MTHFR polymorphisms in chronic migraine
endothelial function and may influence suscepti- patients.
bility to migraines. Two genes that are of interest
are angiotensin-converting enzyme (ACE) and
the C677T polymorphism in the homocysteine MELAS
metabolism gene methylenetetrahydrofolate
reductase (MTHFR). Although the exact role of Mitochondrial encephalomyelitis with lactic aci-
these genes still remains controversial in this pro- dosis and stroke-like episodes (MELAS) is a
cess, testing for polymorphisms in these genes multi-system disorder and is caused by mutations
has been suggested as a possible pathway to in mitochondrial DNA. This is a maternally
treatment, particularly with regard to supplemen- inherited disorder and is caused by mutations in
tation of the MTHFR genotype [68]. mitochondrial DNA [69–71]. The disorder is
Both the MTHFR and the ACE gene have characterized by recurrence of stroke-like epi-
been known to affect the vasculature in change sodes with resultant hemiparesis, cortical blind-
regulation of cerebral blood flow. MTHFR in ness, or hemianopia. Other common features
particular regulates circulating homocyste- include generalized seizures, recurrent migraine-
ine levels which interact with epithelial cells. like headaches, vomiting, short stature, hearing
Experiments in animal models have suggested loss, and muscle weakness [72, 73]. Stroke-like
that hyperhomocysteinemia may cause persons symptoms in MELAS are described as acute-
with this polymorphism to be more susceptible onset neurological symptoms, and MRI imaging
to migraine. It is also been hypothesized that does show high signal on diffusion-weighted
homocysteine-related endothelial dysfunction imaging. The term “stroke-like symptoms” is
may play a role in initiation and maintenance of used for several reasons; as unlike typical embolic
migraine attacks. ACE has been shown to play or thrombotic ischemic strokes, the brain lesions
a role in blood pressure regulation and electro- of MELAS do not follow vascular territories. The
lyte balance and has been expressed in vascular acute MRI signal changes may not be static and
endothelial cells among other cell types. ACE has may actually fluctuate, migrate, or resolve
also been shown to inactivate bradykinin which quickly when compared to a typical ischemic
is a potent vasodilator [67]. To this date investi- stroke. Apparent diffusion coefficient on MRI is
gational efforts have not been shown to be able not always decreased as it is classically with isch-
to demonstrate a reproducible and significant emic strokes; it may also be increased or demon-
influence of a single genetic variant of these two strate a mixed-type pattern [72]. Typically
genotypes on migraine. However, it is important MELAS manifests in childhood with a relapsing
to recognize that the interplay of multiple genetic remitting course and progressive neurologic dys-
variants likely contributes to a much greater function and dementia [69, 73]. Patients with
extent than single variations by themselves. stroke-like episodes before age 40 in addition to
In 2016, Essmeister et al. reviewed 420 encephalopathy and seizures or dementia should
patients with migraine for genotype frequencies be tested for MELAS.
of both the MTHFR and ACE variants. They Testing for MELAS should include appropri-
were unable to show that polymorphisms in ate mitochondrial studies; approximately 80% of
either of these two genes increase susceptibility cases are related to the m.3243A>G mutation and
to migraine alone. They also did not show any 10% to the m.3271T>C mutation; however there
association between polymorphisms in the ACE are over 30 genetic variants that are described
as being associated with MELAS [74]. Blood mated penetrance of this mutation is upward of
work should check for lactic acidosis and skel- 100% [76]. This mutation has also been linked to
etal muscle biopsy for the presence of ragged several types of epilepsy.
red fibers which may aid in the diagnosis of Patients with first member of their family to
MELAS. Genetic testing is typically done via have hemiplegic migraine are categorized as hav-
molecular genetic testing of mitochondrial ing the sporadic hemiplegic migraine variant.
DNA. Patients with atypical presentations or Both de novo mutations and inheritance from an
inconclusive testing may benefit from an evalua- asymptomatic parent could be the cause in these
tion by a genetics counselor. cases. The CACNA1A and ATP1A2 mutations
have been demonstrated in patients with sporadic
hemiplegic migraine [76, 83].
Familial Hemiplegic Migraine Although diagnosis of hemiplegic migraine
remains a clinical diagnosis, the clinician should
Hemiplegic migraine is characterized by unilat- rely on a thorough history as well as a thorough
eral weakness that accompanies a migraine head- family history; genetic testing may be useful, par-
ache attack, which differentiates it from other ticularly in cases of early-onset sporadic hemi-
types of migraine. This weakness is a manifesta- plegic migraine or in cases of familial hemiplegic
tion of motor aura and occurs with other forms of migraine when the phenotype diverges from
aura that can impair visual, sensation, and speech. those of the affected relatives. Genetic testing
Familial hemiplegic migraine comes in three for mutations involves testing for CACNA1A,
varieties; in addition sporadic hemiplegic ATP1A2, and SCN1A mutations.
migraine cases have also been documented.
Familial hemiplegic migraine is transmit-
ted in an autosomal dominant pattern; however Special Cases
penetrance can be variable between the different
types of familial hemiplegic migraine. Familial Pregnancy
hemiplegic migraine type I is associated with
mutations in the CACNA1A gene on chromo- A change in headache pattern or new headaches
some 19p13. This encodes an alpha subunit of the during pregnancy is not uncommon and may be
P−/Q-type calcium channel [75]. This mutation, due to migraine- or tension-type headaches, but a
like all familial hemiplegic syndromes, lowers variety of secondary causes may occur. This
the susceptibility to cortical spreading depres- includes preeclampsia, postdural puncture head-
sion. The estimated penetrance for familial hemi- ache, and cerebral venous thrombosis.
plegic migraine type 1 is somewhere between Preeclampsia must be excluded in every pregnant
67% and 89% [76–78]. woman over 20 week’s gestation. Common labo-
Familial hemiplegic migraine type II is asso- ratory studies include a complete blood cell
ciated with mutations in the ATP1A2 gene on count, complete metabolic panel to include liver
chromosome 1q23. This encodes a subunit of the function tests, and urine studies for protein, and a
sodium potassium ATPase; this mutation has also referral to maternal fetal medicine should be
been associated with migraine with brainstem considered.
aura as well as several types of epilepsy [79, 80].
Familial hemiplegic migraine type II has a pen-
etrance of between 63% and 87% [76, 77, 81]. Immunocompromise
Familial hemiplegic migraine type III is caused
by mutation in the SCN1A gene on chromosome Daily headaches in patients who are immuno-
2q24, which encodes the transmembrane alpha compromised, either by HIV infection, immuno-
subunit of the sodium channel [82]. The esti- suppression, or primary immunodeficiency,
warrant extensive workup, as there are many terol crystals which induced hypoperfusion with-
opportunistic infections as well as tumors which out infarct [33]. A second possible mechanism
may cause headaches. Workup should be exten- linking migraine with aura and hypercoagulabil-
sive and include a lumbar puncture, which should ity is that cortical spreading depression leads to
include basic cell counts as well as protein and endothelial damage and elicits an inflammatory
glucose; an elevated opening pressure may also cascade with subsequent activation of peripheral
be a clue as to the presence of a CNS infection. and central trigeminal vascular neurons. Other
Tuberculosis is a concern at all CD4 counts, but if potential mechanisms may link migraine to
CD4 counts less than 250, coccidioidomycosis hypercoagulability through stress, which is a
and pneumocystosis are of concern. With the common trigger and consequence of migraine.
lower CD4 counts, histoplasmosis, toxoplasma, Stroke in the general population is typically
and cryptococcus are of more concern. CSF fluid atherosclerotic in nature. Migraine-related stroke
should be evaluated for these infections. tends to be most prevalent in young persons, par-
ticularly women, and is likely in persons with
low vascular risk factor profiles. This supports
Traumatic Brain Injury the hypothesis that migraine-related strokes are
non-atherosclerotic in nature. This is also sup-
Headache may occur in as many as 78% of per- ported by several comorbid conditions that are
sons following mild traumatic brain injury. often found with migraine including Raynaud’s
Typically, headache prevalence, as well as dura- disease, non-atherogenic endotheliopathies,
tion severity, is often more of an issue in patients livedo reticularis, preeclampsia, and vasospastic
with milder head injuries than those with more angina [3]. The relationship between patent fora-
severe head injuries. men ovale, thrombophilia states, and migraine
with aura-associated stroke has been shown in
several studies, but the management of these in
Hypercoagulability States migraine remains controversial.
Screening for hypercoagulable states and
Overall, the pathogenesis of migraine is complex patent foramen ovale becomes important if one
and multifaceted; the relationship of migraine to accepts that there’s a spectrum between CSD-
thrombophilia states is not fully understood. related ischemia without infarction and migraine-
Most consistently positive are studies investigat- related stroke. Table 12.3 summarizes our
ing estrogen, platelets, red blood cells, and mark- recommendations for screening in patients with
ers of endothelial activation and dysfunction [3]. migraine with aura in addition to history of endo-
There are several hypotheses which link hyperco- theliopathies, family history of thrombosis, white
agulability to migraine; the first theorized mecha- matter abnormalities, and stroke-like lesions on
nism is via ischemia-induced cortical spreading brain MRI. Management of patients with stroke
depression without infarction. This was sup- symptoms or history of thrombosis in addition
ported by a 2010 study in which cortical spread- migraine with order should not only revolve
ing depression was triggered in a rodent model around management of migraine but should also
by injections of microspheres, air, and choles- involve minimizing stroke risk factors.
Table 12.3 Headache in hypercoagulable state

Evaluation of
stroke risk
Clinical presentation Hypercoagulable evaluation factors
Migraine with aura with CBC, CRP, von Willebrand factor, fibrillation, homocysteine HgbA1C
history of endotheliopathies Fasting lipid
profile
Migraine with aura with a CBC, CRP, von Willebrand factor, fibrillation, homocysteine, HgbA1C
personal or family history of glycosylated hemoglobin, fasting lipid profile, protein C, protein S, Fasting lipid
thrombosis antithrombin deficiencies, prothrombin, antiphospholipid antibodies profile
Migraine with aura with CBC, CRP, von Willebrand factor, fibrillation, homocysteine, HgbA1C
subcortical white matter glycosylated hemoglobin, fasting lipid profile, antiphospholipid Fasting lipid
abnormalities on MRI antibodies, CADASIL profile
Migraine with aura with CBC, CRP, von Willebrand factor, fibrillation, homocysteine, HgbA1C
stroke-like lesions on MRI glycosylated hemoglobin, fasting lipid profile, protein C, protein S, Fasting lipid
antithrombin deficiencies, activated protein C, prothrombin, profile
antiphospholipid antibody, evaluation for PFO (agitated saline TTE
or TEE)
11.
Headache Classification Committee of the
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Monitoring of Chronic Daily
Headaches 13
Sam Hooshmand and Fallon C. Schloemer
Introduction include chronic cluster headache, chronic parox-

ysmal hemicrania, hypnic headache, and primary
In 1996, Silberstein and Lipton proposed their stabbing headache as well as the unilateral neu-
criteria which classified chronic daily headache ralgiform headache [2, 3].
(CDH) as a stand-alone diagnosis [1]. Since then While epidemiological data on CDH is lim-
the significant debate has occurred regarding ited, evidence suggests that US and worldwide
CDH classification. The consensus today per the prevalence is roughly 3–4%, with Central/South
International Classification of Headache American content having the highest prevalence
Disorders 3rd edition (ICHD-3) is that CDH is (5%) and the African continent having the small-
not a specific headache type but rather an encom- est prevalence (1.7%) [4–8]. This prevalence
passing term for several different specific head- translates into the US population having an esti-
ache types. In general, CDH refers to headaches mated 11 million individuals suffering from
that occur on more days than not (at least 15 or CDH. In the USA, the most prevalent subtype of
more days a month for longer than 3 months) [2]. CDH is tension-type headache (TTH). Chronic
Predominantly, clinicians attempt to divide CDH tension-type headache is followed by chronic
into primary versus secondary entities. This ini- migraine [6]. It is no surprise that the prevalence
tial approach allows implementation of appropri- of CDH as well as its debilitating effects has a
ate intervention or therapies as well as referrals. tremendous societal cost through healthcare
In regard to primary entities, one can divide CDH expenditures and loss of economic productivity.
into long-duration headaches (>4 h) and short- Patients with chronic headache utilize more
duration headaches (<4 h). The five major sub- healthcare resources and have healthcare claims
types of long-duration CDHs include chronic for medication twice as much compared to
migraine, chronic tension-type headache, medi- patients with other diseases [9]. To date, no study
cation overuse headache, hemicrania continua, provides the financial impact of all CDH sub-
and new daily persistent headache. Subtypes of types, but when examining the two most frequent
chronic daily headache of shorter duration subtypes, it is estimated to be between 20 and 26
billion dollars annually [10, 11].
Caring for patients suffering from CDH is no
easy task. While the diagnosis can often be made
S. Hooshmand (*) · F. C. Schloemer
Department of Neurology, Froedtert and the Medical
during the initial visit using ICHD-3 guidelines,
College of Wisconsin, Milwaukee, WI, USA the subsequent identification of subtype, treatment
e-mail: shooshmand@mcw.edu strategy, and risk reduction is a large undertaking.

186 S. Hooshmand and F. C. Schloemer
The first step in the effective management of CDH patients see that the first-tier providers and refer-
starts with the monitoring of CDH. The informa- rals are to be made on a case-by-case basis to the
tion gained from monitoring CDH allows clini- second tier. The first tier encompasses OTs, PTs,
cians to exclude secondary causes, identify risk and psychologists, while the second tier includes
factors, recognize the specific CDH subtype, and but is not limited to neurosurgeons, pain manage-
ultimately identify the most beneficial therapy. ment, nurse educators, nutritionist, personal
trainers, various alternative healthcare practitio-
ners, etc.
Office Visit Out of the first-tier team members, the role of
OTs has been the least researched. Overall, OTs
The outpatient visit is the cornerstone to monitor- help patients engage in meaningful activities of
ing any chronic condition, and CDH is no differ- daily living through education and problem-solv-
ent. With the variety of pathology CDH ing through barriers. The Canadian Occupational
encompasses and the multitude of treatment Performance Measure (COPM) is a valid and
modalities, a shift from individual provider to reliable client-centered occupational therapy tool
multidisciplinary therapy (MDT) has occurred that allows patients to identify areas of occupa-
over the past few decades. This multidisciplinary tional difficulty or deficit [20]. With data obtained
focus adds CDH to the growing list of other neu- from COPM, the OT can then implement desired
rological conditions such as muscular dystrophy, treatment techniques that would be of the greatest
amyotrophic lateral sclerosis, dementia, and trau- benefit to CDH patients. OT serves to educate the
matic brain injury which already utilize this patient about headache self-management, help
approach. Consideration of MDT is not a neces- the patient change his or her behaviors and life-
sary first step in the care of CDH unless the style factors that could be influencing the fre-
patient’s headaches are refractory. quency and intensity of headaches, and improve
The establishment of multidisciplinary head- the patient’s ability to function and participate in
ache programs began in the late 1990s and early everyday life.
2000s, for patients with frequent refractory head- PTs are experts in identifying musculoskeletal
aches [12–15]. There is limited data on compar- dysfunction through their analysis of movement.
ing MDT to individual providers. Most of it PTs have a long established role in the treatment
covers a limited time span of 3 to 12 months. It of various headache conditions. A PT monitoring
showed that MDT is advantageous concerning a of CDH consists of both subjective and objective
reduction in headache frequency [16, 17], a measures that help identify abnormalities that
decrease in anxiety and depression [16], and a could be causing or exacerbating patients’ head-
reduction in emergency room and clinic visits aches. The subjective information includes the
[14]. While MDT is not a novelty, what consti- history of symptoms, pain location/description,
tutes the team is under debate with notable differ- and aggravating factors/triggers that help to guide
ences between European versus North American and individualize the objective examination as
health systems [12, 13, 16, 18–20]. well as supplement the clinician’s history.
Regarding CDH, MDT consists of a neurolo- Objectively they examine common areas associ-
gist or headache specialist, occupational thera- ated with headaches such as the jaw and cervical
pists (OTs), physical therapists (PTs), and spine.
psychologists. While each member of the team Psychologists make up the third component in
provides an essential role, the physician has the first tier of providers for CDH. While recog-
remained responsible for establishing the correct nized as a vital member of the CDH treatment
headache diagnoses and developing therapy team, historically they have been underutilized
plans in collaboration with the patients and oth- due to availability, providers’ concerns over
ers on the team. Often, the roles of other mem- appropriate referrals, and patient hesitation for
bers are in tiers with the idea that almost all fear of being labeled. Due to the nature of CDH,
13 Monitoring of Chronic Daily Headaches 187
afflicted individuals are similar to other chronic there is a consensus among headache specialists
pain patients and therefore should be evaluated that this approach is particularly best for refrac-
by a psychologist at least once. Psychologists uti- tory patients [20, 22].
lize many mental health monitoring scales, which
we review in the next section of this chapter.
Many of these scales are quick to perform and do Mental Health Monitoring
not require formal training. Conversely, one com-
monly used monitoring tool, the Minnesota Psychiatric disorders such as depression, anxiety,
Multiphasic Personality Inventory-II (MMPI-II), bipolar disorder, and obsessive-compulsive dis-
can take up to 90 min to perform and is difficult order are exceedingly common in CDH [23, 24].
to interpret without training. This monitoring In fact, some studies indicate psychiatric comor-
measure is useful in identifying personality types bidity rates as high as 90% in patients with pri-
that tend to exaggerate psychopathology or adopt mary CDH [25]. While clinicians are well aware
a sick role, which can influence treatment [21]. of the need to evaluate CDH patients for the exis-
Overall the roles of the first-tier providers tence of comorbid psychiatric disorders, the
have significant overlap, but all have a unique abundance of different scales and metrics can
value that can benefit patients with CDH. Not make this a daunting task.
only can monitoring of CDH patients by first-tier Selecting an appropriate screening tool starts
providers supplement data, but it can also iden- with knowing whether or not you want breadth or
tify overlooked etiologies or barriers that may depth in your coverage. If a patient is already
have prevented effective treatment. Additionally, known to have a specific psychiatric comorbidity,
the efforts of multiple providers allow a role in then disorder-specific measures should be uti-
dealing with medication adherence and trigger lized, as more information about the nature and
management, sleep disturbances, and overall severity of psychiatric symptoms can be gained.
coping with headaches. On the other hand, for patients that do not carry a
In the MDT, the second tier of providers can diagnosis or whose psychiatric presentation is
encompass almost any healthcare provider. The complex, a multidimensional screening measure
breath of integrating the varied expertise of such would likely provide more diagnostic clarity.
providers depends on the clinical presentation of While utilization of disorder-specific multidi-
the patient. In general, the second-tier goal is to mensional measures provides the first step in psy-
provide disease interventions rather than clinical chiatric monitoring, clinicians need to be aware
data through monitoring. It is up to the leader of of the role of transdiagnostic symptoms (TDS)
the MDT to determine the utility of such a refer- [26]. TDS are a disease characteristic that over-
ral or integration within the treatment team. laps two processes. TDS may result in a false-
The most obvious limitation in the MDT is the positive screen, further complicating diagnosis
lack of available providers. Coordinating the and treatment of CDH. For example, changes in
expertise of a variety of practitioners outside sleep patterns, issues with concentration, and
large healthcare organizations or academic cen- changes in appetite occur in both CDH and
ters is extremely challenging. Besides logistical depression. The complexity of TDS and limited
limitations, analyses of the studies examining time physicians have to treat patients raise the
MDT have raised concerns. First, it is not possi- consideration of having a mental health profes-
ble to evaluate by a randomized trial with a pla- sional involved in a CDH patient such as in an
cebo condition due to the nature of the comparison MDT setting, which we described in the above
groups. Second, the measurement of overall out- section.
come does not allow conclusions about the effi- Several multidimensional measures are avail-
cacy of the implementation of different parts of able to screen patients for psychiatry conditions,
MDT. Nonetheless, MDT has become more and which include the Brief Symptom Inventory
more prevalent in the treatment of CDH, and (BSI), the Psychiatric Diagnostic Screening
Questionnaire (PDSQ), and the Pain Patient as it does include nonpsychological symptoms of
Profile (P-3). Each of these screening tools can depression. The PHQ-9 is a subsection of the pre-
provide valuable information; however, due to viously mentioned PHQ. The PHQ-9 starts by
the ease in use and interpretation, the Primary screening for two sentinel symptoms of depres-
Care Evaluation of Mental Disorders sion, anhedonia and depressed mood, and then
(PRIME-MD) is recommended for multidimen- testing for psychological and somatic symptoms.
sional screening over the previously mentioned The PHQ-9 sensitivity and specificity for depres-
tools. PRIME-MD has two components: (1) a 1- sion are both 88% [30].
page self-report called the patient questionnaire Considerably less research exists on assess-
(PQ) and (2) a 12-page provider-guided ques- ment of anxiety compared to depression, but
tionnaire referred to as Clinical Evaluation there are still many various scales to assess for
Guide (CEG). Once the patient has completed anxiety. Like depression, to evaluate the various
the PQ, the clinicians then utilize CEG to evalu- scales, factors such as ease of use, interpretation,
ate the initial positive responsiveness. Overall, and brevity were considered, and this led to the
PRIME-MD assesses five psychiatric categories: identification of the Beck Anxiety Inventory
somatoform, depression, anxiety, substance use, (BAI) and the Generalized Anxiety Disorder
and eating. Although PRIME-MD is adminis- 7-item scale (GAD-7) as the best two tools. The
tered and interpreted with relative ease, it is BAI provides a broad evaluation of anxiety
time-consuming. To reduce time burden, a purely rather than identify specific anxiety subtypes.
self-reported derivative of PRIME-MD known Patients rate 21 symptoms on a 0 to 4 scale. The
as a primary health questionnaire (PHQ) was creator’s goal was to assess only for anxiety
developed. PHQ requires less than 3 minutes of rather than for both depression and anxiety. The
the clinicians’ time for 85% of patients and has a questions include somatic symptom items that
sensitivity (75%) and specificity (90%) similar emphasize panic [31]. Unlike BAI, the GAD-7 is
to PRIME-MD [27]. Pfizer developed both of a disorder-specific anxiety measure. GAD-7
these monitoring tools, and they are both freely evaluates for generalized anxiety disorder and
available. utilizes a seven-item questionnaire, which
Depression has the most extensive variety of patients rate on a 0 to 3 scale. Completion takes
available monitoring tools regarding disease-spe- approximately 2 min [32].
cific screening instruments. Out of the many veri- Overall, no single monitoring tool is the most
fied and researched instruments, preference is for suitable for screening CDH patients in regard to
the Beck Depression Inventory-II (BDI-II) and mental health. A consensus exists that CDH
the Patient Health Questionnaire depression patients should have formal screening for depres-
module (PHQ-9) for their brevity and sensitivity. sion and anxiety at a minimum, while some pur-
Out of the two, BDI-II provides the most depth sue a more comprehensive multidimensional
regarding depression data. The BDI-II accom- psychiatric screening. Any clinician can utilize
plishes this by having patients rate on a 0–3 scale, the above monitoring measures mentioned in this
21 groups of symptoms [28]. These groups cover chapter, but particular attention to the interpreta-
a broad range of depression symptomatology tion of scores should consider the somatic items
including psychological, cognitive, and physical as these may indicate TDS rather than a psychiat-
manifestations. A derivative of BDI-II, Beck ric disorder.
Depression Inventory for Primary Care (BDI-PC),
has been implemented by some clinicians as a
time-saving measure due to it containing only Vitals
seven items, but the BDI-PC is limited in that it
only evaluates for the psychological symptoms of The monitoring of vital signs serves two major
depression [29]. If brevity is of primary impor- purposes for CDH patients. Firstly, vital signs are
tance, the PHQ-9 would be preferred over BDI-II a primary indicator of medication side effects,
and secondly, vitals can reveal various patholo- tial as it is often the only sign of intracranial
gies that can cause and exacerbate hypotension, whether idiopathic or secondary to
CDH. Assessment of the essential information mass lesion or tumor. Visual fields should also be
obtained from blood pressure, heart rate, respira- assessed at each encounter as should acuity with
tory rate, temperature, and weight measurements best-corrected vision. These quick and cheap
occurs each clinical visit. The variety of effects tests can often lead to identification of easily
headache medications can have on the above- treated issues such as glaucoma, hyperopia, or
mentioned vital signs is beyond the scope of this myopia. Examination of extraocular muscles,
section and will be discussed with specific drugs eyelids, and pupils can also reveal cranial nerve
in other chapters. palsy indicating a compressing mass or an aneu-
The evidence is clear that headache patients, rysm. Additionally, appreciation of ptosis or
in general, have increased risk of stroke or car- Horner’s syndrome could be a sign of a cluster
diovascular injury [33, 34]. This risk factor is rea- headache or in some cases a more menacing
son enough to take regular cardiac vitals to entity.
monitor modifiable risk factors. However, no Otolaryngologic assessment should focus more
suggestions or guidelines exist regarding cardio- so on the sinuses and throat. The tympanic mem-
vascular risk screening and testing [35]. brane should be evaluated for pathology as this
The link between obesity and primary head- could be an aggravating factor toward headache.
aches is well-established. A large case-controlled Additionally, the clinical exam should assess the
study indicated that the relative odds of CDH vestibulocochlear nerve, which if pathologic could
were five times higher with a body mass index indicate a compressing mass. The sinuses should
(BMI) of at least 30 and three times higher with a be palpated to assess for a chronic or acute sinus-
BMI from 25 to 29 [36]. The increased inflamma- itis as this is often an undertreated cause of chronic
tory mediators found in obese individuals are headaches. On the other hand, a chronic primary
important in headache pathophysiology, includ- headache disorder can be mislabeled and mis-
ing interleukins and calcitonin gene-related pep- treated as a sinus issue. Assessment of the oral
tide [37, 38]. cavity should focus on the anatomy. An underdiag-
nosed secondary cause of CDH is obstructive
sleep apnea (OSA); furthermore, studies of CDH
Physical Examination patients have indicated that they are more likely to
be habitual snorers. While a Mallampati score
Physical and emotional sensitivity of patients (grade of oropharyngeal appearance) should not
with CDH make it difficult to assess and examine be used exclusively to predict OSA, but with a cor-
them; however, the physical exam is a crucial part roborating history, it can prompt further evaluation
of adequate monitoring. Besides a thorough neu- [39]. The relationship between obstructive sleep
rological exam, we recommend tailoring the apnea and CDH is not fully understood but may
physical exam toward CDH mimics, and there- involve intracranial and arterial pressure fluctua-
fore ophthalmological, otolaryngologic, and tions during snoring. This may occur particularly
musculoskeletal systems should always be in individuals susceptible to pain progression,
assessed. hypoxia, hypercapnia, sleep fragmentation, and
Assessment by a headache specialist or neu- disruptions with increased muscle activation dur-
rologist is often the only time outside of optom- ing awakenings [40].
etry and ophthalmology visits where patients Musculoskeletal pathology is dynamic, and
have their eyes evaluated. Ophthalmological assessment should always include a thorough
assessment begins with examination of fundi for evaluation. Patients with tenderness involving
evidence of papilledema, abnormal cup-to-disk pericranial and paravertebral muscles are likely
ratios, loss of venous pulsation, and retinal to benefit from physical or osteopathic evaluation.
changes. The evaluation of papilledema is essen- Similarly, evaluation of the range of motion of
the cervical spine could also indicate structural by-case basis in the CDH patient. For example, if
deficits or alert concern for meningitis. In older a patient has history of intracranial thrombosis, a
adults, the temporal arteries should be assessed hypercoagulability panel must be pursued.
for pulse, elevation, and tenderness as this is At-risk populations should be screened for
often the first clinical sign of giant cell arteritis. human immunodeficiency virus as it is a common
The temporomandibular joints (TMJ) should be cause of primary and secondary headaches. In
palpated and assessed for mobility in all patients areas of endemic Lyme disease, a screening
regardless of baseline complaints. A TMJ disor- enzyme-linked immunosorbent to assess for anti-
der can coincide with dysfunction of the upper bodies to Borrelia burgdorferi should be consid-
cervical spine as well as with chronic headaches. ered or done if meningismus is present. If
One also assesses trigger point evaluation of the temporal arteritis is of concern, obtain inflamma-
cervicoscapular musculature as a potential pain- tory markers such as sedimentation rate and
generating source. The presence of active trigger C-reactive protein. These are just a few examples
points in the cervicoscapular musculature has for which laboratory and other workups may be
been identified in patients with primary headache different or unique to one specific headache
disorders when compared to age-matched con- disorder.
trols, and these points correlate with longer dura- Monitoring of drug levels can serve to identify
tion and increased intensity of headaches [41]. noncompliant individuals as well as those who
While a tailored exam for CDH does not need engage in medication over usage. We do not dis-
to always include assessment of cardiac, pulmo- cuss the specifics of monitoring individual levels
nary, hepatic, endocrine, and dermatological sys- of pharmaceuticals in this section. Due to predis-
tems, all of these should be at least addressed position to pain sensitivity, CDH patients often
once in the care of the CDH patient. Of note, are wary of engaging in blood testing.
while the clinical exam can often reveal pathol- Additionally, serum levels are more of a snapshot
ogy, a normal examination without focal signs rather than reliable marker of intake over time. A
does not rule out serious etiologies for CDH. new but not commercially available tool is, how-
ever, addressing both of these issues. Researchers
have shown that you can reliably measure via
Laboratory Assessment hair analysis, intake of amitriptyline, citalopram,
delorazepam, duloxetine, lorazepam, and venla-
Similar to vitals, laboratory assessments serve as faxine over previous months [42].
indicators of medication side effects as well as
have the potential to reveal various pathologies
that may be the cause of exacerbating Radiological Monitoring
CDH. Please see Chap. 12 for an in-depth review
of this topic. The ease and multitude of labora- While neuroimaging is not always a regular part
tory tests have prompted some clinicians to use a of monitoring a patient with CDH, it may be an
shotgun approach particularly in cases of refrac- essential part of the initial evaluation. Just like
tory patients. This shotgun method is, in fact, dis- other monitoring tools, consider neuroimaging
advantageous as a false negative can lead on a case-by-case basis. Plain head computed
providers and patients down a dangerous path. tomography (CT) is a good screening test in a
There is little clinical utility in continuously patient, but an enhanced CT often provides more
monitoring laboratory data outside of drug levels information with little risk. Clinicians do need to
or screening for medication side effects, but a avoid enhanced CT in cases where concern for
complete blood count with differential as well as hemorrhage is present. General limitations in CT
comprehensive metabolic needs to be assessed at scan include the exposure to radiation and an
least once during the evaluation of CDH patient. overall lack of sensitivity; however, the latter
Laboratory tests should be considered on a case- helps avoid nonspecific and nondiagnostic white
matter changes that are particularly common on paper diaries have been used to investigate head-
magnetic resonance imaging (MRI). Nevertheless, ache frequency, intensity, duration, and medica-
an MRI with gadolinium enhancement is consid- tion compliance/usage as well as trigger exposure
ered the best testing method for overall evalua- and other patterns, just to name a few data points.
tion of CDH patients. The limitations of MRI However, the paper diary method has led to a lot
may be the missed cases of cerebral venous of criticism because diaries are bulky and require
thrombosis or arterial dissection, but overall it is a lot of effort by the participants and not to men-
more sensitive than CT scan mainly for evaluation they can be lost or forgotten. Furthermore,
tion of posterior fossa, leptomeninges, and dura. compliance with paper diaries can be a problem;
individuals may be completing multiple diary
entries concurrently at a later date which raises
Specialized Testing reliability concerns. Due to the lack of alterna-
tives, for many years the paper-based diaries
The lumbar puncture (LP) is an invasive and were the standard for behavior assessment of
painful test but can provide information that no CDH; however, limitations of paper diaries,
other test can ascertain and considered in patients along with recent advances in mobile technology,
with suspected cerebral spinal hypotension, idio- have led to the increasing adoption of electronic
pathic intracranial hypertension (IIH), or chronic diaries (e-diaries).
meningitis. Due to the invasive nature of the test, E-diaries use a computer-based system to
an opening and closing pressure should always record what would be in a paper diary. Overall
be obtained as well as basic labs (cell count, pro- several studies have indicated that e-diaries may
tein, glucose, and Gram stain) to avoid repeating be superior to paper diaries in that they offer
the test. The opening pressure is of particular advantages such as a reduction of recall bias,
importance during lumbar puncture as this could easy accessibility for physicians and patients, and
be the only indicator of IIH as papilledema is improved compliance [45, 46]. The e-diary for
often not present. It is also imperative to delay many years had its limitations due to lack of
the LP until checking the head imaging for an access to the Internet and overall computer illit-
intracranial lesion and subsequent mass effect as eracy. However, this situation has changed dra-
this could put the patient at risk for brain hernia- matically over last decade with the advent of
tion and demise. handheld computers and smartphones. These
In 1995 the American Academy of Neurology devices have allowed the creation of easy-to-use
published their practice parameter regarding applications (apps) that collect and sort patients’
electroencephalogram (EEG) utility in evaluation headache data. Today’s clinicians face the chal-
of headache. The overall recommendation was lenge of identifying and recommending the best
that EEG is not useful in the routine assessment “e-diary.” Clinicians often express concern
of patients with headache. While this statement is regarding the quality of e-diaries due to lack of
undoubtedly accurate, this does not preclude the oversight in the mobile health app market. One
use of EEG. CDH presentations that have symp- recent comprehensive analysis of e-diary apps
toms of a seizure disorder such as complicated allowed identification of the most clinically rele-
migraines or episodic loss of awareness should vant apps.
include an evaluation via EEG [43]. Published in 2014, Hundert and colleagues ana-
lyzed 38 applications in Apple iTunes and Google
Play store [47]. To assess the applications, the
Headache Diaries researchers set seven criteria that defined an ideal
headache app, and quality of the apps was deter-
Headache diaries have been the standard part of mined by the number of app criteria met. Criteria
most clinicians’ armamentarium in the assess- were as follows: apps created with headache exper-
ment of headaches for decades [44]. Traditionally, tise, formal psychometric and feasibility testing,
clinically relevant headache variables measured, cation of headache disorders, 3rd edition (beta ver-
sion). Cephalalgia. 2013;33(9):629–808.
usable apps, customizable answer options and 3. Dodick DW. Clinical practice. Chronic daily head-
reports, reports linking multiple variables, and abil- ache. N Engl J Med. 2006;354(2):158–65.
ity to export headache data from the app. The three 4. Lanteri-Minet M, et al. Prevalence and description of
highest scoring apps (iHeadache, ecoHeadache, and chronic daily headache in the general population in
France. Pain. 2003;102(1–2):143–9.
Headache Diary Pro) only met five of these seven 5. Lu SR, et al. Chronic daily headache in Taipei,
criteria. Of concern is that none of the apps in this Taiwan: prevalence, follow-up and outcome predic-
study including the three highest scoring had under- tors. Cephalalgia. 2001;21(10):980–6.
gone formal feasibility or psychometric property 6. Scher AI, et al. Prevalence of frequent headache in a
population sample. Headache. 1998;38(7):497–506.
testing. The iHeadache app is appealing in that it 7. Stovner L, et al. The global burden of headache: a
is the only one of the three applications created documentation of headache prevalence and disability
by a physician with headache medicine exper- worldwide. Cephalalgia. 2007;27(3):193–210.
tise. Additionally, it provides succinct informa- 8. Wiendels NJ, et al. Chronic frequent headache in the
general population: prevalence and associated factors.
tion in that it records all clinically relevant Cephalalgia. 2006;26(12):1434–42.
variables without requiring nonessential infor- 9. Lanteri-Minet M, et al. Quality of life impairment,
mation. EcoHeadache, on the other hand, pro- disability and economic burden associated with
vides significantly more information and can chronic daily headache, focusing on chronic migraine
with or without medication overuse: a systematic
generate a variety of chart reports and customiz- review. Cephalalgia. 2011;31(7):837–50.
able reports. The third option Headache Diary 10. Hu XH, et al. Burden of migraine in the United States:
Pro is overall rated less usable compared to the disability and economic costs. Arch Intern Med.
apps mentioned above but is the highest scoring 1999;159(8):813–8.
11. Abu Bakar N, et al. Quality of life in primary headache
Android application as the prior apps are only disorders: a review. Cephalalgia. 2016;36(1):67–91.
available on iOS or Apple systems. 12. Gunreben-Stempfle B, et al. Effectiveness of an inten-
sive multidisciplinary headache treatment program.
Conclusion Headache. 2009;49(7):990–1000.
13. Lemstra M, Stewart B, Olszynski WP. Effectiveness
Chronic daily headache’s wide prevalence in of multidisciplinary intervention in the treatment
society as well its tremendous cost burden has of migraine: a randomized clinical trial. Headache.
made efficacious treatment of this disorder of 2002;42(9):845–54.
utmost importance. Ineffective headache diag- 14. Maizels M, Saenz V, Wirjo J. Impact of a group-
based model of disease management for headache.
nosis and treatment has led to repeated consul- Headache. 2003;43(6):621–7.
tations of different disciplines, expenditure on 15. Saper JR, et al. Comprehensive/tertiary care for

alternative therapies, and unnecessary hospi- headache: a 6-month outcome study. Headache.
talizations. Certainly, this has led to frustrated 1999;39(4):249–63.
16. Wallasch TM, Kropp P. Multidisciplinary inte-

and suffering patients. It is abundantly clear grated headache care: a prospective 12-month
that to manage CDH patients effectively, clini- follow-up observational study. J Headache Pain.
cians need to monitor their patients adequately. 2012;13(7):521–9.
Utilizing the information in this chapter, clini- 17. Harpole LH, et al. Headache management program
improves outcome for chronic headache. Headache.
cians should be able to comprehensively mon- 2003;43(7):715–24.
itor their CDH patients which can lead to 18. Gaul C, et al. Clinical outcome of a headache-specific
better outcomes overall. multidisciplinary treatment program and adherence
to treatment recommendations in a tertiary headache
center: an observational study. J Headache Pain.
2011;12(4):475–83.
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Medication Overuse in Chronic
Daily Headache 14
Hans-Christoph Diener, Dagny Holle-Lee,
and Frederick G. Freitag
Introduction primary headache and the type of overused acute

medication. Treatment of MOH occurs in three
The frequent or regular intake of medication to stages. First, we educate patients about the rela-
treat acute headache episodes can lead to an tionship between frequent intake of acute head-
increase in headache frequency and finally to a ache medication and MOH to reduce intake of
transition from episodic to chronic headache. acute medication. In a second step migraine pre-
Many patients with chronic headache take abor- vention should be initiated in chronic migraine
tive medication on a daily basis. Medication (topiramate or onabotulinumtoxinA in migraine)
overuse headache (MOH) is defined by the or amitriptyline in chronic tension-type head-
International Classification of Headache ache. In patients who fail to cease overuse of
Disorders as a headache in patients with a pre- overused medication with preventive therapy,
existing primary headache disorder (e.g., then detoxification occurs on an outpatient basis
migraine or tension-type headache) occurring on or in a day hospital or inpatient setting, depend-
≥15 days per month for >3 months. Also, these ing on severity and comorbidities. The success
primary headache disorders occur in association rate of treatment is around 50–70%, with higher
with overuse of medication for acute or symp- relapse rates in patients with opioid overuse.
tomatic headache treatment. The prevalence of Patient education and continuity of care in the
MOH in the general population is around 1%. follow-up period reduce relapse rates. This chap-
MOH is more common in people with chronic ter is based on a recently published review on
migraine and chronic daily headache than in MOH in Nature Reviews Neurology [1].
patients with episodic migraine. The phenotype
of the headache in MOH depends on the initial
Definitions
H.-C. Diener (*) Medication overuse headache MOH (8.2 IHS

Clinical Neurosciences, Department of Neurology, Classification 3rd edition) [2] is defined as head-
University Duisburg-Essen, Essen, Germany
ache occurring on 15 or more days per month
e-mail: hans.diener@uk-essen.de
developing as a consequence of regular overuse
D. Holle-Lee
of acute or symptomatic headache medication
Department of Neurology and Headache Center,
University Hospital Essen, Essen, Germany (on 10 or more or 15 or more days per month,
depending on the medication) for more than
F. G. Freitag
Department of Neurology, Medical College of 3 months. It usually, but not invariably, resolves
Wisconsin, Milwaukee, WI, USA after the overuse stops.

196 H.-C. Diener et al.
Diagnostic Criteria studies in headache centers observed that up to 14%

of patients with an episodic headache develop a
A. Headache occurring on ≥15 days per month in chronic headache per year. The majority of these
a patient with a pre-existing headache disorder. patients overuse acute medication [14].
B. Regular overuse for >3 months of one or
more drugs that can be taken for acute and/or
symptomatic treatment of headache. Diagnosis and Clinical Features
Simple analgesics on >15 days per month.
Combination analgesics, triptans, ergots, or The characteristics of headache in MOH depend
opioids >10 days per month. on the primary headache [15]. Migraine patients
C. Not better accounted for by another ICHD-3 who overuse triptans report a migraine-like daily
diagnosis. headache or a marked increase in migraine fre-
quency. In some of the patients, the phenotype of
Chronic daily headaches (CDHs) occur migraine attacks changes with increasing attack
15 days or more a month, for at least 3 months. frequency with fewer and less pronounced auto-
Primary chronic daily headaches were another nomic features. Patients with chronic tension-type
condition that does not imply causation. There headache overusing acute medication report an
are short-lasting and long-lasting chronic daily increase in headache days with features of ten-
headaches. Long-lasting headache last more than sion-type headache [15]. The evolution toward
4 h. They include chronic migraine, chronic ten- MOH is substance-specific and is faster in patients
sion-type headache, new daily persistent head- who overuse triptans, opioids, and combination
ache, and hemicrania continua. analgesics compared with those who overuse sim-
The overuse of any medication to treat acute ple analgesics [15]. This evolution was confirmed
headache episodes can lead to MOH. These medi- by a French study with 82 patients overusing trip-
cations include simple analgesics, combination tans [16]. In a population-based study in the USA
analgesics, ergots, triptans, opioids, and barbi- [17], including 24,000 headache patients, opioids
turates [3–8]. Whether NSAIDs belong in this and barbiturates increased the risk for chronifica-
group is still controversial. The causal relationship tion of headache. This risk was not observed for
between the frequent or daily headache of abortive triptans [18]. A systematic literature review of 29
medication and MOH can only be established when studies [19] confirmed a similar increased risk of
the headache frequency improves with the less MOH related to opioid intake [19].
frequent or termination of intake of the assumed The diagnosis of MOH is based on the
drug or drugs supposed to cause MOH. Frequent patient’s history and documentation of drug
intake of acute medication does not necessarily intake. Patients who develop a chronic headache
lead to MOH. Some patients might use triptans at age >60 years or focal neurological symptoms
on 15–20 days per month for many years without or psychopathological features require imag-
developing a daily headache and without the more ing with CT or MRI. In women with a high
frequent intake of triptans per month. This condi- BMI, measurement of the CSF pressure might
tion is called “medication overuse” [9]. be indicated to rule out idiopathic intracranial
hypertension [20]. Similarly, patients with cer-
tain comorbidities (e.g., positional orthostatic
Epidemiology tachycardia, Marfan’s syndrome, Ehlers-Danlos
syndrome) and long-standing CDH resistant to
Medication overuse headache affects 1–2% of the treatment should be considered for a spontaneous
general population [10, 11]. The prevalence, how- intracranial hypotension evaluation.
ever, depends on the definition of MOH [12]. Most patients with MOH originally suffer
Patients with MOH constitute 25–50% of all patients from a primary headache disorder like migraine
with chronic headache [13] and 40–50% of all or tension-type headache [6, 21]. Some patients
patients seen in tertiary headache centers. Prospective with cluster headache may develop MOH in par-
14 Medication Overuse in Chronic Daily Headache 197
ticular if they also suffer from migraine or have be observed picturing the multidimensional prop-
a family history of migraine [22]. Patients with erties of pain disorders and MOH (sensory dis-
other chronic pain syndromes like chronic low crimination, cognitive, attentional, and emotional
back pain or arthrosis will not develop MOH if dimensions). Results from migraine/pain/depres-
they take NSAIDs on a daily basis [23, 24]. sion questionnaires correlate positively with gray
matter changes detected via Voxel-based mor-
phometry (VBM) [37]. Structural changes may
Pathophysiology also resolve after cessation of medication over-
use [38–40]. However, all observed pathological
The pathophysiological mechanisms leading to changes are not specific for MOH, and similar
MOH are still enigmatic. One clinical observa- changes can be observed in other headache/pain
tion is that patients with migraine and TTH are at or affective disorders.
higher risk to develop MOH compared to patients
without any primary headache disorder [25].
Therefore, one hypothesis is that the migrain- Risk Factors
ous/TTH headache brain itself may be prone to
develop MOH when it is exposed to increased Risk factors for development of MOH include
amount of acute medication over a longer period. primary headache disorders (migraine, tension-
In contrast, patients who suffer from cluster head- type headache), female sex, >10 headache days/
ache usually do not develop MOH except for the month, lower social class, other chronic pain con-
patients who additionally suffer from migraine or ditions, stress, physical inactivity, obesity, smok-
have a family history of migraine [26]. Specific ing, dependency behavior, and comorbid
genetic profiles might be involved, including psychiatric disorders [41, 42]. In a large popula-
angiotensin-converting enzyme (ACE) I/D poly- tion-based study in Norway with 51,383 partici-
morphism [27], brain-derived neurotrophic factor pants and an 11-year follow-up, the incidence of
Val66Met polymorphism [28], and polymor- MOH was 0.72 per 1000 person-years. In the
phism in COMT and SLC6A4 genes [29]. multivariate analyses, a fivefold risk for develop-
Although prolonged exposure to all classes of ing MOH occurred among certain individuals.
pain medication can lead to MOH, some drugs Those individuals who at baseline reported regu-
will more often and faster lead to MOH than lar use of tranquilizers [odds ratio 5.2 (3.0–9.0)]
others. For example, triptan intake is associated or who had a combination of chronic musculo-
with a higher risk for developing MOH than skeletal complaints, gastrointestinal complaints,
overuse of simple analgesics. Alteration of neu- and hospital anxiety and depression scale score
rotransmitter metabolism might be one patho- >/ = 11 [odds ratio 4.7 (2.4–9.0)] had the highest
physiological correlate especially regarding the risk. Smoking and physical inactivity more than
serotonergic [30–32] and endocannabinoid sys- doubled the risk of MOH [43].
tems [33, 34]. Electrophysiological investiga- Patients at high risk of MOH should be iden-
tions (e.g., sensory-evoked potentials [35] and tified via prescriptions for excessive amounts of
laser-evoked potentials [36]) have shown neuro- specific migraine drugs and followed up. In a mul-
nal hyperexcitability of the MOH brain in terms ticenter study, educational strategies applied in a
of increased stimulus response and habituation cognitive-behavioral minimal contact program,
deficits. These observations can be made not only with either group sessions or written material pro-
regarding cephalic but also extra-cephalic stimu- vided for the patient, showed success in reducing
lation [35]. After stopping medication overuse, the rate of MOH occurrence in patients at risk with-
most of the electrophysiological changes were out institution of other medication treatments [44].
reversible [35, 36]. A commonly held concept of medication
Imaging studies in MOH show different kinds overuse headache and chronic daily headache
of structural, functional, and metabolic changes. disorders is that they are truly daily headache dis-
Mainly alterations of the central pain network can orders. However, a variety of studies for treatment
of chronic migraine show this not to be the case. grams in patients with MOH and migraine as
A recent study of chronic headaches associated the primary headache in 137 patients [47]. One
with medication overuse suggests that patients group of 46 patients received intensive advice to
with daily headache are not the same as those reduce the intake of the overused medication(s).
with near daily headache [45]. The patients who The second group of 46 patients underwent a
had migraine or chronic migraine as well as med- standard detoxification program as outpatients
ication overuse entered a program of treatment. (advice + steroids + preventive treatment). The
Only 8 had daily headache, whereas the other 69 third group of 45 patients underwent a standard
had near daily headache with a mean of almost inpatient withdrawal program (advice + ste-
19 headache days per month. The daily headache roids + fluid replacement and antiemetics plus
group was more likely to adhere to treatment, not preventive treatment). The success rate was 60%
relapse back to overuse, while both groups dem- of the patients in the first two groups and 89% of
onstrated a significant reduction in their headache those in the third group. A meta-analysis which
frequency back to the range of episodic migraine. compared outpatient withdrawal with inpatient
treatment found no difference in responder rates
or the reduction in headache days [48]. A pro-
Treatment spective cohort study in Norway was comprised
of 109 participants with chronic headache (mostly
The treatment of MOH is based on four consecu- tension-type headache) and MOH who received
tive approaches: short written information about the possible role
of medication overuse in headache chronification
1. Firstly, informing the patient about the mecha- [49]. Patients were followed for 18 months. At
nism of MOH with the aim to reduce the intake baseline, the mean duration of chronic headaches
of acute medication for headache (below the was 8–18 years, and the mean duration of medi-
threshold of 10 days/previous month for spe- cation overuse was between 5 and 10 years. At
cific drugs and opioids and combination analge- follow-up, the mean medication days went from
sics and below 15 days for simple analgesics). 22 days to 6 days per month. Seventy-six percent
2. Next, begin medical and nonmedical preven- of patients no longer overused medication [49].
tive therapy. The approach of providing advice can also be
3. Thirdly, detoxification from the overused acute applied in the general practice [50].
medication occurs by either abrupt withdrawal Krause and colleagues examined the impact
of drugs by itself or done in conjunction with of a 3-week outpatient interdisciplinary program
“bridge therapies” to aid in the transition. which included medical interventions addressing
4. Lastly, these steps are followed by immediate long-term preventative medications, intravenous
or delayed preventative therapy. bridge therapies such as intravenous dihydroer-
gotamine, and optimization of acute migraine and
Most of the randomized studies investigating headache management strategies [51]. Outcome
these approaches were small and underpowered. parameters were physical functioning and psycho-
A study in Italy compared the effectiveness of logical impairment in chronic headache patients.
advice with either outpatient or inpatient with- Three hundred seventy-nine patients admitted to
drawal in patients with MOH. The study per- an outpatient chronic headache treatment pro-
formed in a tertiary headache center and included gram agreed to provide assessment. Assessments
120 patients with MOH [46]. Advice alone was of headache severity, psychological status, and
as effective as the other two interventions, with functional impairment were completed by 371
a success rate after 2 months of >70%. A second (97.8%) of these at the time of admission. At
study compared the effectiveness of an educa- discharge, 340 subjects (89.7%) provided assess-
tional strategy (advice to withdraw the overused ment data, and 152 (40.1%) provided data at
medication or medications) with that of two 1-year follow-up. At entry subjects’ mean head-
structured pharmacological detoxification pro- ache pain was 6.1, declining at discharge of 3.5
and at follow-up of 3.3. A measure of functional line showed a nonsignificant reduction in mean
impairment, the HIT-6 score improved following monthly migraine/migrainous days compared
treatment from 66.1 on admission to 55.4 at dis- with placebo [54]. The trials differed from the
charge and 51.9 at 1-year follow-up. Depression European trial in inclusion criteria and the classes
and anxiety also showed marked improvement of overused medications [53, 55, 56].
although depression scores lapsed back toward About 65% of patients fulfilled the criteria for
admission levels at the 1 year follow-up. MOH in the two pivotal trials comparing onabotu-
In conclusion, advice alone might be an appro- linumtoxinA with placebo injections in patients
priate approach in patients who overuse triptans with chronic migraine, [57–59]. Excluded patients
or simple analgesics and who do not have major from the trials were those with opioid overuse. At
psychiatric comorbidity. Advice alone can be pro- week 24, statistically significant results favor-
vided by GPs, neurologists in private practice, and ing onabotulinumtoxinA versus placebo were
headache nurses. However, advice alone might not observed for headache days (primary endpoint,
be enough for patients who overuse opioids tran- −8.2 versus −6.2, p < 0.001). Significant result
quilizers or barbiturates or who have had repeated occurred as well for secondary endpoints such as
episodes of overuse. These patients need referral frequencies of migraine days (p < 0.001), moder-
to a headache specialist or a headache center. ate/severe headache days (p < 0.001), cumulative
headache hours on headache days (p < 0.001),
headache episodes (p = 0.028), and migraine epi-
Preventive Migraine Therapy in MOH sodes (p = 0.018) [60].
Observational and underpowered randomized
Most patients with MOH who are referred to trials investigated valproic acid, cannabinoids,
headache centers have already failed preventive pregabalin, occipital nerve stimulation, and acu-
therapy with beta blockers, flunarizine, valproic puncture for the treatment of MOH (summarized
acid, or amitriptyline. At present scientific evi- by [61]). Due to the methodological shortcom-
dence for effective preventive therapy in patients ings, the results of these studies have no impact
with MOH from randomized trials exists for topi- on the practical treatment of patients with MOH.
ramate and onabotulinumtoxinA and some of the
monoclonal CGRP-antibodies.
Topiramate was investigated in a European anagement of Symptoms During
M
study and included patients with chronic migraine Detoxification
who were randomized to topiramate or placebo
for a 16-week double-blind trial. Topiramate was Most studies in patients with MOH investigated
titrated from 25 mg weekly to a target dose of drug withdrawal or detoxification. After discon-
100 mg/day, allowing dosing flexibility from 50 tinuation of migraine drugs or analgesics, most
to 200 mg/day. Thirty-two patients in the inten- patients experience a transient deterioration of
tion-to-treat population received topiramate, the underlying headache with autonomic distur-
and 27 patients received placebo. Seventy-eight bances, anxiety, and sleep problems [6]. These
percent of patients met the criteria for medica- symptoms last 2–7 days depending on the over-
tion overuse at baseline. Topiramate significantly used medication [62]. The shortest duration of
reduced the mean number of monthly migraine withdrawal symptoms is in patients overusing
days by 3.5 compared with placebo (−0.2 days) triptans and the longest in patients overusing
[52]. This trial showed that topiramate was effec- ergots, barbiturate compounds, or opioids.
tive and reasonably well tolerated when used for A systematic review identified 27 studies
the preventive treatment of chronic migraine with reporting the treatment response to discontinuation
medication overuse. A second trial conducted in or withdrawal, 19 of them with preventive medi-
the USA compared topiramate with placebo for cation [61]. In the studies included in the review,
the prevention of chronic migraine [53]. A sub- the withdrawal program was either performed in
group analysis of the patients with MOH at base- an outpatient setting, in a day hospital or inpatient
setting. Therapies included fluid replacement (if period was associated with a significant reduc-
necessary) and some drug treatments, including tion in headache frequency without institution
corticosteroids, neuroleptic drugs, tranquilizers, of new preventative treatments [68]. This may
ergots, and simple analgesics. Adding preventive be the result of the action of naproxen on P2X3
medication to early discontinuation led to a bet- receptors on sensitized trigeminal neurons in
ter outcome than early discontinuation alone. For addition to effects on cyclooxygenase [69]. The
patients with chronic migraine and medication combined use of a tizanidine, an alpha agonist,
overuse, randomized controlled trials supported the coupled with a once daily COX-2 inhibitor led to
use of onabotulinumtoxinA and topiramate with- marked reduction in additional acute medication
out early discontinuation of overuse (see above). use over a several month trial period [70].
Two placebo-controlled trials investigat- Dihydroergotamine mesylate is used in the
ing the use of corticosteroids versus placebo USA in the management of chronic migraine
for the treatment of withdrawal symptoms, one with and without medication overuse headache
in Norway and one in Germany [63, 64]. Both [71]. By comparison to ergotamine tartrate and
studies found no benefit of prednisone or pred- the triptan class of medication, medication over-
nisolone versus placebo. use headache has not been reported, but rather
The majority of the studies of withdrawal-asso- it may be a useful adjunct as part of a compre-
ciated symptoms in MOH conducted to date have hensive management strategy [72]. In chronic
been observational. A large multinational study migraine without medication overuse, it produces
with centers from Europe and South America a robust reduction in migraine during the infu-
(COMOESTAS) recruited 376 patients with MOH sion for most patients and coupled with symptom
[65]. Patients went through detoxification followed management [73] may afford early relief to these
by the initiation of preventive therapy. The choice patients and potentially improve the long-term
of preventive medication was dependent on comor- outcome for reduction of headaches.
bid disorders. The post-detoxification follow-up Historically, in the USA, as well as elsewhere,
lasted 6 months. At the final evaluation, two-thirds the use of an inpatient environment to initiate
of the participants were no longer overusing acute treatment has been used [74]. This allows for
medication, and in 46.5% of participants, the aggressive medical management of the head-
headache had reverted to an episodic pattern of ache and associated symptoms, especially during
headache. When comparing the participants who medication overuse withdrawal. It permits early
underwent outpatient detoxification with those intervention with non-pharmacological strategies
treated with inpatient detoxification, both regimens and behavioral medicine assessments in a con-
proved effective. The dropout rate was higher in the trolled environment. Despite insurance attempts
outpatient approach [65]. The number of patients to reduce this type of treatment for cost concerns,
with depression and/or anxiety decreased over it remains an important method of addressing
time, and the disability improved [66]. the patient’s needs [75] when outpatient services
The use of bridging therapies has been advo- have not proven effective. Moreover, an inpatient
cated to ease the severity of the withdrawal program may be associated with containment of
headaches and associated symptoms. Steroids long-term healthcare costs as well [76]. While
used as a bridging therapy during the first week outpatient treatment of chronic migraine with
of treatment did not offer any long-term advan- medication overuse produced a 4% reduction
tages to standard therapy of changes in preven- in healthcare expenditure, this was compared to
tative medications coupled with use of a triptan nearly 33% reduction in long-term costs among
and a NSAID for acute headache treatment to a those treated initially on an inpatient basis. Both
maximum of twice a week [67]. Bridging therapy groups had about a 75% reduction in MIDAS
with avoidance of all other acute medications for scores, although those treated in inpatient hospi-
migraine and pain and replacement of them with tal had roughly twice the number of day’s reduc-
naproxen sodium alone during the withdrawal tion of headache over 6 months (Table 14.1).
Table 14.1 Outcome parameters comparing outpatient and inpatient treatment of MOH
Chronic migraine without medication overuse Chronic migraine with medication overuse
Parameter Outpatient treatment Inpatient treatment Outpatient treatment Inpatient treatment
Number of patients 27 46 57 23
Age (years) 48 50 52 50
Comorbid medical 2.8 2.8 2.7 2.8
disorders
14 Medication Overuse in Chronic Daily Headache
Disease duration 14 14 15.9 18

Pre- Post- % Pre- Post- % change Pre- Post- % Pre- Post- %
treatment treatment change treatment treatment treatment treatment change treatment treatment change
Cost/6 months 2724 2646 −2.8% 3677 3518 −0.4% 7859 7529 −4.2% 6671 4502 −32.5%
Headache 54.4 48.1 −11.5% 59.2 53.3 −9.9% 75.5 49 −35.1% 65 23 −64.6%
days/3 months
MIDAS 55.1 27.6 −49.9% 83 39.6 −53.4% 123.9 25.4 −79.5% 91 21.5 −76.4%
MD visits/6 months 5.18 0.56 −89.2% 6.8 1.27 −81.3% 10 1.88 −81.2% 7.9 2.8 −64.5%
ED visits/6 months 1.27 0.38 −70.3% 1.41 0.63 −55.3% 1.79 0.95 −46.9% 1.38 0.4 −71%
Inpatient 0.42 0.18 −57.1% 0.26 0.81 +211% 0.51 0.72 +41% 0.48 0.2 −58.3%
admissions/6 months
Reprinted from [76], courtesy of Baylor University Medical Center at Dallas
201
Long-term benefits associated with the use of Relapse of MOH

intravenous DHE during the initiation of treat-
ment revealed significant benefit. The authors Chiang et al. summarized the remission and
found that >90% of patient were headache- relapse rates after discontinuation from 22 stud-
free within 3 days [71]. In a study examining ies [61] with a follow-up of 2 and 60 months
long-term outcomes, 78% of 278 patients had at (most studies 12 months). The relapse rate varied
least moderate reduction in their headache pain between 0% and 45%, with most studies showing
parameters [77]. a relapse rate between 25% and 35%. Predictors
Another potential bridge treatment that has of relapses were chronic tension-type headache
been effective has been the use of daily 25 mg versus migraine as the primary headache, over-
three times per day dosing of sumatriptan given use of opioids versus triptans, and comorbid psy-
steadily until the patient has headache freedom chiatric disorders. Depression is an important
for more than 24 h. In the study by Tepper et al., predictor of relapse [81].
58% of 26 patients had reverted to an episodic The most important recommendations for the
pattern with this treatment in addition to new pre- management of MOH are:
ventative medications [78].
One randomized trial compared three treat- • Patients with MOH should be managed by a
ment approaches for MOH. This 1-year open- multidisciplinary team of neurologists or pain
labelled, multicenter study included 56 patients specialists and behavioral psychologists.
who were randomly assigned to receive pro- • Patient education is of significant importance.
phylactic treatment from the start without • Patients with MOH should undergo drug with-
detoxification, undergo a standard outpatient drawal. One can abruptly terminate in patients
detoxification program without prophylactic overusing simple analgesic, ergot, or triptan
treatment from the start, or to have no spe- medication. In patients with long-lasting
cific treatment (5-month follow-up). The pri- abuse of opioids, barbiturates, or tranquilizers,
mary outcome measure, change in headache slow tapering of these drugs can be an option.
days per month, did not differ significantly • Detoxification can be performed on an outpa-
between groups. However, the prophylaxis tient basis, in a day-care setting or an inpatient
group had the greatest decrease in headache setting. All settings have a similar success rate
days compared with baseline and also a signifi- because of the different complexities suited to
cantly greater reduction in total headache index each setting. Headache history may help to
(headache days/month x headache intensity x assign patients to a given setting (Table 14.2).
headache hours) at months 3 (P = 0.003) and • Patients who do not want to undergo detoxifica-
12 (P = 0.017) compared with the withdrawal tion can initiate migraine preventive therapy
group. At month 12, 53% of patients in the pro- with either topiramate or onabotulinumtoxinA.
phylaxis group had ≥50% reduction in monthly
headache days compared with 25% in the with- Table 14.2 Treatment strategies in MOH
drawal group (P = 0.081) [79]. Outpatient withdrawal Inpatient treatment
A Danish study investigated the effects of a • No opioid, barbiturates, • Long-lasting MOH
2-month medication period in 337 patients with or tranquilizer (>5 years)
• Motivated patient • Overuse of opioids or
probable MOH [80]. Only two-thirds of the • Support by family or barbiturates
patients completed the study. Forty-five percent friends • Overuse of
of the patients improved, 48% had no change Day-care setting psychotropic
in headache, and 7% experienced an increase in • Comorbidity with medication (hypnotics,
depression or anxiety anxiolytics,
headache days. Patients with migraine showed • Comorbidity with other tranquilizers
a higher rate of improvement than patients with chronic pain syndromes • Failed outpatient
tension-type headache. Patients overusing trip- (low back pain, withdrawal
tans improved the most. fibromyalgia) • Psychiatric comorbidity
Disclosures H. C. Diener received honoraria for his par- 8. Abrams BM. Medication overuse headaches. Med
ticipation in clinical trials, contribution to advisory boards, Clin North Am. 2013;97(2):337–52.
or oral presentations from Addex Pharma, Alder, Allergan, 9. Kristoffersen ES, Lundqvist C. Medication-overuse
Almirall, Amgen, Autonomic Technology, AstraZeneca, headache: epidemiology, diagnosis and treatment.
Bayer Vital, Berlin Chemie, Böhringer Ingelheim, Bristol- Ther Adv Drug Saf. 2014;5(2):87–99.
Myers Squibb, Chordate, Coherex, CoLucid, Electrocore, 10. Stovner LJ, Andree C. Prevalence of headache in

GlaxoSmithKline, Grünenthal, Janssen-Cilag, Labrys Europe: a review for the Eurolight project. J Headache
Biologics, Lilly, La Roche, 3 M Medica, Medtronic, Pain. 2010;11(4):289–99.
Menerini, Minster, MSD, Neuroscore, Novartis, Johnson 11. Straube A, Pfaffenrath V, Ladwig KH, Meisinger

& Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, C, Hoffmann W, Fendrich K, et al. Prevalence of
Sanofi, St. Jude, Teva, and Weber & Weber. Financial sup- chronic migraine and medication overuse headache
port for research projects was provided by Allergan, in Germany–the German DMKG headache study.
Almirall, AstraZeneca, Bayer, Electrocore, GSK, Janssen- Cephalalgia. 2010;30(2):207–13.
Cilag, MSD and Pfizer. Headache research at the 12. Westergaard ML, Hansen EH, Glumer C, Olesen J,
Department of Neurology in Essen is supported by the Jensen RH. Definitions of medication-overuse head-
German Research Council (DFG), the German Ministry of ache in population-based studies and their implica-
Education and Research (BMBF), and the European tions on prevalence estimates: a systematic review.
Union. H.C. Diener has no ownership interest and does not Cephalalgia. 2014;34(6):409–25.
own stocks of any pharmaceutical company. HCD serves 13. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton
on the editorial boards of Cephalalgia and Lancet R, Scher A, et al. The global burden of headache: a
Neurology. HCD chairs the Clinical Guidelines Committee documentation of headache prevalence and disability
of the German Society of Neurology. worldwide. Cephalalgia. 2007;27(3):193–210.
D. Holle-Lee has received financial support for 14. Katsarava Z, Schneeweiss S, Kurth T, Kroener U,
research projects from Allergan, Grünenthal, and Lilly Fritsche G, Eikermann A, et al. Incidence and predic-
and research support from EFIC. tors for chronicity of headache in patients with epi-
F. Freitag is an advisor to the Migraine Research sodic migraine. Neurology. 2004;62(5):788–90.
Foundation and BioHealthonomics. He has received 15. Limmroth V, Katsarava Z, Fritsche G, Przywara S,
financial support for clinical research, consulting, and Diener H. Features of medication overuse headache
educational presentations from Alder, Allergan, Amgen, following overuse of different acute headache drugs.
Avanir, Depomed, Mayo Clinic Phoenix, Dr. Reddy, Teva, Neurology. 2002;59:1011–4.
and Weber & Weber. 16. Creac'h C, Radat F, Mick G, Guegan-Massardier E,
Giraud P, Guy N, et al. One or several types of triptan
overuse headaches? Headache. 2009;49(4):519–28.
17. Bigal ME, Borucho S, Serrano D, Lipton RB. The
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Optimizing Acute Headache
Treatment in the Setting 15
of Chronic Migraine
Amanda Tinsley and John Farr Rothrock
Successful reduction of headache burden in

patients with chronic migraine (CM) most often Management Plan for the Suppression of
will require an integrated management strategy Chronic Migraine
that involves much more than simply the pre- • Intensive patient education
scription of an oral prophylactic agent or admin- • Avoidance of acute migraine “trig-
istration of onabotulinumtoxinA. In most cases, gers”/chronic migraine aggravators
pharmacologic prophylactic therapy represents • Elimination/avoidance of symptomatic
the final, albeit critical, component of any man- medication overuse
agement plan designed to suppress CM. An • Aggressive and appropriate treatment
example of a rational, multidimensional plan is of acute “breakthrough” headaches
outlined below. • “Customized”* aerobic conditioning
program
• Treatment of coexisting sleep or mood
disorder
• Use of a headache diary
• Ongoing follow-up with provider
• Appropriate pharmacologic prophy-
lactic therapy
*i.e., appropriate to the patient’s base-
line level cardiovascular fitness
A. Tinsley (*) · J. F. Rothrock

Department of Neurology, GW-MFA Headache The Therapeutic Paradox
Center, George Washington University School
of Medicine and Health Sciences, Washington,
DC, USA For the patient with CM and daily or near-daily
e-mail: ammichael@mfa.gwu.edu headache, two components of this management

208 A. Tinsley and J. F. Rothrock
plan—aggressive treatment of acute headache opinion in the field of headache medicine that
and avoidance of symptomatic medication over- frequent use of virtually any of the over-the-
use—may seem contradictory. Especially in the counter or prescription medications commonly
early weeks of treatment, when any prophylactic used to treat acute migraine headache will lead to
treatment prescribed or administered has yet to an increase in overall headache burden [3–6].
exert a therapeutic effect, how does one manage Although the propensity for the development of
to treat effectively each headache that occurs MOH well may vary from one migraineur to
without straying into the self-defeating realm of another, current International Headache Society
symptomatic medication overuse and medication guidelines indicate that use of “simple” analge-
overuse headache (MOH)? sics (e.g., acetaminophen) more than 14 days per
month for at least 3 consecutive months or use of
an opiate/opioid, butalbital, ergotamine, or trip-
Consequences of Inadequately tan more than 9 days per month will add to the
Treated Acute Migraine migraineur’s primary headache disorder a com-
ponent of MOH [7].
There are both short- and long-term conse- Symptomatic medication overuse is prevalent
quences that result from inadequate acute head- [8]. Among patients presenting to a subspecialty
ache treatment. Aside from the misery, headache clinic, as many as two-thirds report
inconvenience, and cost that attend an untreated overusing symptomatic medication [8]. At least
or incompletely treated acute migraine attack, in this clinic population, both the frequency of
such attacks may negatively influence the MOH and the type of medication overused may
afflicted individual’s subsequent headache pat- vary significantly according to geographic region.
tern. Increasing headache attack frequency is a In one study, patients at a university-affiliated
potent risk factor for “transformation” of epi- headache clinic in the District of Columbia were
sodic migraine (EM) into its chronic variant, and significantly less likely to report or exhibit over-
congruent with this is the observation that pro- use of symptomatic medication than patients at a
longed attacks of severe migraine headache university-affiliated clinic in Nevada, and among
appear to amplify sensitization of the anatomical those in the former group, the prevalence of over-
pathways that signal migrainous head pain [1, 2]. use of an opiate/opioid or butalbital was also sig-
In the setting of CM, wherein those pathways nificantly lower [9, 10].
already have become persistently sensitized, such Patients often use “rebound headache” as a
amplification will serve to render the patient yet term they consider to be synonymous with
more headache-prone and further complicate the MOH. The authors have found that when patients
task of achieving a significant reduction in head- who report “rebound” caused by a given medica-
ache burden. tion are questioned more closely, what the patient
often is describing is an acute migraine headache
that responded to treatment with a given symp-
Medication Overuse Headache tomatic agent but then soon recurred, frequently
with a vengeance. In short, they are describing
If frequent migraine headaches predispose to and precisely what one would expect from an incom-
reinforce CM, why burden the patient with any pletely treated acute migraine episode wherein
limit on the use/frequency of symptomatic medi- early headache recurrence will occur once the
cation? Issues of side effects, abuse/addiction, initially effective symptomatic medication is
and habituation aside, unrestricted acute head- metabolized and eliminated. For example, the
ache treatment unfortunately may result in half-life of subcutaneously administered sumat-
MOH. While some persuasively have argued that riptan is only 1–2 h. While the therapy’s swift
the frequency and clinical influence of MOH Tmax may lead to a rapid and dramatic reduction
have been overstated, it remains the prevailing in acute headache, its short half-life ensures that
15 Optimizing Acute Headache Treatment in the Setting of Chronic Migraine 209
many patients will experience early headache biologic process that generates MOH to dissipate
recurrence (especially if treatment has been and clinical improvement to begin. The rapidity
delayed and the initial headache is reduced but with which improvement occurs appears to vary
not eliminated). according to the class of symptomatic medication
Medication overuse headache is often far less involved. With the triptans and ergotamines, ces-
vivid and much more insidious than the term sation of overuse tends to produce clinical
“rebound” would imply. Although there are improvement within days to a few weeks, but
patients overusing symptomatic medication who with virtually all other symptomatic medica-
exhibit an obvious temporal relationship between tions—from acetaminophen to oxycodone—such
administration of drug and development of head- improvement may be much slower in coming. An
ache (e.g., a consistent pattern of being awakened absence of any early positive reinforcement obvi-
from sleep by recurrent, severe headache), MOH ously can be discouraging for the patient, and on
more often blends seamlessly with the afflicted a more general level, it calls into question the
patient’s primary headache disorder. Medication utility of short-term hospitalization or use of out-
overuse headache takes time to develop. In isola- patient infusion centers for the primary purpose
tion, a “bad week” wherein a patient uses a trip- of treating MOH via acute “detoxification.”
tan 4 or 5 days is unlikely to generate
MOH. Instead, the months pass, the medica-
tion—say, acetaminophen—is taken on what Rational Pharmacologic
amounts to a scheduled basis, the CM patient Management of Acute Migraine
simply continues to suffer from pervasive head- in the CM Patient
ache, and aside from the potential development
of drug tolerance or side effects, the headache The individual with CM typically is more famil-
disorder’s clinical characteristics remain more or iar and experienced with acute therapies than the
less unchanged. average migraineur. Often times, CM patients
Thus MOH may be obscured by the CM itself. have tried numerous symptomatic medications
If the potential for developing MOH varies and experienced disappointing results, leading to
according to the class of symptomatic medication increased direct and indirect costs and patient
involved and, even more problematic, the physi- frustration. In this patient population, it is espe-
ology of the given individual, how, then, can the cially important to obtain detailed information
clinician know when a patient’s CM has become regarding what has constituted treatment “fail-
complicated by MOH? While elegant preclinical ure.” In many cases, suboptimal doses, poorly
and clinical studies have established an objective timed administration of a given medication, or an
scientific basis for the existences of MOH, at this inappropriate formulation may have been
point there is no easily available laboratory test or employed. Ascertain whether the patient has tried
imaging study available to confirm the clinical combination therapies and/or non-oral formula-
suspicion of MOH [11]. The best the provider tions. Simply adjusting the dose or matching
can do is attempt to prevent overuse from the drug and formulation to headache intensity and
start, assume MOH is present if persistent over- associated symptoms may improve the patient’s
use is known to be occurring, and then work with ability to control acute attacks. Perhaps of great-
the patient to curtail overuse. est importance, whenever possible ensure the
The individual with CM who substantially patient treats the acute headache attack early,
reduces his or her use of the offending symptom- while pain intensity is still mild.
atic medication(s) may not be immediately As implied earlier, the major difference in
rewarded for that effort by any meaningful reduc- treating acute migraine attacks for CM patients
tion in headache burden. Just as it may take compared to episodic migraine (EM) patients is
months of overuse for MOH to develop, a simi- that aggressive treatment of all attacks places CM
larly extended period may be required for the patient at risk for developing MOH. About the
best the provider can do is educate the patient as Selecting a Therapy

to that risk, provide parameters for how often a
given medication or class of medications should Acute treatment regimens necessarily are often
be utilized, and prescribe multiple abortive thera- dynamic, changing based on the patient’s
pies intended to “fit” the individual headache’s response to a given medication and other circum-
level of intensity without overuse of one particu- stances (e.g., financial considerations).
lar medication or class. Interactions with other medications the patient is
The patient-provider alliance is of utmost taking and comorbidities such as hypertension,
value when developing a regimen for acute man- vascular disease, and gastrointestinal disorders
agement of CM. A discussion on realistic expec- must be considered when selecting an acute treat-
tations of acute therapy in the office can lead to ment. Many patients with CM do not respond
improved patient education and satisfaction. well to acute monotherapy, and so combination
Although the goals of acute therapy (pain free- therapies with drugs possessing different mecha-
dom, rapid and complete restoration of function, nisms of action may be needed.
and absence of early headache recurrence) are Acute therapies can be either nonspecific or
ideal, this will not be possible in all cases. In many specific, with the latter intended to target recep-
cases of CM, simply achieving the goals of pain tors or other mechanisms of electrochemical
reduction, decreased utilization of urgent care cen- transmission known to be integral to the genera-
ters or emergency rooms (ERs), and reduced tion of migrainous head pain.
migraine-related disability may have to suffice.
Patients should be encouraged to keep a head-
ache “diary” to monitor headache frequency and
severity and acute medication use, and this record
should be reviewed at follow-up visits to track Major Categories of Acute Migraine
the progress of the patient’s headache burden and Treatments
its change (or lack of change) subsequent to Nonspecific Acute Migraine Therapies
implementation of a management plan. While • Nonsteroidal anti-inflammatory drugs
the authors have not found elaborate hour-by- (NSAIDs)
hour journals detailing food and beverage intake, • Acetaminophen
weather, physical and social activity, etc. to be • Opioids
especially helpful in managing CM, for cycling • Benzodiazepines
female patients, the inclusion of menstrual flow • Corticosteroids
onset and cessation in the diary may provide • Propofol (IV only)
another avenue for achieving a reduction in head- • Ketamine (IV only)
ache burden. Specific Acute Migraine Therapies
There is an a priori reason why the develop- • Triptans
ment of an evidence-based plan for acute treat- • Ergots
ment in the setting of CM can be difficult: to date, • Dopamine antagonists
the great majority of clinical trials evaluating • Diphenhydramine
therapies for acute migraine have systematically • Calcitonin gene-related peptide
excluded patients with CM. Navigating the acute (CGRP) antagonists (currently under
management of the CM patient population conse- study)
quently requires a blend of “art” and extrapola- Therapies with Uncertain Mechanisms
tion from clinical trials data relevant to the EM • Valproic acid (IV)
population. At present, there can be no scientifi- • Magnesium sulfate (IV)
cally derived consensus regarding the pharmaco- • Occipital nerve blocks
logic specifics of acute therapy in CM patients.
Nonspecific Migraine Therapies bination medication containing aspirin, acetamin-

ophen, and caffeine, has been shown to be effective
The most commonly used acute medications for and has received US Food and Drug Administration
migraine are the nonsteroidal anti-inflammatory approval for acute migraine treatment [12].
drugs (NSAIDs). NSAIDs exert their effect by Opiate/opioid treatment of acute migraine is
inhibiting cyclooxygenase, decreasing prosta- controversial, and such treatment is typically best
glandin synthesis in the central nervous system avoided or minimized whenever possible. In select
and systemically. Given that migraine is classi- cases of acute, severe migraine headache wherein
fied as a neuro-inflammatory disorder, it’s hardly all other medication options have failed, are con-
surprising that many drugs in this class have per- traindicated, or are not tolerated, opiate/opioid
formed well in trials involving acute migraine. therapy may be considered as an option, but the
The NSAIDs with the most consistently positive frequency of use should be kept to a minimum so
clinical trials evidence of efficacy in the setting of as to reduce the complications of MOH, depen-
acute migraine treatment are aspirin, diclofenac dence/addiction, decreased responsiveness to pro-
potassium/sodium, flurbiprofen, ibuprofen, phylactic therapy, or tardive development of CM.
naproxen sodium, and tolfenamic acid. Benzodiazepines provide sedation but little
Especially when the headache is moderate to analgesic benefit. They are not ideal first-line
severe in intensity, an oral NSAID may fail to abortive agents due to their side effect profile
abort an acute migraine attack. Parenteral ketoro- (drowsiness, confusion), association with depen-
lac can be helpful in these cases and is the only dence/addiction, and risk of overdose. Even so,
NSAID available in intravenous (IV) or intra- benzodiazepines may be particularly helpful in
muscular (IM) formulations in the United States. promoting sleep in a patient with a prolonged
In the ER or urgent care setting, ketorolac migraine attack, and sleep itself may terminate a
15–30 mg IV or 30–60 mg IV is used as a first- migraine attack. Oral diazepam 5 mg tablets can
line treatment; in clinical trials, the IV route has be used in the outpatient setting, and multiple IV
yielded a higher response rate. Theoretically, the formulations exist for urgent care settings.
high concentration of NSAID that reaches the Steroids may suppress the inflammatory pro-
CNS with the parenteral administration of the cesses thought to be involved in migraine. In the
medication accounts for the increase in efficacy absence of little supportive evidence from
relative to the oral formulation. Patients can also research trials, clinicians often prescribe a short
self-administer ketorolac intramuscularly with course (3–10 days) of oral steroids to “break” sta-
prefilled syringes, eliminating the need for utili- tus migrainosus and/or reduce the risk of head-
zation of an ER or urgent care center. ache recurrence following treatment of that
Gastrointestinal (GI) intolerance and bleeding condition. Because chronic steroid use can lead
is the major potential complication associated to a host of long-term sequelae (e.g., osteoporo-
with NSAID use. Oral celecoxib (100–400 mg), sis, aseptic necrosis, cataracts, diabetes, weight
a selective cyclooxygenase-2 (COX-2) inhibitor, gain, skin thinning, immunosuppression), their
can be considered if NSAIDs are contraindicated use must be limited, and even brief courses of
secondary to gastrointestinal bleeding but may oral steroids should be restricted to ~8 times per
convey an increased risk for cardiovascular year. There is currently no evidence available
events. For patients who fail to respond to an oral regarding which steroid and dosing paradigm is
NSAID, exhibit extreme GI intolerance, and can- most effective in the outpatient setting, and cur-
not/will not self-inject ketorolac, indomethacin rent prescribing patterns are based primarily on
50 mg is available as compounded suppository. provider preference. Common regimens include
Acetaminophen, like aspirin often referred to as dexamethasone 4 mg tid for 3 days, prednisone
a “simple analgesic,” may not be as effective for 60 mg in the morning with food for 3–5 days, or
acute migraine treatment as the NSAIDs but has prepackaged tapering regimen of methylprednis-
been consistently superior to placebo in clinical olone (i.e., a “dosepak”). In the ER setting, corti-
trials. Excedrin, a patented over-the-counter com- costeroids (10–25 mg IM/IV) have been shown to
be effective in decreasing the risk of headache oral triptans clearly are more effective if taken
recurrence when used as an adjunctive therapy early in a migraine attack, when pain intensity is
with other abortive agents. mild to moderate, their FDA indications were
The administration of sub-anesthetic doses derived from registration trials involving headache
(1 mg/kg or less) of propofol IV for acute treat- of moderate to severe intensity, and at this writing
ment of refractory migraine has been shown to be we lack data to indicate they are any more effec-
efficacious and safe in several case studies, but tive for early migraine than the NSAIDs or other
practical considerations have limited its use in cheaper, more accessible treatment options. As for
the setting of acute migraine headache [13–16]. the “slow-onset” oral triptans—naratriptan and
In a recently published retrospective analysis, frovatriptan—their relatively slow onset of thera-
sub-anesthetic doses of IV ketamine were peutic action is such that their use is largely
reported to be helpful in treating patients with restricted to patients intolerant of faster-onset trip-
CM and new daily persistent headache who had tans or those requiring triptan “miniprophylaxis”
failed traditional therapies [17]. (e.g., as for menstrually related migraine).
Relative to the triptans, the ergotamines have
the advantage of longer half-lives, a longer dura-
“Specific” Migraine Therapies tion of therapeutic effect, and a lower rate of
early headache recurrence. As for their negative
Relatively more migraine-specific acute treat- attributes, the oral ergotamines are poorly
ments include the triptans and ergotamine deriva- absorbed, subcutaneously administered dihydro-
tives, which act as 5-hydroxytryptamine (5-HT) ergotamine (DHE) is less rapidly effective than
agonists at serotonin receptors inhibitory to head injectable sumatriptan, and the ergotamines as a
pain transmission. While a more central action group are more likely than the triptans to cause
cannot be excluded, these drugs may exert their nausea. Intranasally administered DHE appeared
therapeutic effect by blocking the extravasation in phase 3 trials to offer an intriguing alternative
of pro-inflammatory plasma proteins from dural to the oral and intranasal triptans or to subcutane-
blood vessels and by constricting dilated extrace- ous therapy, but its expense and tendency to pro-
rebral cranial blood vessels. mote nasal congestion have limited its use.
For now, subcutaneously injected sumatriptan As for the dopamine antagonists, with the excep-
(3.4, or 6 mg) must be considered the most effec- tion of oral metoclopramide, self-administration of
tive self-administered therapy for “rescue” from these agents is most commonly reserved to treat
migraine headache of moderate to severe inten- migraine-associated nausea rather than the head-
sity. It’s often astounding efficacy may be attrib- ache itself. Their efficacy in treating headache
uted to the drug’s rapid Tmax and relatively high increases dramatically when they are administered
Cmax, pharmacokinetic variables which unfortu- via the intravenous route (see below).
nately also tend to produce the familiar array of
triptan side effects more frequently and at a higher
level of intensity than other triptan formulations. Status Migrainosus
The intranasal formulation of sumatriptan
appears to offer little advantage over the oral and is Aggressive treatment of acute migraine may be
less effective than the injectable. Intranasal zolmi- beneficial for many reasons, but such treatment is
triptan, however, may represent an attractive especially appropriate for patients with pro-
option for patients who are reluctant to self-inject longed attacks that exceed 3 days or more (“sta-
but do not respond consistently to the oral formu- tus migrainosus”). In the setting of acute
lations of this or the other triptans. Of the “fast- migraine, once a certain level of biologic sensiti-
onset” oral triptans—sumatriptan, zolmitriptan, zation has been reached, medications typically
rizatriptan, almotriptan, eletriptan—patient effective when administered earlier in the attack
response tends to be highly idiosyncratic; some may lose their therapeutic benefit [18]. In addi-
patients prefer one over the others, some respond tion, there is much clinical and biological evi-
well to all, and some respond to none. While the dence to support the adage that “headache begets
headache,” and prolonged attacks of severe decline in its use and, eventually, its availability.
migrainous head pain may be particularly Although there is little evidence to suggest that
inclined to enhance sensitization of the central other dopamine antagonists commonly adminis-
and peripheral pathways integral to signaling of tered for the treatment of acute migraine have more
head pain. As for the worst case scenario, any cli- or less potential for producing QTc prolongation or
nician who sees a high volume of migraine has significant cardiac arrhythmia, the FDA warning
encountered patients whose status migrainosus and the corresponding need to obtain and evaluate
progressed from being atypically prolonged into an electrocardiogram prior to administration of
the pervasive headache of chronic migraine. droperidol and maintain cardiac monitoring over
Provider-administered “rescue therapy” ideally the subsequent hours have served to effectively
should be delivered in a setting absent of stimuli eliminate its role in migraine treatment.
which aggravate acute migraine (e.g., light, noise), As for the other dopamine antagonists often
wherein the patient can be treated rapidly by pro- used to treat acute migraine headache—metoclo-
viders familiar with acute migraine management pramide, prochlorperazine, promethazine, chlor-
and, better yet, familiar with the individual patient’s promazine, and haloperidol—there are few data to
history and particular needs. Unfortunately, such is suggest that anyone is better suited for that pur-
rarely the case in emergency rooms and urgent care pose than another. By virtue of its consistently
centers. Confronted with the option of suffering in positive performance in ER-based clinical trials
silence at home and facing the long wait time and involving migraine headache and relatively high
bright neon lights of the ER, many patients with tolerability, intravenously administered metoclo-
acute migraine understandably choose the former. pramide is considered by many to be the dopamine
The attack persists untreated until it finally runs its antagonist of first choice for migraine therapy.
course, and at its conclusion the migraineur is left Early headache recurrence following transiently
with a yet more sensitized biologic system primed successful termination of status migrainosus is not
to generate more headaches. uncommon, and to assist in avoiding that complica-
A third option for provider-administered acute tion, it may be helpful to add intravenous steroid to
migraine treatment is beginning to gain traction. whatever other else is administered and to prescribe
“Headache rescue rooms” which are embedded a short course of high-dose oral steroid to be taken
in subspecialty headache centers may provide an over the days immediately ensuing.
excellent alternative to an ER, urgent care center, Pharmacologic intervention aside, optimal
or simple endurance in a dark, silent room. management of status migrainosus requires that
“Rescue room” utilization is associated with high the provider ensure the patient is adequately
rates of headache relief, low rates of early head- hydrated and that the blood pressure is main-
ache recurrence, high patient satisfaction, and a tained at an appropriate level. Patients with pro-
significant reduction in direct medical costs [19]. longed migraine frequently have reduced
In the ER and elsewhere, the use of nonspe- intravascular volume due to decreased oral intake
cific parenteral opiates and opioids to treat acute and migraine-associated vomiting, and dehydra-
migraine headache remains discouragingly high. tion reinforces the migraine process. Even typi-
Despite their frequency of use and the potential cally normotensive patients with acute, severe
for abuse, little evidence exists to suggest that migraine headache may exhibit a considerable
these traditional nostrums convey much in the elevation of systemic blood pressure during
way of meaningful efficacy. attacks, and if the elevated pressure fails to
Among the more specific medications which decrease following treatment directed at reduc-
have been used to treat status migrainosus, droperi- tion of headache intensity, then more specific
dol administered intramuscularly became widely antihypertensive therapy is indicated.
utilized by ER physicians for the treatment of acute An evidence-based algorithm for provider-
migraine headache [20]. In 2001, however, the administered treatment of acute migraine is pre-
drugs’ controversial acquisition of a “boxed warn- sented in Fig. 15.1. Interestingly, in one scholarly
ing” related to QTc prolongation led to an abrupt meta-analysis involving ER-based trials that
PROTOCOL FOR ACUTE MIGRAINE MANAGEMENT

Has patient already received injectable sumatriptan?
NO YES
If not contraindicated: If not contraindicated, choose one option:
Sumatriptan SC 6mg + Dexamethasone 10mg IV 1. Metoclopramide 15-20mg IV + Benadryl
(do NOT give if received DHE within past 24 hours) 25mg+ Dexamethasone 10mg IV 0.5-1 L
0.5-1 L normal saline IV normal saline IV
2. Haldol 5mg IM plus either: Benadryl
25mg IV or lorazepam 1mg IV
Monitor for 30 minutes: Is headache improved? Monitor for 30 minutes: Is headache improved?
NO YES NO YES
If not contraindicated, D/c with appropriate med changes If not contraindicated: D/c with appropriate med changes
choose one option: (3-5 days of steroids Magnesium 1g IV plus (3-5 days of steroids
1. Metoclopramide if headache >72 hours) option from box if headache >72 hours)
15-20mg IV + Benadryl
25mg
0.5-1 L normal saline IV
2. Haldol 5mg IM plus either:
Benadryl 25mg IV or lorazepam 1mg IV
Monitor for 30 mins: Is headache improved? Monitor for 30 mins: Is headache improved?
NO YES NO YES
If not contraindicated: D/c with appropriate med changes Option from box D/c with appropriate med changes
Magnesium 1g IV plus option (3-5 days of steroids if headache (3-5 days of steroids if headache
from box >72 hours, avoid triptan for 24 >72 hours, avoid triptan for 24
hrs if given DHE) hrs if given DHE)
Monitor for 30 minutes: Monitor every 30 minutes,

Is headache improved can try other options from box every 30 minutes
as needed: Is headache improved?
NO YES NO YES
Option from box D/c with appropriate med changes Offer hospital/ER D/c with appropriate med changes
(3-5 days of steroids if headache admission (3-5 days of steroids if present
>72 hours, avoid triptan for 24 with headache >72 hours, avoid
hrs if given DHE) triptan for 24 hrs if given DHE)
If not contraindicated:
DHE 1mg IV plus Compazine 10mg IV
plus Benadryl 25mg*
o Do NOT give within 2 hours of SC
sumatriptan or within 4 hours of oral
triptan
Ketorolac 30mg IV
Valproic acid 500-1000mg IV
Haldol 5mg IM plus either Benadryl 25mg IV or
lorazepam 1mg IV*. DO NOT GIVE IF
METOCLOPRAMIDE HAS BEEN GIVEN
*Do not give more than 50mg IV Benadryl per visit
Fig. 15.1 Protocol for acute migraine management

examined various medications used for treatment 9. Choi J, Michael A, Andress-Rothrock D, Rothrock
J. A regional comparison of headache clinic popu-
of acute migraine headache, the authors found lations: demography, diagnoses, and frequencies/
that subcutaneously injected sumatriptan pos- types of symptomatic medication overuse. Headache.
sessed the strongest evidence base of all the ther- 2016;56(suppl 1):45.
apies evaluated [21]. As injectable sumatriptan is 10. Mendizabal J, Rothrock J. An inter-regional compara-
tive study of headache clinic populations. Cephalalgia.
the only therapy among those listed in Fig. 15.1 1998;18:57.
which routinely may be self-administered, it 11. Srikiatkhachorn A, le Grand S, Supornsilpchai W,

would make sense that positively responding Storer J. Pathophysiology of medication overuse
patients for whom this treatment is not contrain- headache-an update. Headache. 2014;54:204.
12. Stewart WF, Ryan RE Jr, et al. Efficacy and safety
dicated should receive a prescription for the med- of acetaminophen, aspirin, and caffeine in alleviat-
ication/formulation so as to preclude the need for ing migraine headache pain: three double-blind,
provider-initiated “rescue” when future attacks randomized, placebo-controlled trial. Arch Neurol.
occur. 1998;55:210.
13. Sato K, Hida A, Arai N, et al. Low-dose intravenous
propofol as a possible therapeutic option for acute con-
fusional migraine. Am J Emerg Med. 2017;35:195.e5.
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Pharmacologic Approaches
to CDH: Evidence and Outcomes 16
Miguel J. A. Láinez and Ane Mínguez-Olaondo
Introduction freedom at 2 h with good tolerability and without

recurrence. But in CDH, the need to alleviate the
Chronic daily headache (CDH) is a frequent con- pain should be balanced with the efforts to avoid
dition in headache referral center; most patients medication-overuse headache and medication
with CDH have chronic migraine (CM). Because side effects. The choice of acute treatment should
most of the recent pharmacologic studies targeted be individualized, depending on patient needs.
CM, therefore, the primary focus of this chapter There are no specific studies regarding efficacy
will be the pharmacologic treatment of CM. CM of different acute treatments in patients with
has a prevalence of at least 1–2% and CDH 4–5% CDH or CM; triptans and NSAIDs are the most
in the general population [1]. The treatment of commonly used. Opiates and opioid combina-
these patients is complex and includes patient tions should be avoided to prevent pharmacologi-
education, lifestyle modifications, strict control cal dependency. If possible, acute treatment
of the predisposing factors, management of the should be reserved for the exacerbations, trying
comorbidities, and pharmacological treatment. to reduce the number of days with acute
Behavioral therapies are also important and dis- medication.
cussed in another chapter. Preventive treatment is the most important
In migraine, the most frequently used drugs pharmacological approach in patients with
for acute attacks are triptans, NSAIDs, antiemet- CDH. In the standard preventive treatments of
ics, and analgesics combinations. A patient with migraine, several drugs have shown a superiority
headaches most days of the month needs acute compared to placebo, but only a few have been
treatment for pain management. Principles of specifically investigated for their effectiveness in
acute treatment in CDH are similar to those for CDH and CM [2]. The objective of this chapter is
episodic headache, and the goals are headache to review the published data on the preventive
pharmacological treatment of CDH and CM.
M. J. A. Láinez (*)
Department of Neurology, Neurology Service, Preventative Treatment
University Clinical Hospital, Catholic University of
Valencia, Valencia, Spain
e-mail: miguel.lainez@sen.es CDH is a condition in which the threshold for
developing headache attacks is lower, and there-
A. Mínguez-Olaondo
Neurology Service, University Clinical Hospital, fore these attacks occur with higher frequency.
Catholic University of Valencia, Valencia, Spain The main objective of treatment is to increase the

218 M. J. A. Láinez and A. Mínguez-Olaondo
threshold for headache and thereby reduce the scarce. OnabotulinumtoxinA is the only FDA-
number of attacks. Additionally the aim of the approved drug for the prevention of CM. The use
preventive treatment beyond reducing headache of topiramate is supported by two double-blind
frequency is to reduce the severity and associated controlled studies, but is not FDA-approved for
disability of the attacks and reduce the need for this indication.
acute care medications which contribute to medi- There are other medications that have shown
cation-overuse headache [3]. For all these rea- some benefit in single randomized or open-label
sons, prophylactic treatment should be considered studies in CDH or CM. These medications may
in all patients with CDH. be considered for patients with CM, particularly
Medication overuse contributes to an when comorbid conditions such as hypertension
increase in headache frequency, which facili- or mood disorders might benefit or when use of
tates migraine progression [4–7]. In a patient the more proven therapies is not feasible [8].
who fulfills criteria for medication-overuse
headache, early discontinuation of acute medi-
cation produces a substantial alleviation of Oral Preventive Treatment: Drugs
headache in a significant proportion of patients,
although the overuse is not always the driver of Antiepileptics (Table 16.1)
the chronification [5]. In this group of patients
with overuse, there is a debate about the ideal In episodic migraine, the American Academy of
time to initiate preventive medication. Some Neurology and the American Headache Society
authors advocate for initial withdrawal of the classify topiramate and valproate sodium as level
overused medication alone, but there is more A medications and recommend offering them to
data in favor of combining withdrawal with patients for prophylaxis. Gabapentin, pregabalin,
early prophylaxis. levetiracetam, zonisamide, and even carbamaze-
Together with prophylactic medication for pine can be useful in selected patients, despite a
migraine, it is important to recognize that many lack of clear scientific evidence [9]. A recent
patients with CDH have other conditions that can meta-analysis suggests that topiramate and dival-
exacerbate their headaches: depression, anxiety, proex (and propranolol) are more efficacious
other pain syndromes like fibromyalgia, or sleep than other prophylactic medications [10].
disorders. These comorbidities also need man-
agement, and there are some drugs that can help Topiramate
both conditions. Topiramate is the only oral drug with a level of
For episodic migraine, multiple drugs have evidence I, grade of recommendation A used as a
proven efficacy in randomized controlled studies, preventive treatment in CM [11]. There are two
but in CM the randomized controlled trials are main studies, one American [12] and the other
Table 16.1 Antiepileptics
Scientific
Drug Studies evidence Adverse events
Topiramate >1 RCT Strong Paresthesia, cognitive impairment
Valproate 1RCT for CM Weak Weight gain, hair loss, and tremor. Notice it is teratogenic
sodium
Gabapentin 1RCT for CM Weak Sleepiness, dizziness, ataxia, tiredness, nystagmus
Pregabalin 1 open-label design Weak Dizziness, somnolence, and thought disturbance
Zonisamide 2 open-label multicenter Weak Anorexia, nervousness, irritability, irritabilidad, confusion,
design depression, ataxia, dizziness, amnesia, somnolence
Levetiracetam 1 placebo-controlled Weak Somnolence, headaches, rhinopharyngitis
trial
16 Pharmacologic Approaches to CDH: Evidence and Outcomes 219
European [13], in which the efficacy was demon- Valproate Sodium

strated comparing placebo with a dose of topira- Valproate sodium at doses of 500–1000 mg per
mate between 50 and 200 mg/day. In those studies day shows good efficacy and tolerability [20, 24,
and others [13], the target dose proposed was 25]. In the extended release formulation, it can be
100 mg/day; however, doses as low as 50 mg/day used as a once-a-day prophylactic antimigraine
can also be effective [2]. The use of topiramate can medication [26]. There is one prospective, dou-
prevent the evolution of episodic migraine to CM ble-blind, randomized, placebo-controlled trial
[14] and can induce a change from chronic to epi- study published on the efficacy of sodium valpro-
sodic migraine [15]. This is not guaranteed, as ate in patients with CDH. Of the 70 patients
shown in the INTREPID trial. In that study, topira- included in the study, 29 had CM. Visual analog
mate intervention to prevent transformation of epi- scale (VAS) and pain frequency (PF) were evalu-
sodic migraine was analyzed for 26 weeks. ated. Sodium valproate 500 mg twice a day, com-
Progression from high-frequency episodic pared with placebo, decreased the maximum pain
migraine to CDH could not be completely pre- VAS levels (MaxVAS) and PF at the end of the
vented by 100 mg topiramate per day, although the study, but did not change general pain VAS
proportion of transformed patients was low [16]. (GnVAS) levels. It was more effective in the
Topiramate reduces headache days effectively group of patients with CM (level of evidence III,
from the first month of treatment [17], which is grade of recommendation C) [27]. In the other
significant for patients. Even though migraineurs study, sodium valproate (800 mg/day) was supe-
are often more sensitive to topiramate-associated rior to placebo in the treatment of medication-
side effects compared to patients with epilepsy overuse headache with history of migraine after
[18], it is well tolerated [19]. Possible side effects detoxification [28]. The most common adverse
include behavioral and cognitive disturbances, events are weight gain, hair loss, and tremor.
impaired vision (due to increased intraocular Valproate is a severely teratogenic drug, which is
pressure), weight loss, renal stone formation, and why it should not be used as first-line migraine
a tingling or prickling sensation in the hands and prophylaxis in women of childbearing age [20].
feet. Most adverse events are minimized by titrat- Other contraindications include thrombocytope-
ing the dose upward by 15–25 mg per week to nia, pancytopenia, and bleeding disorders [29].
reach the target dose [20], and those symptoms
usually resolve over time. The cognitive com- Gabapentin
plaints can be managed similarly [2, 12, 21]. Gabapentin has been studied against placebo for
Since it favors the development of metabolic aci- the prophylaxis of CDH in a multicenter random-
dosis and renal stones, which are an increased ized placebo-controlled crossover study. The tar-
risk in migraineurs, patients should maintain get dose was 2400 mg per day, a total of 133
hydration [18]. Topiramate improves quality of patients were enrolled, and 95 were evaluated for
life [2, 22] and reduces frequency of migraine- efficacy. There was a 9.1% difference in head-
accompanying photophobia, phonophobia, and ache-free rates favoring gabapentin over placebo.
vomiting [23]. The European study results dif- This is the only study with gabapentin. Unlike
fered from previous studies in the treatment of other preventive drugs in episodic migraine, the
CM associated with medication overuse; CM efficacy data of gabapentin is questionable.
patients with acute medication overuse improved Gabapentin (1800 mg per day to 2400 mg per
significantly with topiramate [13] without first day) showed efficacy in a placebo-controlled dou-
having withdrawal of the overused medication. ble-blind trial only when a modified intent-to-
It is not recommended in women of childbear- treat analysis was used [30]. Thus, in several
ing age planning pregnancy as cleft palate has trials, gabapentin was not superior to placebo
occurred in newborns whose mothers used the [31]. Recent reviews [32], including a Cochrane
drug during the first trimester of pregnancy review [33], conclude that further evaluation of
(Pregnancy Category D) [18, 20]. gabapentin in migraine prophylaxis is warranted.
Pregabalin guidelines. Others like atenolol, nadolol, nebivo-

In an open-label study in CM patients, pregabalin, lol, and pindolol are recommended as grade B or
dosed at 75 mg/day, with an increase depending C. There are however few studies with beta-
on the clinical response and the tolerability, was blockers in the prevention of CDH or CM.
associated with significant decreases in headache
frequency and severity and the use of rescue med- Propranolol
ication. Side effects including dizziness, somno- There is one study in which propranolol slow-
lence, and thought disturbance were frequent release 160 mg has been compared to candesartan
[34]. There are no controlled studies on pregaba- 16 mg and placebo in a randomized, triple-blind,
lin in CDH or CM or episodic migraine [33]. Due double crossover study, in patients with episodic or
to its anxiolytic effect, its efficacy in other chronic CM [40]. Both drugs have a similar effect size
pain conditions, and possible reduction of central against placebo but, although they include patients
sensitization, it could be a potential therapy in with a high number of headache days (8.21 per
CM, but more evidence is necessary. 4 weeks), only 1 in 72 patients was affected by
CM. In open-label studies, beta-blockers (propran-
Zonisamide olol or nadolol) combined with sodium valproate
There is some data about the efficacy of [41] and topiramate showed better efficacy and
zonisamide in patients with CM who are refrac- good tolerability in patients refractory to both treat-
tory to other preventives or are responsive to, but ments alone. This strategy was studied in a double-
unable to, tolerate topiramate. The studies are blind, placebo-controlled, randomized clinical trial
open-label, but multicenter and with an adequate conducted through the National Institute of
number of patients, although retrospective [35, Neurological Disorders and Stroke Clinical
36]. These results, obtained in a large sample of Research Collaboration [43]. In CM subjects inad-
patients refractory or intolerant to topiramate and equately controlled (≥10 headaches/month) with
other preventives, indicate that zonisamide, at topiramate (50–100 mg/day) alone were treated
low doses, is an option for the preventive treat- with either propranolol long acting or placebo. The
ment of patients with frequent migraine [36]. It study was terminated because the ability to com-
represents a well-tolerated and effective alterna- plete the trial was not possible. However there may
tive in case of intolerable side effects to topira- be other combinations that are effective [42].
mate [37, 38]. Patients should be informed that
there is insufficient scientific support for their use Atenolol
in migraine [9]. The recommended dose is In an open-label study, atenolol, used at 50 per
between 100 and 200 mg/day. day, was safe and effective in reducing the num-
ber of headache days and intensity, in a small
Levetiracetam population of CM patients [43]. Controlled trials
The only placebo-controlled trial published with have not confirmed this. Two old and small trials
levetiracetam (3000 mg/day) in patients with CDH in migraine patients were negative, which
(most of them having CM) was negative [39]. included some patients with more than 16
headache days a month and using atenolol and
atenolol versus propranolol [31, 44].
β-Blockers (Table 16.2)
Beta-blockers were introduced in migraine pre- Tricyclic Antidepressants

vention by serendipity but can be first-line drugs
in migraine prophylaxis. Metoprolol, timolol, Tricyclic antidepressants are used for migraine
and propranolol, in many studies, have proved prevention; however, only one tricyclic antide-
their efficacy in preventing episodic migraine and pressant (amitriptyline) has proven clear effi-
are recommended at level A in the majority of cacy [7, 45].
Table 16.2 Other drugs
Scientific
Drug Studies evidence Adverse events
β-blockers Propranolol Randomized, triple-blind, double crossover study Weak Tiredness, vomits, diarrhea, sleep disorder, bronchitis
in EM and CM against candesartan and placebo
Atenolol Open-label study Weak Tiredness
Tricyclic antidepressant Amitriptyline >1 RCT (but for EM) Weak Dry mouth, a metallic taste, epigastric distress,
constipation, dizziness, mental confusion, tachycardia,
palpitations, blurred vision, and urinary retention
Selective serotonin reuptake Fluoxetine RCT Weak Nausea, dry mouth, headaches, insomnia, anxiety
inhibitors and serotonin-
norepinephrine reuptake inhibitors
Venlafaxine Randomized double-blind crossover study where Weak Insomnia, nervousness, mydriasis, and seizures
effect of amitriptyline and venlafaxine was
compared
Duloxetine Open-label trial Weak Nausea, headaches, dry mouth, dizziness
Calcium channel blockers Flunarizine Prospective, randomized, open-label, Weak Weight gain and depression
blinded-endpoint
Angiotensin II receptor blockers Candesartan RCT but no specific data in CM Weak Dizziness, vertigo, headaches, abdominal pain,
dyspepsia, nausea, vomits, diarrhea
Alpha-blockers Tizanidine RCT but no specific for CM, single-blind, Weak Somnolence, dizziness, dry mouth, and asthenia
16 Pharmacologic Approaches to CDH: Evidence and Outcomes
placebo-controlled trial
Others Memantine Small, partly open-label studies Weak Vertigo, headaches, somnolence, constipation, high
blood pressure
Ketamine Small case series Weak Anorexia, nausea, vomits, somnolence, hallucination
221
Amitriptyline retention. Other adverse events include weight

The use of amitriptyline is common in clinical gain (rarely seen with protriptyline), orthostatic
practice in patients with chronic headaches. hypotension, reflex tachycardia, palpitations, QT
Approximately 50% of patients with migraine interval prolongation, decreased seizure thresh-
are improved by more than 50%, results compa- old, and sedation [30]. If the tricyclic antidepres-
rable to the use of propranolol and sodium val- sant being used for migraine prevention is too
proate. However, the evidence as treatment for sedating, a switch from a tertiary tricyclic antide-
CM is scarce. There is a strong evidence for its pressant (e.g., amitriptyline, doxepin) to a sec-
use in preventing episodic migraine. It has been ondary tricyclic antidepressant (e.g., nortriptyline,
studied in four placebo-controlled trials, all with protriptyline) is suggested [30].
positive results, using doses of 10–150 mg per
day [46, 47]. Use of low-dosage amitriptyline
may also improve medication compliance, which elective Serotonin Reuptake
S
is an important clinical consideration in the man- Inhibitors and Serotonin-
agement of this common and chronic condition. Norepinephrine Reuptake Inhibitors
This has been an issue in studies for amitriptyline
use in headaches, but not only for CM [46]. In a Fluoxetine
meta-analysis, amitriptyline outperformed can- Fluoxetine, in doses from 10 to 40 mg per day,
desartan, fluoxetine, propranolol, topiramate, and may be effective in the management of episodic
valproate and was equivalent to atenolol, flunari- migraine [49]. In a RCT trial of fluoxetine titrated
zine, clomipramine, or metoprolol. This was not to 40 mg daily, depending upon patient response,
confirmed in head-to-head studies [31]. In a ran- and in a group of patients with migraine and
domized clinical trial with two groups of patients CDH, fluoxetine was moderately effective
with CDH, one group was treated with 25 or (improvement of 50% in overall headache status
50 mg/day of amitriptyline and the other with in the fluoxetine group and 11% in placebo) in
250 U of onabotulinumtoxinA. Amitriptyline CDH, but not in migraine [50, 51]. Other SSRIs,
was as effective as onabotulinumtoxinA for the femoxitine and sertraline, were not more effec-
prophylactic treatment of chronic daily migraines tive than placebo [31].
both reduced by 70% the number of headache
days, more than 50% the intensity, and more than
70% the use of acute medications; the distribu- Venlafaxine
tion of the injection sites was different from
PREEMPT [47]. In other study about the efficacy Venlafaxine has been used (dose, 75–150 mg) in
of amitriptyline in episodic migraine, a small the preventive treatment of episodic migraine
group of patients fulfilling criteria of CDH were found superior to placebo [49] and could be use-
included; in this subgroup there was a trend for ful in some patients with migraine and mood dis-
amitriptyline to be superior to placebo [48]. orders. It is recommended at B level in most
Although there is little evidence supporting guidelines [52]. A randomized double-blind
amitriptyline, this drug and other antidepressants, crossover study, where amitriptyline and venla-
which may treat some comorbidities, are fre- faxine were compared, it was suggested that ven-
quently used in CM. Prophylactic medication lafaxine may be considered for the prophylaxis of
should be tailored according to patient prefer- migraine because of its tolerable side effect pro-
ences, characteristics, and side effect profiles [31]. file [53]. In another study which compared the
Adverse events are common with tricyclic efficacy of venlafaxine to escitalopram, both
antidepressant use; antimuscarinic effects include were found to be effective in the prophylaxis of
dry mouth, a metallic taste, epigastric distress, migraine headache without depression and anxi-
constipation, dizziness, mental confusion, tachy- ety [54]. Adverse events include insomnia, ner-
cardia, palpitations, blurred vision, and urinary vousness, mydriasis, and seizures [30].
Venlafaxine may be a good alternative in patients tion and blood pressure control [61]. There is no
with CM and depression; the efficacy is similar to specific data in CM, only that mentioned above, in
amitriptyline and better tolerated. the comparative study with propranolol.
Duloxetine
The efficacy of duloxetine can be explained by its Alpha-Blockers
multilevel modulatory influence which includes
the activity of antinociceptive systems of the Tizanidine
brainstem and of brain nociceptive systems, Tizanidine is an alpha2-adrenergic agonist, with
through the decrease of central sensitization [31, antinociceptive effects. In a single-blind, pla-
55]. In patients with chronic headache and major cebo-controlled trial in patients with chronic
depressive disorders, duloxetine 60 mg/day was migrainous headache or chronic tension-type
effective, fast acting, and well tolerated [56]. headache, tizanidine was shown to be superior to
placebo in reducing the overall headache index
Nefazodone and other measures. There was no statistically
It is an atypical antidepressant which was first significant difference in outcome for patients
marketed in 1994, but even if efficacy of nefazo- with CM compared to those with migrainous or
done in the prophylaxis of chronic daily head- tension-type headache. Adverse effects included
ache was seen [57], it was discontinued because somnolence dizziness, dry mouth, and asthenia
of the rare incidence of severe liver damage. [62].
Calcium Channel Blockers Other Drugs
Flunarizine There are small open-label studies which support

Flunarizine is effective in migraine prophylaxis the effectiveness of memantine in refractory
at doses of 5–10 mg per day [46]. In a case series migraine (episodic migraine with 8–14 days of
including a study of 348 patients with CM and headache per month or transformed migraine)
medication overuse, flunarizine was compared [63]. Intravenous ketamine has been reported as a
with topiramate; flunarizine was more effective subacute treatment with improvement in a small
in reducing the number of days with headaches number of patients with CM [64].
and had minor side effects compared to topira- Many patients with CM do not experience
mate [58]. In a prospective, randomized, open- substantial improvement with the mentioned oral
label, blinded-endpoint 8-week trial, 10 mg/d preventive drugs. For them, there are other
flunarizine was more effective than 50 mg/d topi- options such as blockades or injections with ona-
ramate for CM prophylaxis [59]. Possible side botulinumtoxinA. Neuromodulation techniques
effects include weight gain and depression [58]. are another alternative and are emerging thera-
This drug is not available in the USA, but it is pies such as antibodies and analogs targeting
commonly used in some European countries, CGRP or its receptors.
Canada, and South America [49].
Anaesthetic Blocks
Angiotensin II Receptor Blockers
Sphenopalatine Ganglion Blockade
Candesartan
It provided effective prophylaxis in episodic Some nonsurgical interventions targeting the
migraine, with a tolerability profile comparable to sphenopalatine ganglion have demonstrated a
that of placebo [60]. Current evidence supports the potential in the management of CM. In a double-
use of candesartan for long-term migraine preven- blind study, the instillation of local anaesthetic
using a small device led to a decrease in the OnabotulinumtoxinA is recommended for

intensity of pain in patients with CM. The admin- patients with lack of response or intolerance to
istration of bupivacaine for 6 consecutive weeks beta-blockers, topiramate, or other preventive
was successful as acute treatment and the medications. Those treatments should be used
Headache Impact Test-6 scores were statistically with an adequate dose and for at least for
significantly decreased [65]. 3 months [72, 73].
In a prospective, open-label, uncontrolled OnabotulinumtoxinA is indicated for CM (level
study after 1-month baseline, bilateral injections of evidence I, grade of recommendation A), after
of 25 IU onabotulinumtoxinA (total dose 50 IU) the publication of two large-scale phase III ran-
in the sphenopalatine ganglion in a single outpa- domized controlled trials called Phase III Research
tient session were administered to 10 patients Evaluating Migraine Prophylaxis Therapy
with intractable migraine. At 12 weeks follow- (PREEMPT) 1 and 2. OnabotulinumtoxinA, at a
up, eight out of ten patients experienced at least minimum dose of 155 U, was shown to effectively
50% reduction of moderate and severe headache reduce total headache days in CM patients with or
days compared to baseline [66]. without acute medication overuse [74–76] when
injected every 12 weeks in frontal, temporal, occip-
ital, and neck muscles in a standardized scheme.
Anaesthetic Occipital Nerve Blockade Treatment effects were observed at 24 weeks [74–
76] and 56 weeks. These results have been repli-
Occipital blockade is a well-tolerated treatment cated in many clinical studies [77–79].
[67], but the results of the trials are inconclusive. In The fact that onabotulinumtoxinA is useful in
a controlled trial, blockade with local anaesthetic the subgroup of patients with CM with an exces-
and methylprednisolone was not superior to pla- sive use of acute drugs was especially significant.
cebo in a group of patients with either episodic or The difference in the decrease of headache days
CM [68]. In another blind trial, blockade of the was notable (−8,2 compared to −6,2 in the pla-
occipital with bupivacaine nerve during 4 consecu- cebo group) [80]. In another randomized con-
tive weeks significantly decreased the number of trolled trial, onabotulinumtoxinA as a
days with headache in a group of patients with CM prophylactic treatment in medication-overuse
[69]. A recent study from 2016 has suggested that headache, without withdrawal of the overused
occipital nerve blockade with bupivacaine is supe- medicine, failed to reduce headache days [81].
rior to placebo, has longer-lasting effect than pla- There are studies in which the discontinuation of
cebo, and is found to be effective for the treatment acute medication overuse was achieved with
of CM [70]. In a recent trial, anaesthetic blocks long-term use of onabotulinumtoxinA [81]. The
appear to be effective in the short term in CM, as prolonged use of the toxin also reduced depres-
measured by a reduction in the number of days sive symptoms in patients with CM and comor-
with moderate-to-severe headache or any headache bid depression [82, 83].
during the week following injection [71]. Occipital In a sub-analysis of the PREEMPT study,
blockade has shown superiority to placebo in 49.3% of the patients responded for the first time
patients with triptan-overuse headache [70]. during the first cycle (decrease of at least 50% in
This procedure could be an alternative short- the number of days of headache). 11.3%
term treatment in some patients with CM to avoid responded for the first time during the second
medication overuse and as a transitional therapy cycle and 10.3% responded for the first time dur-
in combination with other treatments. ing at least two cycles [84]. It is necessary to wait
until completion of the third cycle to know
whether the patient is responsive [73].
Preventive Treatment In the meta-analysis, conducted by the US
with OnabotulinumtoxinA Agency for Research and Quality of Health,
which compiled information from 20 randomized
trials with onabotulinumtoxinA, involving 4237
patients, it was more effective than placebo in 4 months. Long-term treatment led to additive
patients with CDH and CM. Only 26/1000 (95% adverse effects in two cases with more than
CI 10–43) abandoned the treatment because of 5 years of therapy, in which well-tolerated fron-
side effects [85]. tal and temporal atrophy occurred [95].
In double-blind comparative studies, onabotu- The clinical trials and the clinical practice
linumtoxinA compared to other prophylactic results strongly support the use of onabotulinum-
standard medication (topiramate and amitripty- toxinA for the prophylaxis of CM. This interven-
line), the toxin demonstrated similar efficacy for tion has proven to be effective, safe, and well
subjects with CM [47, 86]. tolerated in patients [96]. The safety and efficacy
There is controversy about the ideal timing of of onabotulinumtoxinA for CM prophylaxis have
administration. In a Spanish study with 69 patients, been demonstrated for up to nine treatment cycles
onabotulinumtoxinA provided greater benefits in [97]. Currently an ongoing study named Chronic
patients with shorter history of CM [87]. migraine OnabotulinumtoxinA Prolonged
It is common knowledge that allodynia is Efficacy open-label (COMPEL) study, aims to
more frequent in chronic migraine [88, 89]. There investigate the long-term safety, efficacy, and tol-
have been several studies on this symptom; as an erability of nine cycles of repetitive injections
extensive study on this aspect and its relationship administered every 12 weeks [98]. The prelimi-
with the chronification of migration, it seems that nary results of this study (716 patients followed
allodynia could improve with the administration during 108 weeks) confirm the progressive effi-
of botulinum toxin [90], even if no clear clinical cacy and tolerability of the toxin. The side effects
or demographic markers have been found to pre- described in the PREEMPT trials arose from the
dict the response to onabotulinumtoxinA [91]. injection sites and the involvement of the trape-
Pretreatment CGRP levels measured outside a zius muscles in the neck. Specifically, 6.7% of
migraine attack can predict the response of the patients had cervical pain, compared to 2.2%
patients with CM [92]. of the placebo group, and muscle weakness in
OnabotulinumtoxinA not only reduces the 5.3% in the treated group compared to 0.3% in
number of headache days and the use of rescue the placebo group. Ptosis appeared in 3.2% of the
medication, it improves other parameters. treated group, compared to 0.3% in the placebo
Besides the clinical trials, there are also many group [74, 99].
studies done in a clinical practice. One with 254
patients showed a decrease in work absenteeism
and an improvement in the quality of life [78]. How to Use it
There are studies indicating that the efficacy of
onabotulinumtoxinA increases after the second A dilution of 5 U is required for each inoculum of
injection [93] with a significant decrease in emer- 0.1 ml. To do this, dilute the product in 2 ml of
gency room visits and the use of triptans as a saline, if the vial is 100 U, and in 1 ml if it is
symptomatic treatment, specifically subcutane- 50 U. The corresponding quantities (5 U per
ous sumatriptan [94]. injection point) will be applied at key points
With long-term use, according to a study car- where sensory nerve terminals are responsible
ried out in a typical clinical setting of a head- for painful conduction [100]. Table 16.3 shows
ache unit, a positive response to the toxin distribution in each muscle until com-
onabotulinumtoxinA was observed in more than pleting 155 U.
100 patients for whom treatment lasted for more The PREEMPT protocol allows the use of
than 1 year. 74.2% of these patients continued to 40 U in additional areas to follow the pain (2
respond in the second year of treatment. In 10% additional points at a temporary level, 2 addi-
the treatment was temporarily suspended due to tional occipital points and 4 extra points at the
lack of attacks, and in 43.9% it was possible to trapezoid level). If bruxism is present, injection
extend the time between injections from 3 to of masseters could be helpful [97].
A recent dose comparison study with onabotu- ow to Manage Preventive

H
linumtoxinA in a clinical setting demonstrated the Treatment in CM
superior efficacy of onabotulinumtoxinA 195 U
compared to 155 U in CM patients with medica- A paradigm to manage CM is shown in Fig. 16.1.
tion-overuse headache during a 2-year treatment Topiramate is recommended as primary treat-
period with similar safety and tolerability ment, and if this fails or is not well tolerated,
profile [101]. change to another neuromodulator, e.g.,
In summary, onabotulinumtoxinA is a good zonisamide. If the response is insufficient, add
choice in the management of patients with amitriptyline or other SNRI (the effects are inde-
CM. The efficacy in short and long term is well pendent of depression). A combination with pro-
documented in clinical trials and in clinical prac- pranolol or flunarizine may be helpful. If there is
tice, and it is well tolerated. an insufficient response with two or more preven-
Table 16.3 OnabotulinumtoxinA units distribution tives (or because of poor tolerability), onabotu-
according to the protocol PREEMPT [100] linumtoxinA is recommended. An initial dose of
OnabotulinumtoxinA units according to the protocol 155 IU could be administered; in case of partial
PREEMPT or no response or short duration of improvement
Muscle Units (U)
(less than 3 months), a higher dose (195) is rec-
Corrugator 10 (5 in each side)
ommended [72].
Prócer 5
Frontal 20 (10 in each side)
Temporal 40 (20 in each side)
Occipital 30 (15 in each side) Future
Cervical paraspinal 20 (10 in each side)
Trapezoid 30 (15 in each side) There are a number of promising molecules in
155 the pipeline with potential impact on chronic
Preventive treatment Topiramate 50-100 mg/dl
Bad tolerability No response
Change to
another - Propranolol 40-160
neuromodulator mg/dl or another
B-blocker.
- Flunarizine 5 mg/dl
If no response to 2 or more
preventives
Combine Amitryptiline 25-

50 mg/ dl or another
SSRI if insomnia,
depression, anxiety
OnabotulinimtoxinA OnabotulinumtoxinA
155 U If no response
195 U
Fig. 16.1 Practical management of CM

daily headache. The first novel agent likely to 9. Bagnato F, Good J. The use of antiepileptics in
migraine prophylaxis. Headache. 2016;56(3):603–15.
come to market will be agents that block calcito- 10. He A, Song D, Zhang L, Li C. Unveiling the rela-
nin gene-related peptide (CGRP). CGRP is a tive efficacy, safety and tolerability of prophylactic
potent vasodilator and pain-signaling neuropep- medications for migraine: pairwise and network-
tide, and it has shown to be a useful therapeutic meta analysis. J Headache Pain. 2017;18(1):26.
11. Aurora SK, Brin MF. Chronic migraine: an update
target for migraine [102]. This represents the first on physiology, imaging, and the mechanism of
specific, mechanism-based, migraine prophylac- action of two available pharmacologic therapies.
tic treatment and appears to be without signifi- Headache. 2017;57(1):109–25.
cant adverse events such as cardiovascular effects 12. Silberstein SD, Lipton RB, Dodick DW, Freitag
FG, Ramadan N, Mathew N, et al. Efficacy and
[103]. Four different antibodies from four differ- safety of topiramate for the treatment of chronic
ent companies are in development, as well as at migraine: a randomized, double-blind, placebo-
least two small-molecule CGRP antagonists. A controlled trial. Headache. 2007;47(2):170–80.
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Schwalen S, Goadsby PJ, et al. Topiramate reduces
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CGRP: mAbsMAbs are effective as antimigraine double-blind, placebo-controlled study. Cephalalgia.
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equivalent to that seen in the PREEMPT trials, it reducing the risk for chronic forms of headache.
is noteworthy that the side effect profile is excel- Headache. 2007;47(1):13–21.
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benefits [106]. If these results are confirmed in migraine. Clin Neuropharmacol. 2006;29(5):269–75.
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arsenal. tion to prevent transformation of episodic migraine:
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Behavioral Approaches to CDH:
Evidence and Outcomes 17
Shalonda S. Slater and Hope L. O’Brien
Non-pharmacological treatments are often used Psychological Interventions

in conjunction with or in place of pharmacologi-
cal treatments for chronic daily headache. These Cognitive behavioral therapy (CBT) is a behav-
non-pharmacological treatments include behavioral approach widely supported as an efficacious
ioral approaches such as cognitive behavioral treatment for many chronic pain conditions
therapy, relaxation training, biofeedback, accep- including chronic daily headaches. CBT is often
tance and mindfulness treatments, and a focus on a part of a multidisciplinary treatment plan,
healthy lifestyle recommendations. Behavioral which often includes medication, physical ther-
approaches to headache care may be preferred for apy, and complementary and alternative medi-
patients with a poor response to medications, cine (CAM) in the management of headache
actual or planned pregnancy, history of overuse symptoms. Given the advanced knowledge of
of acute headache medication, a preference for psychological principles and intense clinical
non-pharmacological treatments, significant training required, this behavioral treatment
stress, poor coping, or comorbid medical or psy- should be conducted by a psychologist or other
chological disorders [1, 2]. Relaxation training, trained mental health professional.
thermal biofeedback combined with relaxation CBT is a psychological treatment that teaches a
training, electromyographic biofeedback, and patient to cope with pain and stress by identifying
cognitive behavioral therapy are treatment and challenging negative thoughts and problem-
options supported as Grade A by the American atic beliefs that generate stress and worsen head-
Academy of Neurology [3]. Behavioral treat- aches and by identifying and changing behaviors
ments aim to reduce functional disability, that may trigger or increase pain episodes. CBT,
improve coping, and decrease pain intensity. based on the biobehavioral model of chronic pain,
asserts that physical symptoms such as pain are
S. S. Slater (*) influenced by emotional, behavioral, and social
Division of Behavioral Medicine and Clinical factors [4]. CBT for pain is typically a time-lim-
Psychology, Department of Pediatrics, Cincinnati
Children’s Hospital Medical Center, ited course of 6–10 weekly to bi-weekly sessions.
University of Cincinnati College The length of a course of treatment depends on the
of Medicine, Cincinnati, OH, USA patient’s pain severity, the level of disability, and
e-mail: Shalonda.Slater@cchmc.org comorbid psychological issues. Also, CBT
H. L. O’Brien describes a structured intervention that follows a
Division of Neurology, Department of Pediatrics, course of treatment involving instruction in spe-
Cincinnati Children’s Hospital Medical Center,
University of Cincinnati College of Medicine, cific strategies for coping with chronic pain. Each
Cincinnati, OH, USA treatment session includes a focus on instruction in

232 S. S. Slater and H. L. O’Brien
coping skills, self-monitoring, homework review, deal of pain. However, if the gate is closed, the
and a homework plan for the practice of skills out- pain signals do not pass through, and although
side of the session. Self-monitoring refers to the pain signals are present in the body, they do not
patient keeping track, often with a pain diary, of carry their message to the brain, and the person
environmental and internal factors that may be does not feel pain. Factors such as emotions, cog-
contributing to headaches. Identifying factors that nitions, or focus on pain can affect the position of
may be triggering or worsening headaches is the gate and change the pain experience, even
important to progress in treatment. when the pain stimulus remains the same. An
understanding of this pain process can help a
patient recognize how cognitive and behavioral
Components of CBT strategies impact the experience of chronic pain.
CBT typically includes biobehavioral treatment

components of cognitive training (e.g., cognitive Cognitive Strategies
modification, problem-solving, and distraction)
and behavioral strategies (e.g., relaxation training nother core component of CBT is the focus
A
with or without biofeedback, activity pacing, and on identifying cognitions that trigger or worsen
adherence). chronic headaches. Cognitive strategies help
the patient change thoughts and interpretations
• An example of skills taught in each week of of events. These cognitive changes can lead
treatment. to an adjustment in behavior and improve
–– Week 1: Rationale for treatment and expla- the patient’s ability to cope with pain and distress
nation of gate control theory of pain. effectively. In CBT, patients with negative thought
–– Week 2: Relaxation instruction (diaphrag- patterns are taught skills to alter these patterns by
matic breathing). using strategies such as thought stopping, cogni-
–– Week 3: Progressive muscle relaxation and tive restructuring, and positive self-talk.
imagery.
–– Week 4: Cognitive strategies.
–– Week 5: Behavioral activation, pleasant Behavioral Strategies
activities, and distraction.
–– Week 6: Activity pacing. Activity pacing is an intervention often included
–– Week 7: Problem-solving. in CBT for chronic pain conditions. This strategy
–– Week 8: Summary of coping strategies. involves teaching a patient to structure daily activ-
ities in a way that prevents over- or under-exertion
and a worsening of chronic pain. Behavioral acti-
Psychological Education vation or pleasant activities are another core skill
included in CBT. Chronic headaches can often
At the start of treatment, one provides education result in a patient restricting participation in activ-
about the connection between thoughts, feelings, ities due to fear that the activity will worsen pain.
and pain. Information is provided about the gate Scheduling regular physical activity, or an enjoy-
control theory of pain. This theory of pain pro- able activity, can be beneficial in improving mood
cessing explains how psychological factors can and activity level by increasing opportunities for
change a person’s experience of pain [5]. positive experiences.
According to this theory, there is a process of
communication between the spinal cord and the
brain that functions like a gate opening and clos- Relaxation Techniques
ing, and pain signals must pass through the gate
to reach the brain. If the gate is open, many pain Relaxation strategies are a core component in
signals pass through, and a person feels a great behavioral treatments for chronic headaches.
17 Behavioral Approaches to CDH: Evidence and Outcomes 233
These behavioral strategies have been studied a recent review, these three biofeedback methods
extensively for the treatment of primary head- showed effectiveness in preventing migraine [8].
ache and migraine [6]. Patients are taught skills Few studies have evaluated the use of biofeed-
to reduce muscle tension and stress to prevent or back for treatment of chronic daily headaches. A
reduce distressing physical symptoms. These recent review described two studies, which sup-
strategies include deep breathing, progressive ported the use of biofeedback in the preventive
muscle relaxation, imagery, and hypnosis. treatment of chronic headaches [7]. A study com-
Diaphragmatic or abdominal breathing is a paring a biofeedback group to a control group in
technique of taking slow, deep breaths from the a sample of patients with MOH found that the
diaphragm instead of short, shallow breaths from biofeedback group reported a lower number of
the chest. Progressive muscle relaxation (PMR) headache days and a lower risk of MOH relapse
involves systematically tensing and relaxing vari- relative to the control group at the 3-year follow-
ous muscle groups to increase awareness of dis- up, though not at the 1-year follow-up [9].
tinctions between tension and relaxation, Another study found that EMG biofeedback
ultimately increasing feelings of relaxation over reduced headache frequency from chronic to epi-
time. Imagery refers to a strategy in which relax- sodic at 8 weeks and 1 year [10].
ation is induced by instructing the patient to think
about a peaceful and calming scene. Hypnosis
describes the use of three components (induction, Evidence and Outcomes for CBT
deepening, suggestions) to help the patient
achieve a deep state of relaxation. Note that hyp- CBT is well established as a treatment of migraine
nosis requires special training, provided through in adults though efficacy varies widely from 20 to
several professional organizations. Though relax- 67%, as described in a systematic review by
ation strategies are often included as a component Sullivan [11]. This review showed that CBT,
in studies evaluating the effectiveness of treat- relaxation therapy, and biofeedback resulted in
ments such as CBT and biofeedback, no random- significant improvements in headache, psycho-
ized controlled trials (RCTs) have been conducted logical disability, and quality of life outcomes
with relaxation skills alone [7]. when combined with pharmacological treatment.
Many studies that were reviewed utilized CBT
Biofeedback and Neurofeedback plus relaxation therapy and had a minimal con-
Relaxation therapies have been examined in contact study design, though higher contact therapies
nection with biofeedback training. In addition, had a larger effect. The authors noted that mini-
biofeedback without relaxation has been used as mal contact designs had been used more often in
a treatment for chronic pain. Biofeedback, a self- recent studies because of concerns about cost
regulation technique, involves monitoring and effectiveness. In addition, a review of treatments
voluntary control of physiological processes such for chronic migraine concluded that cognitive
as muscle activity, skin temperature, respiration, behavioral therapy, biofeedback, and relaxation
and blood flow to reduce sympathetic arousal. techniques were associated with a significant
Patients are attached to specific devices and improvement in headache symptoms and are rec-
receive feedback on selected parameters to learn ommended treatments for chronic migraine [7].
ways to control or refine their physiological Another recent review of CBT for migraine
response [6]. found that the treatment reduced the physical
Peripheral skin temperature feedback (TEMP), symptoms of migraine in adults but concluded that
blood-volume-pulse feedback (BVP), and elec- other benefits are unclear [12]. Harris et al. noted
tromyographic feedback (EMG) are the most that differences in treatment outcomes might have
commonly used biofeedback techniques for been due to variations in the components of CBT
migraine treatment. Many systematic reviews employed in these studies or differences in the way
have found that biofeedback is an effective treat- the therapy was implemented. Ten RCTs evaluat-
ment for migraine and tension-type headaches. In ing the use of CBT for the treatment of chronic
migraine/headache met criteria for review, indicat- expectations that cannot or need not be changed.
ing that a small number of studies have been con- As a result, the goal of therapy is learning how to
ducted with this patient population. accept life’s uncontrollable events. Acceptance
A large study assessing the use of CBT was and commitment therapy (ACT), mindfulness-
conducted by Holroyd and colleagues [13]. The based stress reduction (MBSR), and mindful-
researchers evaluated the use of CBT and preven- ness-based cognitive therapy (MBCT) are
tive medication treatment in a randomized pla- therapy approaches that are emerging as treat-
cebo-controlled trial. Patients with frequent ment options. Acceptance and commitment ther-
migraine headaches were randomized to one of the apy (ACT) is a mindfulness-based approach that
four preventative treatment groups: β-blocker, has been used with patients with chronic pain,
matched placebo, behavioral migraine manage- including headaches. ACT emphasizes the neces-
ment plus placebo, or behavioral migraine man- sity of pain acceptance to improve functioning.
agement plus a β-blocker. Behavioral treatment Exposure strategies aim to guide the patient to
was a structured, manually guided treatment and engage in functional behaviors, which result in
included four monthly migraine management ses- valued actions.
sions and learning with the application of skills In a review of mindfulness-based therapies for
through a behavioral migraine management and headaches, the researchers suggest that mindful-
workbook and accompanying ten audio lessons. ness alone may be comparable to pharmacologi-
Skills included deep breathing, progressive muscle cal treatment alone for chronic migraine
relaxation, imagery, thermal biofeedback, cogni- accompanied by medication overuse [16].
tive behavioral stress management, and medica- However, the review noted that additional
tion adherence. Results suggested that the addition research is needed to more fully document the
of combined β-blocker and behavioral migraine role and long-term value of mindfulness for spe-
management, but not the addition of β-blocker cific headache types.
alone or behavioral migraine management alone,
improved outcomes of optimized acute treatment.
In addition, an RCT evaluated the benefit of Healthy Habits
CBT in pediatric patients with chronic daily
headache prescribed amitriptyline as a preventa- This section reviews the evidence to support daily
tive headache medication [14, 15]. Participants activities or lifestyle practices that promote healthy
were randomized to receive CBT plus amitripty- living and well-being for those with chronic daily
line or headache education plus amitriptyline. headaches. It is important to educate patients on
Participants attended ten psychotherapy sessions ways to modify their lifestyle and to encourage
for 20 weeks and less frequent follow-up sessions taking an active role in managing their headaches
for 1 year. The CBT group received instruction in that may not involve taking medication. Adhering
relaxation skills, activity pacing, cognitive skills, to regular daily exercise, eating a well-balanced
and problem-solving, and the headache educa- diet that includes vegetables and protein, limiting
tion group received information about headache caffeine intake, staying hydrated, and maintaining
management. Results of the study showed that good sleep hygiene are common recommenda-
participants in the CBT plus amitriptyline group tions among those who treat headache disorders.
had greater reductions in days with headache and Unlike conventional treatment options, lifestyle
migraine-related disability compared to the head- modification may take longer to show benefit
ache education plus amitriptyline group. compared to traditional therapies [17]. Research
determining whether physical and behavioral
changes are linked to improvement of headaches
Acceptance-Based Interventions has been difficult to study for many reasons.
Determining measures for obtaining headache
Mindfulness-based therapy approaches empha- diagnosis, preconceived biases, and subjective
size developing cognitive distance from facing responses are just a few of obstacles toward deter-
mining a unified treatment plan. The recommen- ingested in one meal and results may be delayed.
dations made in the past are based on ancient and Checking vitamin levels may be reasonable to
historical remedies and physician consensus. provide guidance about which supplements and
Although generalizable, these recommendations amounts are needed to increase levels to normal
should be individualized to the patient. values [32]. However encouraging patients to
incorporate such foods in their diet may help
improve levels and may be an alternative than
Nutrition having to oral medication.
Avoiding potential food triggers is a common
Traditionally, diet has played an important role in practice among migraineurs, despite limited sci-
headache management. Few studies have shown entific evidence supporting the relationship
that vitamins, contained in food, can help reduce between headache and certain foods. A low-fat
headache frequency and severity, and foods that diet resulting in weight loss may improve head-
contain nutrients and vitamins are essential in aches over time especially as obesity is a known
headache control [18, 19]. Vitamins in the form risk factor associated with worsening headache
of nutraceuticals that have been most studied outcomes [33–35]. Individuals with food sensi-
include coenzyme Q10, magnesium, and ribofla- tivities and those adhering to a ketogenic or modi-
vin. Coenzyme Q 10 is a cofactor involved in fied Atkins’s diet may benefit from eliminating
energy metabolism within the cell mitochondria, foods that result in antibodies against certain food
and studies have shown that increasing levels antigens [36–39]. Avoiding fasting states and
may be linked to improving headache outcomes hypoglycemic episodes and increasing the intake
[20, 21]. Foods that contain coenzyme Q10 of omega-3 fatty acids may offer reduction in
include meat and oily fish such as salmon, mack- headache frequency [18, 40, 41]. Other triggers
erel, and peanuts [19]. Magnesium is a chemical identified by patients believed to cause or worsen
element, endogenous to the body, and essential headache include the following: stress, bright
for hormone regulation, neurotransmitter func- lights, odors, loud noises, physical activity, choc-
tion, and anti-inflammatory properties. Low lev- olate, nitrates, monosodium glutamate, artificial
els of magnesium have been associated with sweeteners, nuts, cheese, nicotine, menstruation,
cortical spreading depression, vasoconstriction, and atmospheric changes [42]. An individual may
and neuro-inflammatory release linked to the have more than one trigger, and once identified,
onset of headache [22–24]. Although there are patients are instructed to avoid potential triggers
conflicting studies on the benefits of magnesium that are under their control. Avoidance and imple-
in reducing migraine frequency, there may be a menting behavioral medicine interventions such
benefit in those with migraine aura [25–28]. as cognitive behavioral therapy may help in cop-
Foods rich in magnesium include almonds, spin- ing and managing pain if triggers have been iden-
ach, potatoes, sunflower seeds, whole grains, and tified. In general, recommendations regarding
dairy products [19]. Riboflavin, also known as trigger avoidance are based on small studies that
vitamin B2, is also a cofactor involved in energy are limited in quality, and further research is
metabolism and is derived from a reduced sugar needed to determine whether this is effective in
and a structure that when oxidized, forms a bright improving migraine outcomes. It can be helpful to
yellow appearance in urine. Studies of patients remind patients that triggers are often partial and
taking riboflavin show improvement in headache additive in their effect on headache and that abso-
frequency, although the proper dosing required lute triggers are much less common.
remains unclear [29–31]. Patients are encouraged
to consume foods rich in riboflavin and magne-
sium such as dairy products, almonds, fortified Hydration
grains, and dark green vegetables. When recom-
mending dietary supplementation, keep in mind Dehydration has been described as a headache
that the doses studied are higher than ordinarily trigger [43]. The underlying mechanism is
unclear but thought to be due to low vascular poor sleep quality, lack or excess of sleep, may
fluid volume resulting in a decrease of oxygen precipitate headaches [54, 55]. The causal rela-
flow to the brain, triggering head pain response. tionship between sleep and headaches is unclear.
Increasing the intake of fluids that contain salts One study with primary headaches showed that
and electrolytes can improve vascular tone and insufficient and poor quality sleep was associated
hydration and help “dizziness” commonly with increased headache frequency and intensity
described in migraine patients [44]. Drinking [56]. In another study, improvement of sleep
200–1500 ml of water may provide headache hygiene through cognitive behavioral therapy led
relief in as early as 30 min [45]. The consensus to a reduction in migraine frequency [57].
among headache providers regarding fluid intake Recommendations to improve good sleep
is for patients to stay well hydrated and avoid or hygiene could have a positive impact on head-
limit alcohol and caffeine intake, which have ache control.
been shown to be potential triggers for migraine
[46–48]. Conclusion
There are options for treating chronic daily
headache aside from traditional pharmaceuti-
Exercise cal therapy. Behavioral management interven-
tions such as CBT offer the most evidence,
Patients who present with the complaint of fre- particularly among adolescent patients.
quent headache are often told to exercise as part Although there is limited evidence on the
of their treatment regimen [49]. Outside of obser- impact of lifestyle modification, develop-
vational reports, there is limited evidence to sup- ing the habit of eating foods that contain key
port that exercise can decrease headache vitamins and nutrients, staying hydrated, and
frequency and severity, especially among patients optimizing restful sleep and regular exercise
with migraine. Busch and Gaul [50] did a litera- can have a positive impact on physical health,
ture review and reported that studies on patients which can improve overall function and lessen
with migraine and the influence of exercise were disability caused by chronic daily headache.
small with poorly defined methods used in deter- The causal relationship between triggers
mining headache diagnosis, frequency, and inten- and headache remains unclear; avoidance of
sity of attacks, type, length, and adherence to potential triggers should be individualized to
exercise program. One study suggested regular the patient. Non-pharmacological options for
exercise averaging 8 h per month may reduce managing chronic daily headache have been
headache pain intensity, and there were conflict- used in combination or conjunction with phar-
ing studies that did not show any change in head- macotherapy; however, based on this review,
ache outcomes [51, 52]. There is no dispute that further research is needed regarding outcomes
regular exercise is important to improving and and to further guide recommendations.
maintaining good physical health overall and has
been incorporated in multidisciplinary programs
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Complementary and Alternative
Approaches to Chronic Daily 18
Headache: Part I—Mind/Body
Rebecca Erwin Wells, Laura Granetzke,
and Brielle Paolini
I ntroduction to Parts I, II, and III: become a critical problem, especially with

Complementary and Alternative chronic daily headache and the potential develop-
Approaches for Chronic Daily ment of medication-overuse headache.
Headache Some CAM therapies may be appealing
because of their minimal cost, as well as patients’
The refractory nature of chronic daily headache views that such products are more aligned with
makes it challenging to treat. Both patients and their personal health and wellness beliefs. Since
providers become frustrated with the often-poor they can be used concurrently with medications,
treatment responses and persistent symptoms, many patients may use them without discussing
and as a result many patients turn to complemen- them with their providers. However, these thera-
tary and alternative medicine (CAM) for relief. pies may have side effects, and their costs may
CAM therapies include diverse medical and not be negligible. Understanding the benefits and
healthcare systems, practices, and products not risks of these therapies is critical for patients,
presently considered as part of conventional who should seek appropriate provider counseling
medicine [1]. These options can be used as alter- about CAM treatment options for headache [2].
natives or complements to traditional western Headache is among the most common neuro-
medical options. Many CAM therapies address logical conditions associated with CAM use [3–
and target other factors (e.g., stress) that may be 5]. The prevalence of CAM use in patients with
involved in development or persistence of medi- headaches ranges from 29 to 74% [3, 6–13]. This
cal symptoms. Typical pharmacologic options may even be an underestimate; one study
are often limited by side effects, poor tolerance, (n = 484) determined prevalence based on initial
limited efficacy, patient noncompliance or non- admittance of use to be 17%, but follow-up ques-
adherence, medication contraindications, and tioning determined actual use to be 42% [3]. In
comorbidities or coexisting conditions (e.g., an analysis of the 2007 National Health Interview
pregnancy/nursing). Overuse of medications can Survey (NHIS, n = 23,393), 49.5% of adults with
self-reported migraines/severe headache reported
using CAM therapies versus 33.9% of those
R. E. Wells (*) · L. Granetzke without migraines/severe headaches (p < 0.001)
Neurology, Wake Forest School of Medicine, [6]. Therapies reported included mind/body ther-
Winston-Salem, NC, USA apies (30.2%), biologically based therapies such
e-mail: rewells@wakehealth.edu
as herbs/supplements (23.7%), manipulation-
B. Paolini based therapies such as chiropractic and massage
Wake Forest School of Medicine,
Winston-Salem, NC, USA (20.6%), and alternative systems such as acu-

240 R. E. Wells et al.
puncture and homeopathy (5.2%). This study was CAM therapies does not exclude the use of con-
limited because patients did not report using the ventional therapies, and some research suggests
CAM therapy specifically for their headaches. An the contrary. For example, youth with headaches
analysis of the 2012 NHIS data reports similar who used CAM, compared to nonusers, had
prevalence of CAM for adults with migraines/ higher expenditures while using most types of
severe headaches (44%) but with manipulation- conventional care [11].
based therapies most commonly used (23.7%), Many of the surveys assessing CAM use have
followed by biologically based therapies (22.2%), also questioned perceived efficacy. A survey from
and then mind/body therapies (19.0%) [13]. a UK headache clinic (n = 92, with 32% reporting
Differences in rates from the 2007 to the 2012 CAM use) demonstrated that 60% of CAM users
analyses may be due to actual changes in use or perceived the therapy as beneficial in helping
different definitions of the CAM modalities in the reduce headache frequency or intensity, 58%
analyses [6, 13]. A smaller survey from a Turkish reported being satisfied or very satisfied with the
headache clinic reported massage (51%) as most treatment, and none felt the CAM therapy wors-
frequently used [7]. Since pediatric patients and ened their headaches [8]. However, several sur-
their parents and providers often wish to avoid veys report less than half of patients experiencing
pharmacologic options due to risks of side effects satisfaction from their CAM therapy. A
and fear for long-term use, CAM is often used in Norwegian survey with 62% prevalence of CAM
children and adolescents [10]. In a survey of 124 use in those with primary chronic headaches
pediatric headache patients from Italy, 76% found a range of 0–43% perceived efficacy, with-
reported using CAM, most often herbal prepara- out significant differences between gender, head-
tions (64%). Eighty percent of respondents used ache diagnoses, medication use, physician
CAM as a preventive treatment option [10]. contact, and co-occurrence of migraine [12].
If patients decide to use CAM, most report Another survey, based out of a Turkish headache
using three or more types of therapies [8, 14]. In clinic, found that out of all CAM modalities, only
addition, if used for headache, patients will often those using massage reported benefit and in only
use CAM for other medical conditions. Headache 33% of those patients [7]. Only 23% of 2477
patients most commonly use CAM based on pro- chronic migraineurs reported satisfaction with
vider recommendation, cost or ineffectiveness of their CAM treatment [14]. The type of headache
conventional treatments [6], the wish of avoiding treated may also affect perceived efficacy, as a
chronic use of drugs with their related side survey of CAM use in cluster patients reported
effects, the desire for an integrated approach, that only 8% perceived benefit and 28% had par-
inefficacy of conventional medicine [10], the tial effectiveness [9].
hope for a potential improvement of headache Compared to those not using CAM, those who
[9], or as a last resort after trying all conventional use CAM are more likely to have comorbid men-
therapies [15]. The most common source of tal health issues, have more intense headaches,
CAM referral is usually a friend or relative [8, 9]. and experience more negative life impact from
For those who report using CAM, up to 42–62% migraines [14]. Interestingly, CAM treatment
do not discuss their use with their provider [6, 8, satisfaction was inversely related to the number
9], although many say this is because the proof psychiatric comorbidities, the frequency of
vider did not ask about their use, rather than fear migraines, and the number of migraine symp-
of discouragement or lack of understanding [8]. toms, although CAM treatment satisfaction was
In headache patients, predictors or correlates of more strongly correlated with migraine outcomes
CAM use include headache disability (e.g., head- than psychiatric comorbidities. Disability associ-
ache impact test-6 [HIT-6] scores) [8], higher ated with chronic headaches may make it difficult
income, more frequent headaches [9], anxiety, to use extensive non-home-based CAM treat-
joint or low back pain, alcohol use, higher educa- ments, although for the same reasons chronic
tion, and living in the western USA [6]. Using migraineurs may be more amenable to home
18 Complementary and Alternative Approaches to Chronic Daily Headache: Part I—Mind/Body 241
options such as meditation. The 2012 NHIS daily headache, is limited. The goal of this review
analysis of CAM use in adults with migraines is to describe the research on CAM therapies for
found that women are more likely to use CAM headache and, when available, chronic daily
than men and that CAM use was associated with headache. If not available, the research presented
decreased odds of moderate mental distress only for headache can be extrapolated for consider-
in women [13]. The authors argue that women ation in the treatment of chronic daily headache.
with migraines/severe headaches may have ben-
efited from CAM for their mental distress.
Providers have also been surveyed to assess ind/Body and Chronic Daily
M
their opinion on CAM efficacy. A survey was Headache
administered to 223 different UK CAM organiza-
tions, and headaches/migraine was the second Mind/body practices are based on the awareness
most commonly cited condition that would ben- of the mind and body connection, to enhance the
efit by CAM (behind stress/anxiety) [16]. The mind’s positive influence on the body’s physical
recommended treatment options for headache/ functioning and thus promote health. Mind/body
migraines included massage, yoga, reflexology, therapies are often considered treatments that tar-
aromatherapy, and chiropractic treatments, along get stress. Since stress is the most cited trigger for
with other options not discussed in this chapter migraine attacks [18] and has a complex relation-
(Bowen technique, hypnotherapy, nutrition, ship with headaches [19], headaches may be par-
Reiki). A survey completed by 1247 healthcare ticularly amenable to mind/body therapies. Many
professionals in Switzerland reports that they mind/body therapies are also considered “behav-
would most likely refer patients for acupuncture ioral treatments.” Currently, “behavioral treat-
for migraine (75%) or tension headaches (71%), ments” for headache include cognitive behavioral
although over half had never referred a patient to therapy, biofeedback, and relaxation training
a CAM provider, and 84% felt they lacked the (Table 18.1) [20], with the goal of training
knowledge to inform their patients on CAM [17]. patients in these “headache management skills.”
This review focuses on the evidence and out- These therapies have been researched within the
comes to date for CAM therapies of mind/body context of headache medicine for many years; the
therapies, Part I (e.g., meditation, yoga, tai chi, first study evaluating biofeedback for headaches
deep breathing); manipulation-based therapies, appeared in 1969. Based on a large systematic
Part II (e.g., acupuncture, acupressure, dry nee- review evaluating behavioral treatments for head-
dling, chiropractic manipulation, massage, cra- ache [21], the US Headache Consortium gave
niosacral therapy, reflexology); and other CAM Grade A evidence for the use of relaxation train-
options (aromatherapy, homeopathy, hydrother-
apy, daith piercing, and hyperbaric oxygen ther- Table 18.1 Behavioral and mind/body treatment options
apy) for headache. Part III summarizes this Behavioral Mind/body
evidence for nutraceutical options for headache, • Cognitive behavioral • Meditation
specifically feverfew, riboflavin, magnesium, therapy
coenzyme Q10, melatonin, vitamin D, and – Stress management • Yoga
ginkgo. Most of these therapies have very little – Coping skills • Guided imagery
research supporting their use, and the research • Biofeedback • Biofeedback
that has been conducted is limited by critical • Relaxation training • Hypnosis
– • Tai chi
methodologic concerns (e.g., small sample sizes,
– • Qi gong
no active control groups, etc.). By the very nature
– • Deep breathing exercises
of being “CAM,” these therapies do not yet have – • Progressive muscular
the research evidence base to be accepted into relaxation
mainstream medicine. Further, research on these Reproduced with permission from John Wiley & Sons,
therapies for headache, and specifically chronic Inc. from the journal Headache [19]
ing, thermal biofeedback with relaxation, in a particular way: on purpose, in the present
electromyographic (EMG) biofeedback, and cog- moment, and non-judgmentally” [26]. Through
nitive behavioral therapy [22]. Because of their the daily practice of mindfulness meditation, par-
increasing acceptance into mainstream headache ticipants are encouraged to apply mindfulness in
medicine, these therapies may not be considered daily activities. The practice of mindfulness pro-
“CAM” anymore. motes an attitude of acceptance, curiosity, and
However, many typical “mind/body” openness. His original research focused on those
approaches have been used in Eastern medicine with “chronic pain,” including headache.
for many years and are only now gaining atten- Participants had improvements in pain symp-
tion in Western medicine, with limited research toms, anxiety, depression, and drug utilization,
evidence for their use. Many mind/body thera- with most effects maintained at 15 months fol-
pies incorporate components of evidence-based low-up [27, 28]. This program blossomed into
behavioral treatments, such as relaxation, deep the “mindfulness-based stress reduction
breathing, and guided imagery. Although clearly (MBSR)” program, a standardized program of 8
there is overlap between the two categories, weekly 2.5 h classes that has been taught to over
Table 18.1 delineates the differences between 22,000 individuals, with referrals from over 6000
behavioral treatments and mind/body treatments. providers.
For this chapter, the evidence and potential As a standardized intervention, MBSR has
mechanisms for the mind/body approaches of been helpful for a multitude of different medical
meditation, yoga, tai chi, and deep breathing will conditions [29], with chronic pain being one of
be discussed. Few studies have been conducted the most commonly studied conditions. A sys-
evaluating these approaches in general and even tematic review evaluated the benefits of MBSR
fewer that are specific to chronic daily headache. or a variation of the program for chronic pain in
Therefore, much of the evidence described will 38 randomized clinical trials (RCTs) [30]. The
focus on these approaches to any type of head- authors reported that mindfulness meditation
ache, with the consideration of extrapolating the improves pain, depression, and quality of life,
information to chronic daily headache. although they argued that larger, more well-
designed and rigorous RCTs are needed to pro-
vide better estimates of efficacy [30]. Five of the
Meditation RCTs included in this review evaluated mindful-
ness for headache; all are limited by lack of an
Meditation has long historical roots in religious active control [31–35].
and spiritual traditions, with goals of reaching We conducted the first RCT of MBSR in
heightened levels of spiritual awareness. In the adults with episodic migraine (n = 19), one of the
last several decades, meditation has been studies included in the systematic review. Both
researched for its physiological benefits. Benson groups received usual care, and the active group
published early investigations of meditation and also received MBSR. Most participants (89%)
its ability to elicit the “relaxation response” [23]. were taking migraine prophylactics daily and had
His research on the effects of the relaxation an average of ten headaches/month. We observed
response through mantra-based transcendental statistically significant improvements in head-
meditation for cluster, migraine, and tension ache duration (captured with daily headache
headaches demonstrated that twice-daily, 20-min logs), disability (HIT-6 and Migraine Disability
sessions for 4–14 months resulted in significant Assessment [MIDAS]), self-efficacy, and mind-
clinical improvements for 6 of 17 headache fulness. Adherence and study participation were
patients [24, 25]. excellent, with no adverse events. Although our
Kabat-Zinn’s research further developed this small sample size limited the study’s power to
line of inquiry through a program to teach “mind- detect statistically significant differences in head-
fulness meditation,” defined as “paying attention ache frequency or severity, a strength of this
study (standard for strong headache studies but Scale compared to the control group. The study
unusual in the CAM literature) was use of daily was limited by significant dropouts (58 random-
headache logs for assessment of headache out- ized but only 42 analyzed), no active control
comes, with baseline data completed prior to ran- group, and a novel intervention with unknown
domization. The major limitation was the lack of reliability and validity. Another RCT evaluated a
an active control group. variant of MBSR, mindfulness-based cognitive
Additional studies included in this review [30] therapy (that incorporates facets of both MBSR
evaluated MBSR or variations for different types and CBT), for adults with “headache pain” (3+
of headaches. Two studies were conducted in days/month of any primary headache disorder)
Iran. One evaluated MBSR for “chronic head- compared to delayed treatment control (n = 36)
ache” (primary chronic migraine or tension-type [33]. Compared to the control group, intervention
headache) versus usual care (n = 40), with pain participants reported better pain acceptance and
and quality of life (SF-36) questionnaires at base- self-efficacy, with additional improvements seen
line and follow-up [35]. MBSR improved pain in pain interference and pain catastrophizing
intensity and quality of life vs. the control group. among those who completed the study (n = 24).
However, the study was considered of “poor” Improvements in headache outcomes were not
quality in the systematic review because of weak seen. Limitations included lack of an active con-
statistical analyses, no active control group, and trol and limited headache log data (only 1-week
how headache outcomes were assessed. Rather baseline data, no posttreatment data); these weak-
than daily headache logs, headache outcomes nesses may have affected outcome assessments
were limited to a perceived pain intensity of of headache. In a follow-up analysis to evaluate
headache at each time point, with a cumulative responders versus nonresponders, the authors
assessment and score for pain ratings, duration, reported pain acceptance and pain catastrophiz-
and frequency of headaches in the prior month ing were key factors underlying treatment
(not a typical headache outcome). Another RCT response [33].
conducted in Iran of MBSR for tension headache After the systematic review [30] was con-
(uncertain if episodic or chronic, n = 60) demon- ducted, a unique clinic-based “effectiveness”
strated improvements in headache severity (mea- trial compared a mindfulness-based training
sured by daily headache logs) and mindfulness group (6 weekly 45-min sessions, an MBSR vari-
(mindfulness attention awareness scale) [34] and ant) and prophylactic medication group in 44
reported separately perceived stress and general adults with chronic migraine and medication-
mental health (Brief Symptom inventory) [36]. overuse headache [37]. Participants first com-
Although this study had a 3-month follow-up, it pleted a withdrawal program in a day hospital
was also limited by lack of an active control and then were given the option of which group to
group. join; participants were not randomized. Both
An RCT in Australia evaluated a briefer ver- groups had statistically significant decreases in
sion of MBSR (classes twice weekly for 3 weeks) monthly headache days, monthly use of abortive
vs. wait-list control (n = 58) for ICHD-II defined medications intake, headache disability, and
chronic tension-type headache, with headache depression after the intervention compared to
outcomes captured with 2-week headache diaries baseline, without differences between groups,
before/after the intervention and mindfulness with effects persisting to 12-month follow-up.
assessed before/after with the Five-Factor Although limited by its non-randomized
Mindfulness Questionnaire. Headache frequency approach, this study provides evidence that a
decreased in the intervention group compared to mindfulness program may be as effective as stan-
the control group; headache duration and inten- dard of care for patients with chronic migraine
sity did not show improvements with MBSR. The and medication-overuse headache.
intervention group had better scores on the A few other meditation studies for headache,
observe scale from the Five-Factor Mindfulness not specifically of mindfulness meditation, were
not included in the mindfulness for chronic pain being randomized (from 84 to 68 in one study
systematic review [30]. A study from India in and from 107 to 74 in another study) [39, 43].
chronic tension-type headaches compared two A small non-randomized study [44] of a mind-
groups of 70 patients [38]. Both received twice- fulness-based intervention in 20 adolescents with
daily abortive medications; one group also “recurrent headaches” (4 or more per month)
received eight additional lessons in a form of showed safety (no adverse events), feasibility
spiritual meditation known as “Rajyoga medita- (median class attendance 7 out of 8), and
tion,” which incorporates visualization of mean- improvements in depression, quality of life, and
ingful images with a focus on positive thoughts acceptance of pain; no changes in headache fre-
of a universal force. Within-group analyses quency or severity were seen. This was a pilot
showed that both groups had improvements in study and was not powered for headache out-
headache severity, frequency, and duration, comes but shows the possibility of using mind-
although significant relief in headache severity, fulness interventions in adolescents with
duration, and frequency was much higher in the headaches.
meditation group (94/91/97% vs. 36/36/49%). In a study that tracked outcomes after an
This study was limited by within-group analyses MBSR course in patients with a variety of chronic
and high participant dropout (only 50 partici- pain conditions, those with chronic headache/
pants completed). migraine experienced the smallest improvements
Several studies have compared “spiritual med- in pain and quality of life compared to the other
itation” (spiritually inspired mantras) to “secular chronic pain conditions [45]. However, this study
meditation” (secular mantras) to “relaxation” was limited by its observational nature and lacked
(progressive muscular relaxation) [39–43]. The a control group and direct measures of pain. The
first study [39] in 68 healthy college students small sample sizes for each specific chronic pain
showed that “spiritual meditation” (20 min/day condition limited statistical power and reliability
for 2 weeks) appeared to have the most benefits of effect sizes (e.g., only 34 of 133 participants
on anxiety, mood, spiritual health, and pain toler- had headaches).
ance compared to “secular meditation” and
“relaxation” [39]. Two follow-up studies in adults otential Mechanisms of Meditation
P
(n = 83 and n = 92) with two or more migraines Proposed mechanisms to explain the potential
per month also showed improvements with “spir- impact of meditation on pain (including head-
itual meditation” compared to “secular medita- aches) include neurobiological changes in pain
tion” and “relaxation” on measures of headache processing, stress reduction, changes in relevant
frequency, anxiety, negative affect, pain toler- psychological constructs, effects on other behav-
ance, headache related, and self-efficacy [40, 41]. iors, and/or placebo [46]. The strongest evidence
A third study reported that a 20-minute medita- comes from the neuroscientific research that has
tion intervention improved immediate pain and demonstrated the specific neural pathways
emotional tension scores in 27 adults who had involved in meditation and pain relief. Mind/body
2–10 migraines/month [42]. A more recent study therapies may be effective because they target the
(n = 107 randomized, 74 analyzed) showed that cognitive and affective control of pain [47].
mindfulness meditation improved pain-related Meditation may attenuate pain by improving its
stress compared to simple relaxation and the emotional and cognitive modulation at the corti-
mindfulness meditation intervention provided cal level [48]. In studies assessing the impact of
similar outcomes to spiritual mindfulness in meditation on experimentally induced heat pain in
pain-related outcomes [43]. Unfortunately, since healthy controls, meditation-induced decreases in
participants in these studies were generally pain intensity were associated with increases in
healthy, non-treatment seeking young adults, the anterior insula and anterior cingulate activity
results may not generalize to other populations. detected on MRI—key regions for cognitive mod-
Further, many participants dropped out after ulation of pain processing [49]. Meditation-
induced decreases in pain unpleasantness were ment in pain after MBCT [61]. Additional sec-
associated with orbitofrontal activation (that ondary analyses also demonstrated the importance
could explain the cognitive reframing of sensory of pretreatment expectations, patient motivation,
events with meditation) and thalamic deactivation and the development of strong rapport with the
(suggesting that meditation may downregulate the therapist as critical components to improving
thalamus, the key relay station for pain transmis- pain outcomes [62]. Day and colleagues devel-
sion from sensory receptors to the brain). oped a theoretical model to explain mindfulness-
Additional research has shown that meditation- based pain relief, organized into the overarching
based pain relief does not require or use endoge- factors of environment, brain state, cognitive
nous opioids [50] and has a distinct neurobiological content and coping/processes, behavior, and
signature from placebo analgesia [51]. emotion and affect [54]. The cognitive factors not
Further research on the neuroscientific under- already discussed that they included in this model
pinnings of meditation has indicated that medita- include increased self-efficacy, emotion regula-
tion may enhance frontal attentional control, tion, positive affect, and decreased pain catastro-
increase cortical thickness, and activate areas of phizing and negative affect.
the brain important for pain modulation (hippo- In mindfulness meditation, participants are
campus, insula, cingulate cortex, prefrontal cor- taught to notice sensations distinct from the
tex, and parietal cortex), thereby helping to thoughts related to the sensation; this detachment
decouple sensory-discriminative and cognitive- may alter pain perception. Participants may con-
evaluative brain networks [52–54]. tinue to have headaches but are able to better
Meditation also fosters a calm state of focused cope with the pain [28]. This flexible attentional
attention that may better balance the parasympa- capacity may help relieve the suffering of pain
thetic and sympathetic systems. Meditation low- and improve quality of life.
ers stress levels [55], the most frequently cited Finally, mindfulness meditation, like all mind/
trigger for migraine [18]. Further, the presence of body therapies, may work by helping to improve
migraine may impact stress-related dysregulation other behaviors that result in improvement of
of the autonomic nervous system [56–58]. In a headaches. For example, meditation may improve
study that assessed heart rate variability in head- sleep, and this effect could improve headaches.
ache patients (randomized to either a mindful- Meditation may also enhance a person’s ability to
ness intervention or a control group) after a engage in other healthy behaviors, such as
cognitive stress induction test [59], headache improved diet and more exercise, which also
patients were more likely to have dysregulated could improve headaches.
stress recovery compared to controls. These data
suggest that mindfulness practice may promote ummary: Meditation and Chronic
S
effective heart rate regulation, especially after a Daily Headache
stressful event. The research on meditation for headaches is lim-
Other research has suggested the important ited by the lack of active control groups, small
role cognitive and psychological factors play in sample sizes, and lack of long-term follow-up.
the relationship between meditation and However, the evidence suggests that meditation
migraines. In a cross-sectional study that com- could benefit headache patients as a complement
pared stress-coping styles among migraineurs, to standard of care. Meditative practices can be
meditators, and healthy controls, migraineurs practiced anywhere, increasing adherence. Once
used negative stress-coping strategies signifi- the technique is learned, it requires little financial
cantly more than the other groups, especially investment, so it may be applicable to a broader
“rumination” [60]. In secondary analyses of the audience than typical psychological resources
previously described RCT of MBCT for head- such as biofeedback. It does require active par-
ache by Day and colleagues [33], pain acceptance ticipation and self-responsibility, which may be
was a significant mediator underlying improve- critical ingredients for its success. Although such
active involvement may improve self-efficacy, it Those in the yoga group had significant decreases
does require significant time, energy, and a com- in headache intensity, frequency, pain rating
mitment to regular practice. In a case report of a index, affective pain rating index, total pain rating
migraineur ultimately benefiting from mindful- index, anxiety, depression, and symptomatic med-
ness training, it took years of encouragement ication use. Unfortunately, analyses did not com-
from a provider before the patient was ready to pare baseline and end-of-study results; it only
adopt a mind-body practice [63]. Another case compared post-study results between groups. The
report suggested that mindfulness meditation ini- study lacked matching on time and attention
tially induced headaches in one patient but then between the two groups, and the participants were
became a powerful treatment option [64]. If help- not blinded. There was no long-term follow-up to
ful, research suggests that benefits may persist assess treatment durability, and no adverse events
for up to 4 years [65]. Most research to date has were mentioned.
focused on mindfulness meditation, although A few smaller studies provide additional
spiritual meditative techniques and transcenden- insight on the impact and potential mechanisms
tal meditation have also been explored. Future of yoga on headache. As tension-type headache
research needs to include active control groups has long been viewed as a condition of muscular
and larger studies of appropriate design and lon- tension, many have felt yoga may be particularly
ger follow-up periods. applicable. A different study from India (n = 16)
compared EMG biofeedback with yogic shav-
asana relaxation (both practiced twice per week
Yoga in 30-min sessions for 10 weeks); the two groups
had equally improved tension headaches (occur-
Yoga is a mind/body treatment that combines the ring at least twice per week for over a year) [70].
physical exercise of postures (“asanas”) with Interestingly, “complete remission” was achieved
breathing (“pranayama”) and deep relaxation after only 13 sessions with the yoga group, com-
(“shavasana”) to create a meditative experience. pared to 16 sessions with the biofeedback group.
Evidence suggests yoga may be beneficial for Although small, this study suggests yoga may
many health conditions and their associated have similar benefits to EMG biofeedback.
symptoms (cancer, hypertension, diabetes melli- Another small study (n = 15 headache patients)
tus type 2, multiple sclerosis, Parkinson’s, depres- compared NSAID treatment (undefined dosage/
sion, anxiety, pregnancy, pre−/postpartum frequency), botulinum toxin (undefined fre-
depression, etc.) [66]. Although yoga has long quency), and an intense yoga program (3 h/day
been used to treat many different chronic pain for 2 weeks) for treatment of chronic tension-
conditions [67], a systematic review looking for type headache [71] and found that subjective pain
RCTs of yoga specifically for headache [68] scores improved in all three groups. In another
found only one publication from a headache clinic study, 32 women with migraines (uncertain if
in India [69]. This study compared 12 weeks of episodic or chronic) were randomized to either
yoga to a headache education group in 72 12 weeks of medication treatment under a neu-
migraineurs without aura (uncertain if episodic or rologist’s supervision (undefined medication
chronic). The yoga group practiced 5 days/week type, dosage, frequency) or medical treatment
for 60 min, and participants were also instructed plus yoga [72]. Metabolites of nitric oxide,
to practice as an abortive migraine treatment but hypothesized as having a role in the mechanism
only during the prodromal phase of a migraine. of yoga on headache, were measured in both
The intervention involved yoga postures, breath- groups. Those in the yoga group (75-min guided
ing practices, yoga breathing, relaxation prac- sessions three times per week) had significant
tices, and meditation. Headache education group reductions in headache frequency and severity,
participants received headache education once/ but plasma nitric oxide levels were not different
month for 3 months plus handouts on self-care. between groups before and after the study.
A more recent study assessed changes in ioral treatments (like biofeedback) more chal-
endothelial function after yoga (three 75-min ses- lenging; yoga could be a more easily accessible
sions per week for 12 weeks) compared to medi- and inexpensive treatment option [70].
cation (undefined drug/dose/frequency) in 42
migraineurs (unclear if episodic or chronic) [73].
The study focused on plasma concentrations of Tai Chi
intercellular adhesion molecule (ICAM) and vas-
cular cell adhesion molecule (VCAM) as possi- Tai chi is a form of traditional Chinese medicine
ble mechanisms for triggering vascular that incorporates physical, cognitive, social, and
inflammatory responses; no headache measures meditative components into this mind/body
were assessed. After treatment, plasma concen- activity [75]. As a “moving meditation,” the goal
trations of ICAM decreased in the yoga group is to rebalance the body’s own healing capacity.
compared to the control group, with no differ- Evidence suggests it can prevent falls and
ences detected in VCAM concentrations. improve balance and is helpful for many chronic
Although the authors concluded that the inter- musculoskeletal pain conditions [76]. Since tai
vention might improve vascular function in chi overlaps with both mind/body interventions
migraineurs, the methodologic concerns (only and other traditional Chinese medicine treat-
data from 32 participants were reported), lack of ments like acupuncture, and both may help head-
headache measures/outcomes, and inconsistent aches, tai chi has been hypothesized to improve
results between ICAM and VCAM limit such a headaches. However, only one RCT has assessed
conclusion. tai chi for headache [77]. This study compared
In a recent pilot study of 8 weeks of 75-min biweekly 60-min tai chi sessions for 15 weeks to
yoga classes for pediatric patients with headache a wait-list control group using the classical Yang
[74], 19 of 57 patients approached agreed to par- style of tai chi with 24 standardized movements.
ticipate, but only 7 actually attended classes, with Those in the intervention group demonstrated
the weekly no-show rate ranging from 1 to 3 par- improvements in pain, energy/fatigue, social
ticipants. This study demonstrates the challenges functioning, emotional well-being, and mental
of adherence to interventions that involve signifi- health summary scores on the HIT-6 and SF-36
cant time, although children may have more instruments. Although 47 were randomized, only
scheduling limitations than adults. 30 completed the study; outcomes did not assess
headache measures but rather only quality of life
Summary: Yoga and Headache measures. Nonetheless, while this study suggests
Yoga may be a valuable treatment option for tai chi may be helpful for tension-type headaches,
adults with headaches, but most studies are lim- larger, more rigorous studies are needed for fur-
ited by serious methodologic concerns. In addi- ther recommendations.
tion, the interventions studied to date have been
intense programs, requiring significant time and
motivation, limiting feasibility for many patients. Deep Breathing
Several studies have attempted to assess patho-
physiologic mechanisms of yoga on migraine, In the National Health Interview Survey, “deep
with unclear results. Additional research is breathing” is assessed as a mind/body CAM
needed to assess other potential hypothesized medical treatment option. Of adults with a his-
mechanisms, such as the improvement in para- tory of severe headaches/migraines, 24% report
sympathetic tone and calming of the stress using deep breathing exercises, the highest preva-
response through active yoga postures, deep lence of all mind/body therapies [6].
breathing, and deep relaxation states. However, Unfortunately, what “deep breathing” entails is
yoga is now widely available, and among some not defined in the survey or by participants.
settings, illiteracy and poverty make some behav- Although most proponents of mind/body thera-
pies would argue that breathing is a critical com- long-term follow-up. The one RCT of yoga for
ponent of the intervention, no specific studies migraine suggests a benefit, but additional studies
evaluate the sole benefit of deep breathing for are needed. Other yoga studies for headache have
headache. Many patients in pain often hold their been limited by significant methodologic con-
breath or in moments of anxiety take shorter, cerns, and the yoga interventions have been time-
more shallow, and frequent breaths; thus, deep intensive. Tai chi has minimal evidence to suggest
breathing may help ease pain, anxiety, or panic. benefit for tension-type headache. Research needs
Despite the lack of research for this modality for to be conducted to assess “deep breathing” as an
headache, many providers may recommend it, independent modality for headache.
with specific instructions on how to achieve ideal Part II summarizes manipulation-based treat-
“deep breathing” [78]. Some argue that patients ment options (acupuncture, chiropractic, and
may be more receptive to this technique than less massage) and other CAM treatments. Part III
familiar interventions such as meditation. A sur- reviews the evidence regarding nutraceuticals
vey of adolescents with headache demonstrated and homeopathy for chronic daily headache and
that 72% were interested in learning deep breath- final conclusions from Parts I, II, and III.
ing, while only 21% wanted to learn the relax-
ation response or biofeedback, and none were Acknowledgments Dr. Wells is supported by the
interested in meditation [11]. Deep breathing for National Center for Complementary and Integrative
Health of the National Institutes of Health under Award
pain is not a new concept—e.g., in the Lamaze Number K23AT008406. The content is solely the respon-
technique, deep breathing is taught to help ease sibility of the authors and does not necessarily represent
the pain of childbirth. Migraine involves dys- the official views of the National Institutes of Health. We
function of the autonomic nervous system [56– gratefully acknowledge the editorial assistance of Karen
Klein, MA, in the Wake Forest Clinical and Translational
59], so targeting this dysfunction through deep Science Institute, funded by the National Center for
breathing may provide headache benefit. Advancing Translational Sciences (NCATS), National
Additional research into this modality for head- Institutes of Health, through Grant Award Number
aches is needed, especially evaluating its role in UL1TR001420. We also thank Mark McKone, Librarian
at Carpenter Library, Wake Forest School of Medicine, for
all mind/body therapies. his help with the use of Zotero. We are appreciative of the
help from Nakiea Choate from the Department of
Neurology at Wake Forest Baptist for her administrative
ummary: Mind Body and Chronic
S support.
Daily Headache
Chronic daily headache is often refractory to con- References

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Headache: Part II—Manipulation-
Based Therapies and Other CAM
Therapies
Brielle Paolini, Laura Granetzke,
and Rebecca Erwin Wells
Manipulation-Based Therapies: points throughout the body based on meridians

Overview (i.e., channels in the body). These needles are
thought to help balance the traditional Chinese
The manipulation-based complementary and medicine concept of Qi, or “life force,” resulting
alternative medicine (CAM) therapies assessed in improved imbalances and illnesses.
in this chapter for headache include acupuncture, Acupuncture is one of the most widely used
acupressure, dry needling, chiropractic manipu- CAM therapies [3–5]. Its effects are believed to
lation (spinal manipulative and mobilization be due to a combination of local effects, spinal
therapy), massage, craniosacral therapy, and and supraspinal mechanisms, and other cortical
reflexology. Only a few have evidence specific (i.e., psychological or placebo) responses.
for chronic daily headache (acupuncture and chi- Although acupuncture is extensively used clin-
ropractic); for the other therapies, we review the ically, research into acupuncture has challenges,
evidence for other headache types with intent to especially complete blinding of the control group.
extrapolate findings for chronic daily headache. Sham control is traditionally considered the ideal
Notably, in most studies, manipulation-based strategy. The most common sham methods are
techniques are used as preventive therapies rather touching needles to acupuncture points, touching
than abortive treatment. non-acupuncture points without penetration, or
superficial needling at non-acupuncture points.
No technique is perfect; touching needles to acu-
Acupuncture puncture points may affect meridians, and physi-
ologic effects of superficial needling may
Acupuncture dates back to 200 BC [1, 2] and resemble those of true acupuncture. Ideal studies
involves the placement of needles at specific would include a non-active control group and a
sham control group, to fully elucidate treatment
effects of placebo responses.
B. Paolini
Wake Forest School of Medicine, cupuncture and Chronic Daily
A
Winston-Salem, NC, USA
Headache
L. Granetzke · R. E. Wells (*) Many acupuncture studies use “chronic head-
Neurology, Wake Forest School of Medicine,
ache” as an umbrella term, while others differen-
e-mail: rewells@wakehealth.edu tiate the type as either “chronic migraine” or

254 B. Paolini et al.
“chronic tension-type headache” or “chronic Twelve studies reported acupuncture side

mixed type.” Also, several studies use the term effects and 11 provided details. Common acu-
“chronic headache” to imply the headache has puncture side effects reported included minor
been present for a certain period of time, rather bleeding, bruising, or local paresthesias at needle
than using ICHD diagnostic criteria of “chronic” insertion sites, or triggering of a headache by
defined as meeting a threshold of headache fre- needle insertion. There were fewer side effects
quency/month (e.g., >15 days/month for migraine compared to medication treatment trials. The het-
and tension-type) for at least 3 months. erogeneity of the studies (in treatment protocol
The most comprehensive assessment of acu- and headache type and the frequent lack of proper
puncture for chronic daily headache was a sys- control groups) makes it difficult to fully eluci-
tematic review published in 2008 that summarized date the placebo response in the reported results.
results of 31 clinical trials with 3916 partici- When compared to sham or medication, the
pants—17 trials for migraine, 10 for tension-type results favor acupuncture, suggesting it may have
headache, and 4 for mixed chronic headache [6]. a specific effect beyond placebo for chronic
Only 19 trials used ICHD criteria to diagnose headache; however, the evidence is still quite
chronic headache. Three trials used ad hoc infor- limited.
mation, two trials used resistance to traditional Since publication of this systematic review in
therapy, and seven trials used no formal criteria 2008, a few other studies have investigated acu-
for diagnosis. Using the modified Oxford scale to puncture for chronic headache. A large study
assess quality (maximum score of 7; 4+ was con- compared acupuncture to routine care for pri-
sidered high quality), 14 trials scored more than 4 mary headache (defined as more than 12 months
points, and 5 studies scored a maximum score of of having 2 or more headaches per month) in
7. The duration of treatment varied (average 10 11,874 non-randomized participants and 3,182
sessions, range 6–16) over a mean of 8 weeks randomized participants [7]. In both groups acu-
(range 4–24 weeks). The sham designs were het- puncture decreased headache days and intensity
erogeneous. Randomization was sufficiently of pain and persistently improved quality of life
addressed in only nine trials, and the longest fol- through the 6-month follow-up period. One small
low-up period was 2 years (used in five trials). study (n = 26) showed within-group improve-
In the 14 studies comparing acupuncture vs. ments (i.e., no control group) on frequency, dura-
sham with reported follow-up data, the true acu- tion, and intensity of chronic daily headache
puncture group had a significantly higher diagnosed with IHS criteria after acupuncture
response rate, defined as at least a 33% improve- (30-min sessions twice a week for 4 weeks, fol-
ment in headaches (measured by the headache lowed by once a week for 4 weeks) [8].
index or headache frequency) than sham (53% Acupuncture point injection (API) involves the
vs. 45% response rate, respectively) [6]. Subgroup injection of a small amount of medicine or vita-
analyses revealed similar outcomes for tension- min to enhance the stimulation of acupuncture
type but not migraine headache. No differences points. One randomized, double-blinded study of
were found in headache intensity, frequency, or 40 participants with chronic daily headache
health-related quality of life when data for the (minimum of 15 headaches per month) demon-
two groups were pooled for each follow-up strated that Carthami-Semen (safflower seed)
period. Of the eight studies of acupuncture com- extract API compared to normal saline API
pared to medication treatment, headache inten- resulted in improved quality of life and headache-
sity and frequency were reduced in the free days after biweekly injections for 4 weeks
acupuncture group. Three of the four trials that [9]. No adverse events were reported.
compared acupuncture to other non-pharmaco- In summary, acupuncture appears to have ben-
logical treatments found that the other therapy eficial effects on chronic daily headache com-
(e.g., massage or physiotherapy) was more effec- pared to sham acupuncture and medication
tive than acupuncture. treatment, with minimal side effects. The data
19 Complementary and Alternative Approaches to Chronic Daily Headache 255
suggest that acupuncture may have a potential migraine frequency and intensity after 16 weeks
role in management of chronic daily headache. compared to sham acupuncture [13].
To better assess acupuncture’s clinical efficacy
and significance regarding chronic daily head- cupuncture and Tension Headache
A
ache, further studies with more rigorous blinded- A number of studies have evaluated acupuncture
controlled designs, longer follow-up periods, and specifically for chronic tension-type headaches
more standardized treatment interventions are and are well summarized in a Cochrane system-
needed. atic review (initially published in 2009, updated
in 2016 including only one new trial) [14]. The
Acupuncture and Migraine review analyzed 12 RCTs of at least 8-week
In 2011, a randomized controlled trial (RCT) was duration, which included 2,349 patients with
published comparing effects of acupuncture and either episodic or chronic tension-type head-
topiramate in 66 patients with chronic migraine ache. Treatments varied (6–15 weekly sessions
[10]. Both the acupuncture (24 sessions over and follow-up periods of 8–24 weeks).
12 weeks) and the topiramate groups (25 mg daily, Acupuncture point selection also varied across
titrating weekly to 100 mg/day for 8 weeks) dem- studies. Quality assessment of all studies was
onstrated improved headache frequency after treat- low to moderate due to a high risk of bias, lack
ment; however, acupuncture’s improvement was of blinding and variable effect sizes in diverse
larger (20.2 days to 9.8 days vs. 19.8 days to trials. Seven studies compared acupuncture to
12.0 days, p < 0.01). Differences persisted even in sham acupuncture; of the five studies with data
participants with medication overuse. Adverse for meta-analyses, acupuncture had benefit over
events were 66% in the topiramate group and only sham acupuncture (51% vs. 43% with at least
6% in the acupuncture group. This study lacked a 50% reduction in headache frequency), with
sham acupuncture control group, limiting the inter- effects lasting 6 months. Only three of the seven
pretation since active procedures such as acupunc- trials reported an adverse event (17% with acu-
ture consistently have higher placebo response puncture and 12% with sham). In the two trials
rates than those with oral medication. Additionally, that compared acupuncture to routine care,
the acupuncture group had significantly more pro- those who received acupuncture had a greater
vider time than the topiramate group (24 versus 6 likelihood of a 50% reduction in headache fre-
visits), and patients were unblinded. Despite these quency. Four trials compared acupuncture to
limitations, this study demonstrates acupuncture physiotherapy, massage, or exercise; acupunc-
may be of similar benefit for chronic migraine as a ture was not superior to the other interventions,
daily prophylactic medication such as topiramate, and some outcomes demonstrated better results
without the frequent side effects. Future work for the other treatment option. The review con-
should focus on whether acupuncture as an add-on cluded that the quality of evidence is moderate
therapy to topiramate or other prophylactic medi- or low and that acupuncture is effective for
cation has additive or synergistic effects on chronic treating frequent episodic or chronic tension-
migraine [11]. type headaches.
A Cochrane database review in 2016 investi- It is unclear whether patients with tension-
gating acupuncture for episodic migraine pro- type headaches respond differently to acupunc-
phylaxis (22 trials with 4,985 participants) found ture compared to migraine patients and whether
a small but statistically significant reduction in the presence of more than one headache type
headache frequency over sham, usual care and influences outcome. A study of self-reported
drug prophylaxis at 2 months; however, the find- CAM efficacy reported that acupuncture was
ings were statistically heterogeneous [12]. A effective in 38% of participants with chronic ten-
recent study (n = 249) demonstrated that 30-min- sion-type headache and co-occurrence of
ute sessions of acupuncture (5 days/week for migraine, compared to only 11% without the co-
4 weeks) with electrical stimulation decreased occurrence [15].
Considering its low risk, acupuncture may be RCTs investigated the cost-effectiveness of acu-
a worthwhile option for patients suffering from puncture for headache. In 1 study of 401 patients
chronic tension-type headache, especially those with “chronic headache” (defined as at least 2
unwilling or unable to tolerate long-term medica- headaches/month) in Wales and England, partici-
tion management [16]. Future work should pants were randomized to acupuncture (12 ses-
include comparing acupuncture with other treat- sions over 3 months) or usual care alone.
ment options [14, 17]. Acupuncture was more expensive (~$768 vs.
$413/year), but the mean health gain from acu-
cupuncture and Cluster Headache
A puncture was 0.021 quality-adjusted life years
Limited evidence exists for CAM therapies and (QALYs), and the cost difference for acupuncture
cluster headache [18–20]. In one small case was substantially lower when evaluated per
report, four patients with cluster headaches (three QALY. The authors conclude that since “acupunc-
with episodic and one with chronic) reported ture for chronic headache improves health-related
reduction or elimination of attacks with acupunc- quality of life at a small additional cost, it is rela-
ture treatment (twice/week for 2 weeks, then tively cost-effective [25].” A similar RCT involv-
once/week for 8 weeks, and then once/alternate ing 3,182 patients in Germany found similar
weeks for 2 weeks) combined with verapamil or increased costs with acupuncture, but it still met
alone [21]. Such a report is encouraging, but fur- the international thresholds for cost-effectiveness
ther research is needed to evaluate acupuncture [26]. Nonetheless, insurance companies rarely
for cluster. cover acupuncture. In addition, the time and
energy to complete a course of acupuncture treat-
cupuncture and Pediatric Headache
A ment must be considered. To be compliant, one
Only a few studies have evaluated acupuncture in needs lifestyle flexibility to attend treatment with-
pediatric headache patients and none specifically out negative impact on missed partial days of work
for chronic headache. One RCT of 43 patients or school [27]. Future studies should consider
under 18 years old with episodic migraine these additional factors in assessing cost benefit
(n = 22) or tension-type headache (n = 21) for acupuncture with long-term follow-up.
showed that 4 weekly treatments of laser acu-
puncture was more effective in decreasing head- cupuncture Summary of Evidence
A
ache frequency, severity, and duration than and Recommendations
placebo laser acupuncture [22]. This research Acupuncture research is challenging to evaluate
suggests that laser acupuncture, which uses a because of the variability of protocols (e.g., fre-
low-energy laser to stimulate headache-related quency and duration of treatment, location of acu-
acupuncture points [23], could be a useful non- puncture points), the heterogeneity of control
traumatic, non-painful treatment for children groups and blinding, and the resulting high risk of
(considered safe as long as the proper energy bias. Despite these limitations, the evidence for
dosage is used with eye protection), especially acupuncture for headache is promising. Some
those who are afraid of needles or intolerant of moderate evidence supports the use of acupunc-
medications. A study of 19 pediatric patients who ture in chronic daily headache, and weak evidence
received auricular acupuncture (where acupunc- supports the use of acupuncture point injection
ture needles are applied to the ear) demonstrated (API) therapy in the treatment of chronic daily
it might be an option for abortive treatment in the headache. Acupuncture may be as efficacious for
emergency department [24]. However, this study chronic migraine as topiramate and has many
did not have a control group. fewer side effects [10]. There is only weak or
moderate evidence for acupuncture in treating
cupuncture and Cost Analysis
A episodic or chronic tension-type headaches. The
Lack of affordability is one of the most frequently limited data on acupuncture for cluster headaches
cited reasons for not having acupuncture. Two preclude any recommendations. Although acu-
puncture costs more than usual care alone, its is defined by the American Physical Therapy
improvements in health-related quality of life Association (APTA) as a “skilled intervention
might be worth the small additional cost. In a par- using a thin filiform needle to penetrate the skin
ticipant with the financial means and time avail- and stimulate trigger points, muscles, and con-
ability, acupuncture may be an effective treatment nective tissues for the treatment of musculoskel-
for chronic daily headache, chronic migraine, and etal disorder [32].” Unlike acupuncture, dry
possibly chronic tension-type headache. needling is not based in the theoretical concept of
Considering the overall low risks, acupuncture is Qi, and it is not administered along meridians.
an important headache treatment consideration, Instead, the practitioner identifies tender taut
especially in those unwilling or unable to tolerate bands within a muscle that are thought to be
long-term medication management [16]. hyperalgesic [33]. The most common technique
is the “fast-in and fast-out” technique [34] where
a needle is inserted into a trigger point until a
Acupressure quick twitch is observed (a sudden contraction of
the muscle fibers in the taut band). Once the
Acupressure uses fingers instead of needles at twitch is obtained, the needle is then moved up
acupuncture points and is a low-cost, noninvasive and down around 3–5 mm at a frequency of 1 Hz.
technique with very limited side effects [28]. A The duration of treatment depends on the irrita-
small (n = 28) RCT in “chronic headache” tion of the trigger point [31]. The pathophysiol-
(defined as over 6 months of headaches, with four ogy and mechanism of action of dry needling is
or more per month) demonstrated the benefit of under debate but is thought to decrease concen-
acupressure plus “placebo” (15 mg/day of ribo- trations of pro-inflammatory substances locally
flavin/vitamin B2) over the muscle relaxant [31, 35] and to induce ischemia and hypoxia
mephenoxalone, based on self-appraised pain resulting in vasodilation, potential angiogenesis
scores at 1 and 6 months of follow-up. and altered glucose metabolism [30].
Unfortunately, this study did not include head- Additionally, dry needling is thought to decrease
ache frequency or duration effects, and the “pla- peripheral sensitization and mitigate central sen-
cebo” pill of vitamin B2 may have benefited sitization [30, 31] by diminishing the prolonged
headache, limiting its clinical usefulness [28]. cause of peripheral nociceptive input modulating
The acupressure wristband Sea-Band®, used to the dorsal horn’s response and activating central
stimulate a distinct acupoint that helps nausea, inhibitory pain pathways [36].
showed benefit in aborting migraine-associated Despite its increasing use, the evidence sup-
nausea in a study of 40 participants [29]. porting dry needling therapy for headache is lim-
Limited research and methodologic concerns ited. A recent systematic review on dry needling
of acupressure for headache prevents the recom- for cervicogenic or tension-type headache [37]
mendation of its use. If an individual has chronic resulted in the analysis of 3 studies, two RCTS
migraine and cannot tolerate an antiemetic, acu- (with n’s of 45 and 30 participants with tension-
pressure may be a non-drug option. Future RCTs type and/or migraine headaches) and a third case
should include active placebo groups as well as a report (n = 1) on cervicogenic headache. All three
non-active control to tease out placebo responses studies showed significant improvement with dry
and include metrics of headache frequency, dura- needling over 4–5 weeks of treatment; however,
tion, and medication use. they did not show greater effectiveness than other
techniques (e.g., lidocaine injections, lidocaine
plus corticosteroid injections, or superficial dry
Dry Needling needling). The case report supported the addition
of dry needling to conventional physiotherapy
Dry needling has becoming increasingly popular versus dry needling alone in cervicogenic head-
over the last decade to treat headaches [30, 31]. It ache. Adverse effects were not sufficiently
reported or described. The three studies used dif- cific to chronic headache (including migraine,
ferent needling methodologies and had very het- cervicogenic, and muscle-tension headache).
erogeneous samples with varying control groups, Many studies had very poor to adequate method-
limiting the power of their evidence [31]. One ologic quality and heterogeneous methodologies
prospective study investigating adverse events which prevented pooled analyses, greatly limit-
found that out of 7,629 treatments, only 1,463 ing the review’s conclusions. In addition to the
(9%) reported mild adverse events (e.g., bruising, evidence described, the Cochrane database plans
bleeding, or pain), and no physiotherapists to release a review on manual treatments for pre-
reported serious adverse events [38]. In summary, vention of migraine, tension-type headache, and
there is insufficient evidence to strongly support cervicogenic headache that will provide addi-
the use of dry needling to treat chronic daily head- tional understanding of the evidence to date [49].
ache or other types of headache. Further research
should be done with greater methodologic rigor Chiropractic Manipulation
and with attention to potential side effects. and Cervicogenic Headache
A 2015 Cochrane review of chiropractic manipu-
lation for neck pain [50] included 51 trials but
Chiropractic Manipulation only 2 trials [51, 52] for treatment of cervico-
genic headache (total n = 125 participants). Both
Chiropractic manipulation includes spinal studies had low methodologic quality; the authors
manipulation (more commonly used) and spinal concluded that multiple sessions of spinal manip-
mobilization. Spinal manipulation uses high- ulative therapy were superior to light massage in
velocity, low-amplitude forces to move a joint improving pain and function of chronic cervico-
slightly beyond its passive range [39]. Through genic headache at short-term and immediate-
spinal mobilization, the application of low-veloc- term follow-up [50, 53]. Of the 51 studies, less
ity, variable amplitude force is intended to cause than half reported adverse events; of those, only
movement of the joint within its natural passive temporary and benign side effects were reported
range [39]. Spinal manipulation and mobilization [50]. The needed frequency and duration of treat-
are thought to exert benefit in two ways—by ment for effect remain unclear. Although 12 ses-
decreasing nociceptive input from the cervical sions appear better than 3 sessions [51], no
spine structure and by modulating pain centrally differences were seen between 12 to 16 and 3 to
through spinal and supraspinal mechanisms [40– 8 treatments [51, 52]. A recent review of 10 RCTs
47]. However, other cortical modulators also may (n = 685) investigated chiropractic manipulation
play a role, such as expectancy, placebo, and for cervicogenic headache [47], and all studies
other nonspecific effects [39]. had an active control group (physical therapy) or
placebo [36, 41, 51, 53–58]. Many of the studies
Chiropractic Manipulation in this review have already been discussed. One
and “Chronic Daily Headache” study determined that manipulation was more
A 2001 systematic review of spinal manipulation effective than mobilization in decreasing cervico-
for “chronic headache” (tension, migraine, and genic headache duration, frequency, and associ-
cervicogenic) included 9 RCTs with nearly 683 ated disability [47]. A dose-response study of
patients [48]. Spinal manipulation was consid- spinal manipulation for cervicogenic headache
ered superior to massage for cervicogenic head- [59] with pending results per clinicaltrials.gov
ache and may have an effect similar to first-line [60] may provide additional insight on the effect
prophylactic medications for tension-type and of cervical manipulation for cervicogenic head-
migraine headaches. Importantly, the review ache. In addition, a single-blinded, placebo-con-
included studies with episodic headache (one trolled RCT investigating spinal manipulative
study of episodic tension, one study with both therapy for cervicogenic headache [61] also has
episodic and chronic tension), and four were spe- pending results [62].
hiropractic Manipulation and Tension

C pending [49, 65]. A 2006 review of six studies
Headache included a variety of manual therapies, limiting
Currently, two RCTs have investigated its specificity for spinal manipulative therapies;
spinal manipulative therapy for chronic tension- this review concluded that there was no evidence
type headaches. Some studies evaluating the that manual therapies are effective for tension-
effectiveness of spinal manipulative therapy tend type headache [66].
to group it with massage and physical therapy, A 2012 systematic review of five (n = 348),
under the umbrella term “manual therapies.” For mostly high-quality RCTs (Jada scores between
instance, one partially blinded, multicenter RCT 2 and 4, scale is from 1 to 5) investigated spinal
(n = 82) found that manual therapy (mobilization manipulative therapy for tension-type headache
of the cervical and thoracic spine, exercises, and [67]. Two of the studies were mentioned above
postural correction; maximum of nine treatments and found a benefit of spinal manipulative ther-
over 8 weeks) reduced headache frequency, apy for chronic tension-type headache [64, 68].
improved disability and cervical function, and Of the three other studies, one found no signifi-
decreased medication use more than usual care cant difference between spinal manipulative ther-
for chronic tension-type headaches [63]. Since apy and control groups in daily headache hours,
this study included multiple modalities, the find- headache intensity, or medication use in individ-
ings are not specific for spinal manipulation. uals with tension-type headache (IHS criteria)
Adverse events were not reported. [69]. There were no adverse events. Another
A well-designed older RCT (n = 150; included study (n = 22) found improved subjective ratings
in the review above with chronic headaches) of pain relief after osteopathic spinal manipula-
showed that 6 weeks of amitriptyline was more tive therapy versus palpatory examination or no
effective in reducing pain than spinal manipula- intervention for muscle contraction headache;
tive therapy (twice weekly for 6 weeks at 20 min/ however, the limited outcome measures and lack
session) to treat chronic tension-type headache (1 of randomization limit its clinical usefulness
headache/week for at least 3 months). Those [70]. Adverse events were not reported. The final
receiving amitriptyline had more side effects study (n = 19) compared cervical spinal manipu-
(82% vs. 4%); as expected, effects disappeared lative therapy plus amitriptyline to cervical spinal
once amitriptyline was stopped. However, manipulative therapy + placebo vs. sham cervical
4 weeks after treatment, those who underwent spinal manipulation plus amitriptyline vs. sham
spinal manipulative therapy had statistically sig- cervical spinal manipulation plus placebo (three
nificant improvement in headache frequency, times/week for 6 weeks, one time/week for
intensity, medication use, and functional health 4 weeks). The only group that had a statistically
status (on the SF-36 instrument) compared to significant reduction in headache frequency was
baseline [64]. Of the participants who completed the combined treatment (spinal manipulative
the study, 43 (82.1%) in the amitriptyline group therapy and amitriptyline) [71]. The small sam-
reported side effects (drowsiness, dry mouth, and ple size and wide confidence intervals limit the
weight gain), and three (4.3%) in the spinal clinical usefulness of the findings. Four subjects
manipulative group reported side effects (neck experienced AEs after spinal manipulative ther-
soreness and stiffness). apy (e.g., minor aggravations of neck pain or
Both of these studies lacked blinding, increas- headaches) and five after amitriptyline (e.g.,
ing their risk of bias. The preliminary data are nausea, fatigue, sleep disturbance, dry mouth,

somewhat promising for spinal manipulative and constipation).
therapy for chronic tension-type headache, but Since these reviews appeared, two additional
currently there are not enough strong data to sup- RCTs were published investigating spinal manip-
port its use. A Cochrane database protocol was ulative therapy and tension-type headache. One
published assessing manual treatment for the pre- study randomized participants (n = 84, episodic
vention of tension-type headache, but results are tension-type headache 57.1%, chronic tension-
type headache 42.9%) into manual therapy, compared with a control group that underwent
manipulative therapy, a combination of manual or detuned interferential therapy (electrodes with-
manipulative therapy (4 treatments over 4 weeks out current) [78]. However, this study lacked
for all previous groups), or a control group. All appropriate randomization, blinding, and inten-
treatment groups had statistically significant tion-to-treat analysis and included selective
improvements in pain perception, frequency, and reporting (Jadad scale 1). One observational
intensity; however, the manipulative treatment study and one recent RCT have been published
was most effective, showing statistically signifi- subsequently. The first study (n = 11, n = 6
cant improvement in all pain dimensions at post- chronic migraine) found a statistically and clini-
treatment and 4-week follow-up. Importantly, the cally significant reduction in headache days and
control group also had significant differences in headache disability after atlas vertebra realign-
three of five dimensions of pain (sensory, evalua- ment compared to baseline; however, there was
tive, and intensity) on the McGill Pain no control or placebo group. Studies of pharma-
Questionnaire. Headache frequency was signifi- cologic interventions indicate that the placebo
cantly lower at follow-up in the combination response is high in migraineurs [79]. Future stud-
treatment group [72]. No adverse events were ies should include a proper control.
reported. The second RCT (n = 105) published in A recent, well-designed, single-blinded, pro-
2016 found that manipulation treatment plus mas- spective RCT (n = 104) investigated spinal manip-
sage (4 treatments over 4 weeks) decreased head- ulative therapy for migraine (at least one attack/
ache frequency compared to massage only in month) [80]. The study had three groups includ-
patients with tension-type headache. Headache ing spinal manipulative therapy, a placebo group
disability inventory (HDI) scores improved in (i.e., sham maneuvers to the scapula and/or glu-
both groups. This study lacks a true control group, teal region), and a control group of usual care.
so it is impossible to differentiate the results from The treatment period was 3 months, and follow-
a placebo response, providing limited evidence up occurred at 3, 6, and 12 months. The study
for massage alone or combined with manipulative used a newly validated sham placebo for manual
therapy for tension-type headache [73]. therapy [81], and this is the first manual-therapy
One study assessed the benefit of using a self- RCT to document successful blinding [80].
acupressure pillow daily versus chiropractic care Migraine days were significantly reduced for all
alone for patients with both tension-type and cer- three groups compared to baseline, and this effect
vicogenic headache (n = 34). Both groups remained at follow-up for the spinal manipulative
improved, but no difference between groups was and placebo groups at all time points. The control
found [74]. group (usual care) did return to baseline posttreat-
ment. The authors concluded that improvements
Chiropractic Manipulation in migraine with chiropractic spinal manipulation
and Migraine were likely only due to placebo response.
In 2011, a systematic review summarized three
RCTs that investigated spinal manipulative ther- Chiropractic Manipulation
apy for migraine [75]. The RCTs had mostly poor and Pediatrics
methodologic quality (1–3 on Jadad scale that One prospective, randomized, single-blind multi-
ranges from 1 to 5) [76–78]. Two were described center study (n = 52) found that both spinal
above in the chronic headache review and sug- manipulative therapy and placebo (i.e., light
gested no effect of spinal manipulation on the touch in a specific cervical segment without
headache index or migraine duration and disabil- manipulation) decreased the frequency of head-
ity compared to drug therapy, spinal manipula- aches posttreatment compared to baseline in chil-
tion plus drug therapy, or mobilization [76, 77]. dren and adolescents with cervicogenic headache;
One RCT showed significantly reduced migraine however, no difference existed between treatment
frequency, intensity, duration, and disability and placebo [55]. Neither placebo nor spinal
manipulation decreased the duration or intensity case-control study (n = 457), spinal manipulative
of the headaches or use of medication from base- therapy was independently associated with verte-
line to posttreatment. bral arterial dissection, even after controlling for
neck pain [89]. However a case-control and case-
hiropractic Manipulation and
C crossover study using 100 million person-years
Cost Analysis of data found no excess risk of stroke in those
Little data are available on cost-benefit analysis who had chiropractic care versus medical care
of spinal manipulative and mobilization therapy [90]. The authors argue that the association arises
for headache. One Cochrane review published in from individuals seeking treatment for neck pain
2004 concluded, “there is moderate evidence for and headache, symptoms that precede 80% of
an economic advantage in using multidisciplinary vertebrobasilar strokes. However, as we recently
care, defined as mobilization and manipulation concluded, “[arterial dissection or stroke post
plus exercise, for mechanical neck disorders” spinal manipulative therapy] are catastrophic
[82]. In addition to the financial cost of treatment, events which, however rare, must weigh heavily
participants need flexible schedules to attend in any assessment of this approach” [91].
treatments regularly. Lack of insurance coverage
also impacts availability and access to care. hiropractic Manipulation: Summary
C
Future studies should be conducted on the cost- of Recommendations
benefit ratio for spinal manipulative and mobili- There is no specific evidence for the use of spinal
zation therapy with long-term follow-up. manipulative therapy for chronic daily headache.
There is some evidence supporting its use in
hiropractic Manipulation and
C chronic cervicogenic headache based on two
Adverse Events RCTs. The data for episodic cervicogenic head-
A recent review found that out of 118 reviews, 54 ache are heterogeneous, limiting their clinical
concluded that manipulation was safe, 15 con- usefulness. One well-designed RCT suggested
cluded that it was harmful, and the remainder that spinal manipulative therapy was helpful for
were neutral or unclear [83]. The most common the long-term treatment of chronic tension-type
adverse events were stroke, headache, and verte- headaches. Amitriptyline outperformed spinal
bral artery dissection, with incidence estimates manipulative therapy in the short term, but it was
for such serious adverse events ranging from 1 in associated with more adverse events. The other
20,000 to 1 in 250,000,000 manipulations. A study on chronic tension-type headache used a
2017 literature review assessing the risk of number of modalities, limiting specificity for spi-
adverse events after cervical spinal manipulation nal manipulative therapy treatment. The data for
found that although women had a slightly chiropractic treatment and episodic tension-type
increased risk compared to men, the authors headache are weak. Most studies investigating
could not delineate a clear patient profile related spinal manipulative therapy and migraine are of
to risk [84]. The recent well-designed RCT with poor methodologic quality. A recent well-
three arms evaluating chiropractic spinal manipu- designed RCT concluded that the benefit of spi-
lation in migraineurs (with the sham maneuver nal manipulative therapy for migraine is likely
control group) [80] closely monitored for side due to the placebo response [80]. No evidence
effects prospectively in the 70 participants and supports the use of spinal manipulative therapy in
found that of the 703 sessions, local tenderness children or adolescents. While the studies pre-
(7–11%) and fatigue (1–9%) were the most com- sented reported only minor adverse events, the
mon side effects, with no severe or serious AEs risk of a cervical dissection or stroke, however
reported [85]. A few case-control studies have unlikely, is serious and must be weighed into any
also suggested a link between spinal manipula- clinical decision. At this time, the lack of strong
tive therapy and stroke from cervical artery dis- data supporting the use of spinal manipulation
section [86–88], and in one large nested therapy combined with the lack of good data
investigating its potential serious risk precludes a Thai massage (45-min Thai massage twice per
recommendation for treatment of chronic daily week for 4 weeks) had lower pain intensity (VAS
headache. scores) at 2, 4, and 6 weeks compared to medica-
tion treatment (25 mg of amitriptyline daily for
4 weeks). The court-type traditional Thai mas-
Massage sage group also had decreased tissue hardness
and increased heart rate variability suggesting
Massage is defined as the manipulation of mus- that this treatment is a modulator of parasympa-
cles and other soft tissues. There are many spe- thetic activity [95]. However, the study lacked
cific types (e.g., trigger point therapy, Swedish, relevant metrics for headache parameters, limit-
structural, relaxation, Thai massage, traditional, ing its clinical significance.
traditional court-type Thai, connective tissue Three additional small studies were done on
release, and cross-friction massage) [39]. The chronic tension-type headache and massage. The
mechanism of action is considered to be similar to first (n = 11) found a single session of massage
spinal manipulative therapy and dry needling (see was associated with significant increases in heart
above) by decreasing nociceptive input from the rate variability, decreases in head pain at 24 h,
cervical spine and by modulating pain centrally. and decreased negative mood states (tension-anx-
iety and anger-hostility subscales of the profile of
assage and “Chronic Headache”
M mood states) after treatment; the placebo group
Currently, no studies directly investigate massage (detuned ultrasound) did not have these changes
therapy for chronic daily headache. A few exist [94]. This study also lacked relevant headache
for chronic tension-type headache, and one study parameters. The second study (n = 11) found a
included both chronic tension-type headache and significant decrease in headache frequency
chronic migraine patients. Many studies are small 1 week after massage treatment (4 weeks of
and do not include headache frequency or dura- biweekly 30-min massage treatments) that lasted
tion measures, significantly limiting their clinical until the end of the study [96]. There was no
relevance. The study of both migraine and ten- change in headache intensity after treatment
sion-type chronic headache patients (n = 72) ran- compared to the 8-week baseline, but a trend
domized individuals to receive traditional Thai existed for a shorter duration of headaches. This
massage or sham ultrasound (both groups study had a high dropout rate (6/10), and it did
received nine sessions over 3 weeks) and found not have an adequate control or placebo group,
no statistically significant difference in headache limiting its conclusions. The third study (n = 21)
intensity [92]. included only women and found that upper body
massage (ten sessions) significantly decreased
assage and Tension Headache
M pain intensity (VAS scale), the number of days
The first systematic review of manual therapy for with neck pain, and scores on the Finnish Pain
primary chronic headache was published in 2014 Questionnaire while increasing range of motion
and included six RCTs; however, only one study [97]. This study lacked a control or placebo
addressed massage therapy [93]. It was a pro- group, as well as measurements of relevant head-
spective crossover RCT of 11 participants with ache parameters.
chronic tension-type headache; headache inten- Two RCTs [98, 99], one previously mentioned
sity decreased 24 h after a massage (2 treatments study [73] and one pilot study [100], have exam-
within 1 week) compared to the control group ined massage therapy for tension-type headache.
(which received detuned ultrasound and elec- The first recent RCT [98] (n = 97) included indi-
trodes without current) [94]. viduals with both chronic and episodic tension-
A RCT (n = 60) published in 2015 reported type headache diagnosed by ICHD criteria. Its
that individuals with chronic tension-type head- four-arm design included placebo superficial
ache randomized to receive court-type traditional massage, soft tissue techniques, neural mobiliza-
tion techniques, or a combination of soft tissue The study reported that massage therapy (30 min/
and neural mobilization techniques (each arm week for 5 weeks) reduced pain intensity by
included 6 15-min treatments). The soft tissue, 71% compared to a control group (unchanged
neural mobilization, and the combination group from baseline). It is unknown what questionnaire
all reported increased pain pressure thresholds, criteria were used to diagnose chronic migraine,
fewer headaches, less maximal intensity of head- and the study did not track migraine frequency
aches, and improved quality of life (HIT-6) com- or duration, limiting the clinical significance of
pared to baseline and the placebo group. The its findings.
combination group had the highest pain pressure Two RCTs [102, 103] and one small study
threshold and the lowest headache frequency and [104] have also been conducted on massage and
HIT-6 values after intervention. migraine. The first RCT (n = 64) randomized
In one study described above in the chiroprac- individuals with migraine (with and without
tic section, Espi-Lopez et al. found that massage aura, diagnosed by IHS criteria) to lymphatic
treatment improved Headache Disability Index drainage (a gentle pressure technique thought to
(HDI) scores and cervical range of motion in 105 improve lymphatic flow), traditional massage,
patients with tension-type headache; however, or a waiting group [102]. After a 4-week base-
the effect was enhanced when combined with line, the treatment period was 8 weeks followed
spinal manipulative therapy [73]. This study by a 4-week observation period. At the end of
lacks a true control group limiting evidence for the observation period, both treatment groups
massage alone or combined with manipulative had significantly fewer migraine attacks and
therapy for tension-type headache. migraine days than the waiting group. The lym-
Another RCT conducted in 2015 found myo- phatic drainage group also had significantly less
fascial trigger point massage (12 45-min treat- medication use during the intervention than the
ments over 6 weeks) decreased headache other two groups. The second RCT [103]
frequency significantly from baseline for recur- recruited 47 individuals with migraine (51%
rent tension-type headache in 56 participants; had more than one attack/month, with 48-h
however, the placebo group (detuned ultrasound) mean duration) diagnosed by questionnaire. The
also had statistically significant decreases in massage group (weekly massage sessions for
headache frequency from baseline, and no differ- 5 weeks) had greater improvements in migraine
ences were found between groups [99]. This frequency and sleep quality during the interven-
study likely only captured a placebo response, tion and in the 3 follow-up weeks compared to
underscoring the importance of including both the control group. There was no difference in
active placebo and control groups in a well- the intensity of the attacks between groups or
designed trial [99]. medication use, but a trend existed for perceived
In 2008, a pilot study with tension-type head- stress and coping efficacy for the massage
ache (2004 IHS guidelines and physician confir- group. Migraine duration changes were not
mation, 13 = chronic, 3 = episodic) found reported. The final study investigated the use of
massage therapy (45-min biweekly massages for massage and spinal manipulation during an
6 weeks) significantly reduced headache fre- acute migraine attack in ten men [104]. After
quency, intensity, and duration and improved treatment, the participants had a statistically
HDI scores compared to baseline [100]. Future significant decrease in pain intensity. No adverse
work should include a larger sample size, a pla- events were reported, but other headache param-
cebo group, and proper controls. eters were not investigated.
Massage and Migraine assage and Cervicogenic Headache

M
Only one RCT has addressed chronic migraine Three studies have been conducted on massage
and massage [101]. In this study of 26 individu- for the treatment of cervicogenic headache,
als, migraine was diagnosed by questionnaire. including one pilot RCT and two small studies.
One randomized study (n = 136) published in should be conducted on cost benefit for massage
2015 found a specific form of micro-regulating therapy with long-term follow-up, including
massage (described as “micro-regulating with quality -of -life metrics.
vertical cross press lying on one side”) was asso-
ciated with lower headache intensity and assage and Adverse Events
M
decreased headache frequency, compared to tra- Many massage studies do not report on adverse
ditional massage. It is unknown what criteria events. A systematic review of adverse events
were used to diagnose cervicogenic headache, due to “pain-related massage” from case reports
and the study did not have a control group, seri- published between 2003 and 2013 (clinical trials
ously limiting its clinical interpretation [105]. were excluded) found 43 case reports, with only
A pilot RCT (n = 20) found that trigger point 7 containing reports of 95 adverse events [110].
therapy (manual therapy on active trigger points From the seven reports, massage was only
in the sternocleidomastoid muscle) decreased reported in one of the cases as the manual therapy
headache and neck pain intensity and improved utilized, and cervical disc herniation was
motor performance more than a control treatment reported. The other treatment modalities were
(simulated trigger point therapy without pressure actually spinal manipulative therapies.
application) in individuals with a known diagno-
sis of cervicogenic headache, using the criteria of Massage: Summary
Sjaastad and Fredricksen [106]. This study dem- of Recommendations
onstrated feasibility of study design; however, it Currently, no studies have examined the use of
did not include measures of headache duration or massage therapy for chronic daily headache.
frequency, limiting its clinical utility [107]. Those that have investigated massage and chronic
A single-group, pre-post test pilot study found headache are severely limited by their exclusion
that soft tissue cervical massage (three treatments of standard headache metrics. Many studies were
of 8 min over 1 week) improved range of motion small and lacked proper control groups. There
in eight individuals with cervicogenic headache; are some preliminary data from two RCTs sup-
however, headache intensity, duration, and fre- porting massage for episodic migraine treatment;
quency were not studied [108]. however, the optimal mode of treatment, inter-
It is unknown how much range of motion clin- vals, and frequency are still unknown. The long-
ically relates to these important headache term impact of massage therapy on disease
variables. process should also be studied in larger patient
groups. The three studies investigating massage
assage and Pediatric Headaches
M for episodic cervicogenic headache were too
One small pilot study (n = 9, all girls) found that poorly designed to provide any evidence for the
trigger point-specific physical therapy (twice use of massage for cervicogenic headache. There
weekly over 4 weeks) reduced headache fre- is some preliminary evidence supporting mas-
quency by 67.7%, intensity by 74.3%, and dura- sage therapy for episodic tension headache, based
tion by 77.3% [109]. This study lacked a control on the findings of one well-designed RCT [98].
group, making it impossible to detect placebo The efficacy of massage therapy for pediatric
effects. patients is currently unknown.
The current evidence on massage and chronic
assage and Cost Analysis
M daily headache is inconclusive. There is some
Few data are available on cost-benefit analysis of weak evidence for massage for episodic migraine
massage therapy for headache. In addition to the and tension-type headache. The studies reviewed
financial cost of treatment, participants need to used a variety of manual therapy techniques and
have flexible schedules to attend treatment regu- study designs, making global clinical inferences
larly. Lack of insurance coverage also impacts challenging. At this time evidence is lacking to
availability and access to care. Future studies recommend massage for treatment of chronic
daily headache. It may be a useful adjunct for Other Complementary

medication-resistant or medication-intolerant and Alternative Treatment
individuals, as massage is typically considered Approaches
safe; however, additional research into adverse
events is needed. The biggest barrier for most Several other complementary therapies discussed
patients’ use of massage therapy is cost, as it is include aromatherapy, hydrotherapy, daith pierc-
rarely covered by insurance. Some patients report ing, and oxygen administration.
using a pretax health savings or flex spending
account to help cover the costs.
Aromatherapy
Craniosacral Manipulation Aromatherapy and oils have been used as early as

800–900 AD [113]. Peppermint, eucalyptus,
Craniosacral therapy is based on the idea that a chamomile, and lavender are examples of oils
craniosacral fluid rhythm exists and, if restricted, commonly used by patients. Inhaler lavender sig-
can be released by a practitioner who is manually nificantly reduced headache severity in control
identifying restrictions in the craniosacral system (3.6 ± 2.8) compared to placebo (1.6 ± 1.6)
and using gentle hand adjustments to release and groups in one clinical trial (n = 47). Another
restore these rhythms [111]. One small study study analyzed neurophysiologic and analgesic
(n = 20) of CST vs. wait-list control demonstrated effects of peppermint and/or eucalyptus and/or
improvements in HIT-6 scores after 6 craniosa- ethanol when topically applied to the forehead
cral treatments over 4 weeks for treatment of and temples (n = 32) [114]. Although no combi-
migraine (via ICHD criteria; at least 5–15 head- nations were associated with reduced experimen-
aches per month for at least 2 years) [111]. The tal pain sensitivity, sensitivity to head stimulus
lack of a control group limits the interpretation of was significantly reduced in the peppermint plus
these findings. The lack of high-quality evidence ethanol group. Further research is needed to fur-
limits the recommendation of craniosacral ther- ther elucidate the potential benefits of aromather-
apy for chronic daily headache. apy for headache.
Reflexology Hydrotherapy
Reflexology is a type of foot massage based on Hydrotherapy, the use of water for pain relief, is
the theory that various reflex zones on the feet a very old treatment reported to help many
correspond to a particular organ of the body and chronic pain and arthritis conditions. There are
its associated energy level. Reflexologists believe many different techniques, but most either
that circulation improves when the reflex zones submerge the body or part of the body in hot or
are stimulated with pressure [112]. No specific cold water and/or apply hot or cold compresses to
studies have investigated reflexology for chronic the body. Due to the hypothesized pathophysiol-
daily headache. One prospective, exploratory ogy of local vasoconstriction followed by reflex-
study without a control group assessed the impact ive vasodilation, it has been theorized to be
of 6 months of reflexology treatments on 220 beneficial for migraine [115]. One small study
migraine or tension-type patients in Denmark; (n = 40) evaluated hydrotherapy (45 days of hot
81% reported improvements in their headaches. arm and foot bath of 103–110 °F and 20 min of
Due to the lack of high-quality evidence, reflex- daily head ice massage) plus conventional medi-
ology is not recommended for the treatment of cation therapy or conventional medication ther-
chronic daily headache. apy alone for chronic migraine [115]. Both
groups had improved headache outcomes and visual symptoms at 60 min were better in oxygen
HIT-6 scores, although more so in the hydrother- group compared to air group, without any signifi-
apy group. Better heart rate variability in the cant adverse events. Hyperbaric oxygen therapy
hydrotherapy group led to the assessment of has limited evidence yet many purport its bene-
“improved vagal tone.” However, the paucity of fits, with the hypothesized mechanism of oxygen
data limits our ability to recommend hydrother- as a serotonergic agonist, an immuno-modulator
apy for chronic daily headache at this time. of substance P and neuropeptides, and a modula-
tor of inflammatory pathways [120–125]. The
remainder of this section will discuss evidence
Daith Piercing for hyperbaric oxygen use for headache treat-
ment. There is currently no specific data on oxy-
Daith piercing, a piercing located in the inner- gen administration for chronic daily headache.
most cartilage fold of the ear, has become increas- A 2015 Cochrane review (11 studies and 209
ingly popular for the treatment of headaches due participants) had 2 new studies to update the
to individual reports via social media and a web- prior 2008 review [126] investigating the effec-
site that reports 40 anecdotal cases of benefit tiveness and safety of oxygen administration for
after receiving the piercing [116]. The piercing migraine and cluster headache [124]. For preven-
does not coincide with any known acupuncture tion of migraine, one study failed to show a dif-
point for headache treatment [117]. There are no ference between hyperbaric oxygen (n = 20) and
systematic studies investigating its effectiveness, sham (n = 20) for mean number of headache
and experts believe that the relief is often tempo- days, proportion of participants with nausea/
rary (1–2 weeks). The cost is usually minimal; vomiting, or the use of rescue medicine com-
however, extreme care must be taken up to pared to sham therapy [127]. Three of the five
6 months after the piercing to avoid infection studies were pooled (n = 58) and found hyper-
[117]. Given the potential risk of infection and baric oxygen to be more effective in treating
the lack of evidence supporting benefit, daith acute migraine headaches compared to sham.
piercing is not recommended for chronic daily One study (n = 56) found a significant reduction
headache. in pain intensity (VAS scores) after 1 h of normo-
baric oxygen administration compared to sham
for acute migraine treatment. Only two small
Oxygen Administration (n = 16 and n = 16) studies have evaluated hyper-
baric oxygen for abortive [128] and prophylactic
Oxygen administration therapies take two forms. [129] cluster treatment (respectively), and both
One administers oxygen at high percentage of were negative.
normal atmospheric pressure (normobaric oxy- While oxygen administration has major risks,
gen therapy), and the other administers 100% such as fire (especially for smokers—and most
oxygen at pressures above one atmosphere cluster patients smoke), respiratory arrest (which
(hyperbaric oxygen therapy). Normobaric oxy- can occur in chronically hypercarbic patients
gen therapy has Grade A evidence for its use as relying on hypoxic drive for respiration), pulmo-
an abortive treatment option for cluster headache nary barotraumas, worsening of shortsightedness
[118] and is thus not considered a CAM therapy (reversible), claustrophobia, and oxygen poison-
for cluster treatment. Interestingly, one recent ing, only two trials specifically mentioned
2016 pilot study (n = 22) demonstrated potential adverse events [127, 130], and only four very
efficacy for the use of normobaric oxygen treat- minor adverse events (claustrophobia and run-
ment for migraine [119]. While the primary end- ning out of trial gas) were reported [124].
point was negative (mean decrease in pain score In summary, there is minimal evidence for
at 30 min), overall relief of pain, nausea, and the use of hyperbaric oxygen for abortive
migraine treatment and no evidence for its use at Carpenter Library, Wake Forest School of Medicine, for
his help with the use of Zotero. We are appreciative of the
for preventive migraine treatment or chronic help from Nakiea Choate from the Department of
daily headache. Hyperbaric oxygen has failed Neurology at Wake Forest Baptist for her administrative
to show any benefit for abortive or prophylac- support.
tic cluster treatment and has the potential for
major risks.
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Pain. 1993;52(2):243–5.
Headache: Part III—Nutraceuticals
Laura Granetzke, Brielle Paolini,
and Rebecca Erwin Wells
Nutraceuticals maintain quality and safety standards. Thus,

dietary supplements are not required to pass
The term “nutraceutical” was coined by Dr. safety and efficacy studies in humans before pro-
Stephen DeFelice in 1989 as a combination of duction and sale. Voluntary adverse event report-
“nutrition” and “pharmaceutical” and was ing exists, and if the FDA has scientific proof and
defined as “a food, or part of a food, that provides determines a product to be unsafe, the FDA can
medical or health benefits, including the preven- issue a warning or require that it be removed [4].
tion and/or treatment of a disease” [1]. Currently, Past products have required numerous years to
this term is used loosely and has no regulatory assemble sufficient data and prove harm prior to
definition. The Dietary Supplement Health and market removal [3]. The FDA also oversees the
Education Act (DSHEA) of 1994 defined the US health claims that are used for dietary supple-
Food and Drug Administration’s (FDA) statutory ments. Specifically, supplements are allowed to
authority over dietary supplements [2]. A dietary make claims of health benefit, nutrient content,
supplement is “a product that is intended to sup- and structure/function, but not of specific disease
plement the diet and may contain one or more treatment or prevention [5].
dietary ingredients. A dietary ingredient may be The supplement market has grown from 4000
any of the following: a vitamin or mineral; an products in 1994 to over 85,000 by 2014, and the
herb or other botanical; amino acid; a dietary ability to purchase them online has increased
substance for use by humans to supplement the their accessibility [3]. In addition, the high cost
diet by increasing the total dietary intake; a con- of prescription drugs, disparities in prescription
centrate, metabolite, constituent, extract, or com- coverage, and the public’s perception that all
bination of the preceding ingredients.” “natural” medicines are good are cited as reasons
Dietary supplements are used by nearly half of for the explosion of this market [1]. Many patients
the US population [3]. Unlike pharmaceutical report using supplements to avoid side effects
products, the FDA expects the manufacturer to associated with some prescription medications
(70%) or because they have an integrated
approach to their health (52%) or are generally
L. Granetzke (*) · R. E. Wells dissatisfied with conventional medicine (32%)
Neurology, Wake Forest School of Medicine, [6]. However, since the FDA allows companies
e-mail: rewells@wakehealth.edu control over the manufacturing process, the accu-
racy of labeling and purity of some supplements
B. Paolini
Wake Forest School of Medicine, have come into question. Investigations of sup-
Winston-Salem, NC, USA plements are ongoing for (1) claims of potential

274 L. Granetzke et al.
contaminants [7] and (2) poor quality (lack of Feverfew

advertised ingredient or different dosage from
claim) [8]. Supplement companies can pay for The herb Tanacetum parthenium (feverfew) is a
third-party testing to confirm content and accu- perennial plant that belongs to the family
racy. Consumers can use this “stamp of approval” Asteraceae (daisy). Its Latin origin febrifugia
on bottles to confirm accuracy and quality of the means “fever reducer” [4]. Although native to the
product. Balkan Peninsula, it can now be seen growing
In the 2007 National Health Interview Survey along roadsides, field, and wooded areas in the
(n = 23,393), 26.7% of adults with self-reported USA, Africa, Australia, China, Japan, and Europe
migraines/severe headaches reported using [14]. It is used for numerous medical conditions
herbal/other supplements (even without includ- [14] and comes in a variety of formulations, but
ing multivitamins in this category); usage was its mechanism of action is not fully understood. It
split across 44 different supplements [9]. Children is thought that parthenolide, a sesquiterpene lac-
also frequently use supplements. In an Italian tone, is the principle active ingredient [4, 12, 15].
survey of 124 4- to 16-year-old children with a Parthenium may inhibit the release of serotonin
primary headache diagnosis by IHS criteria, 64% and potentially serve as an anti-inflammatory
reported use of herbal remedies (such as agent by inhibiting prostaglandin and phospholi-
Valeriana, Ginkgo biloba, Boswellia serrata, pase A production, thus improving vascular con-
Vitex agnus-castus, passionflower, linden tree), traction and relaxation [4, 12, 15]. It may also
and 40% reported use of vitamins/mineral sup- inhibit platelet secretion and histamine release
plements (such as magnesium, 5-hydroxytrypto- [14]. Parthenolide may not be the only active
phan, vitamin B6 or B12, multivitamin ingredient; some varieties of feverfew also con-
compounds); baseline CAM use in this group tain a high concentration of melatonin [15],
was 76% [6]. A larger, multicenter Italian study which is also thought to be helpful in many head-
(n = 706 children/adolescents with a primary ache types (see below).
headache disorder using ICHD-IIIβ criteria)
found a lower, but still meaningful, prevalence of vidence of Feverfew for Headache
E
nutraceutical use (32%) and melatonin use (10%) Feverfew is one of the most thoroughly studied
[10]. Of note, perceived efficacy of melatonin nutraceuticals for headache prevention, and two
and nutraceuticals was similar to prophylactic Cochrane reviews have evaluated its efficacy [15,
drugs (75% vs. 68% vs. 75%, respectively). 16]. The first review in 2004 concluded that
Despite such frequent use, it is estimated that insufficient evidence exists to suggest an effect of
60% of patients do not report CAM use to their feverfew over placebo in preventing migraine.
providers [9, 11]. The publication of a larger (n = 218) and more
Few studies have evaluated the benefit of rigorous study [17] with a stable feverfew extract
nutraceuticals specifically for chronic daily head- (MIG-99) resulted in a new Cochrane review in
ache. Therefore, the research evidence conducted 2015. This new review evaluated all randomized,
for headache will be described, with the hope that placebo-controlled, double-blind trials assessing
this information can help inform use in those feverfew mono-preparations for preventing
with chronic daily headache. Based on evidence migraines in all ages, resulting in an analysis of 6
and efficacy for headache, nutraceuticals included studies with 561 participants. Pooled analyses
in this review are Tanacetum parthenium (fever- were not possible due to study and dose heteroge-
few), riboflavin, magnesium, CoQ10, melatonin, neity; participant inclusion criteria, feverfew
vitamin D, and ginkgolide B (Ginkgo biloba). preparation/dosage, and length of treatment var-
The evidence for homeopathy is also discussed. ied considerably. Of the 4 studies that found
Although Level A evidence exists for Petasites some benefit [17–20], 3 had small sample sizes
(butterbur), it is not currently recommended sec- (between 17 and 60 participants). Two more rig-
ondary to potential for liver toxicity [4, 12, 13]. orous studies (n = 50 and 147 participants,
20 Complementary and Alternative Approaches to Chronic Daily Headache: Part III—Nutraceuticals 275
respectively) found no significant effects [21, (EFNS) considers the evidence for efficacy of
22]. The newest study [17] had the largest sample feverfew as Level C [26].
size of all studies to date (n = 218) and found that
feverfew may reduce migraine by 0.6 headaches
per month compared to placebo [17] (from 4.8 to Riboflavin
2.9 attacks/month vs. 4.8–3.5, respectively,
P = 0.0456). Adverse events were mild and not Riboflavin, or vitamin B2, is a water-soluble vita-
significantly different from placebo, with gastro- min that is a cofactor in the mitochondrial elec-
intestinal complaints the most common side tron transport chain. The name originates from
effect. A “post feverfew syndrome” was reported “ribitol” (sugar whose reduced form provides
when the substance was withdrawn in long-term part of the chemical structure) and “flavin” (func-
users. Symptoms included joint/muscle aches tional group which gives patient’s urine the char-
and stiffness, nervousness, anxiety, and poor acteristic yellow color upon oxidization) [4]. It
sleep [18]. The new study added positive evi- has a 1 h half-life, so absorption is poor unless
dence to the prior mixed and inconclusive find- taken with food [27]. Riboflavin plays a role in
ings, but the overall quality evidence is still low the Krebs cycle, production of ATP, and mito-
and not conclusive. chondrial energy metabolism and generation [12,
While the Cochrane reviews evaluated the evi- 28]. There may be a relationship between
dence for feverfew as a prophylactic migraine migraine and mitochondrial dysfunction which
treatment, a recent study evaluated feverfew plus leads to “decreased ATP production and energy
ginger given sublingually (1 unit dose applicator; metabolism, imbalance in calcium ions, increased
exact dose was not listed) as first-line abortive for neuronal information processing, decreased
mild headache [23]. After 2 h, 32% of patients migraine threshold, and ultimately cortical
who received active medication were pain-free spreading depression” [27].
versus 16% who received placebo (P = 0.02).
However, the two groups were not randomized vidence of Riboflavin for Headache
E
with respect to baseline average severity of head- Dating back to 1946, a case series was published
ache (1.41 in active group, on a scale 0–3, versus in which 19 patients with migraine reported posi-
1.67 placebo group). In summary, although tive results from using riboflavin for variable
robust data may be lacking in support of feverfew lengths of time [29]. In a randomized clinical trial
for migraine, its side effect profile is favorable. (RCT) in 1998, 3 months of 400 mg daily ribofla-
Care must be taken to obtain a high-quality prod- vin resulted in statistically significant reductions
uct, as the amount of parthenolide may vary in migraine headache days (P = 0.012) and fre-
among brands. Feverfew should be avoided dur- quency (P = 0.005) compared to placebo.
ing pregnancy because it may stimulate contrac- Treatment effect was seen at 1 month but was
tions. Thus, it should be recommended with highest after 3 months of treatment [30]. Another
caution for women of childbearing age. study comparing 4 months of preventive use of
beta-blockers (n = 11) to riboflavin (n = 15) for
everfew Guideline Recommendations
F migraine found that treatment response (patients
The evidence for efficacy of feverfew (studied with ≥50% decrease in attack frequency) was
dose, 50–300 mg bid; 2.08–18.75 tid of MIG-99) similar in both groups (beta-blocker 55% and
is considered Level B (probably effective) per riboflavin 53%), but auditory evoked cortical
the 2012 American Headache Society (AHS) responses tended to normalize only after beta-
and the American Academy of Neurology (AAN) blocker use, suggesting different pathophysiolog-
guidelines [24]. The recent Canadian Headache ical mechanisms of action [31]. A small (n = 23)
Society guidelines recommend against its use open-label study showed that 400 mg daily ribo-
[25], citing insufficient evidence of benefit. The flavin decreased migraine frequency (from 4 to
European Federation of Neurological Societies 2 days/month at 3 and 6 month follow-ups,
P < 0.05) and use of acute medications, but not energy metabolism. Nearly half of US adults have
headache duration or intensity [32]. Minor side poor dietary intake of magnesium [37]. Diets low
effects (diarrhea, abdominal pain, facial erythema, in magnesium have been associated with type 2
and polyuria) were reported by a few patients. diabetes, premenstrual syndrome symptoms,
The few studies of riboflavin for headache in asthma, osteoporosis, elevated plasma levels of
pediatric patients have yielded conflicting results. C-reactive protein, hypertension, cardiovascular
A double-blind RCT showed that 200 mg daily disease, and sudden death [37, 38]. Magnesium
riboflavin did not improve headaches more than deficiency may play a role in many factors associ-
placebo in 48 children. The placebo rate was high ated with migraine pathophysiology, including
(66.6%) and the dose used for this study was lower cortical spreading depression, substance P release,
than typical [33]. Another double-blind, crossover serotonin-related vasoconstriction, N-methyl-d-
RCT in 42 children with migraines also found no aspartate (NMDA) glutamate transmission, and
benefit of riboflavin (at 50 mg/day) vs. placebo, nitric oxide production [39]. Magnesium defi-
although they did find a reduction in frequency of ciency may be present in up to half of patients with
tension-type headaches [34]. No adverse reactions migraine [38]. However, conflicting evidence
were noted in this study. In a retrospective chart exists regarding serum magnesium levels in
analysis of 41 pediatric/adolescent patients with migraineurs. In one study using a magnesium load
various headache subtypes, those receiving either test (3000 mg of magnesium lactate), 24 h urinary
200 mg or 400 mg of riboflavin daily for 3, 4, or magnesium excretion was lower in the migraine
6 months had fewer headaches (68.4% of patients) group versus controls, suggesting magnesium
and less intense pain (21% of patients). Full bene- retention occurred in the migraineurs because of
fit was seen after 4 months of treatment. A few systemic underlying deficiency, but baseline serum
patients reported decreased or resolution of aura. levels were similar between groups [40]. In a case
One patient stopped due to vomiting, and another control study (50 migraineurs and 50 healthy con-
complained of increased appetite, otherwise few trols), serum magnesium levels were lower in
side effects were reported [35]. Results of this migraineurs vs. controls at baseline, although
study need to be interpreted with caution, as it was there were no differences in serum magnesium
retrospective and lacked a placebo group and during or between migraine headache events [41].
blinding. A case study of three children reported In a separate matched case-control study (40
that riboflavin significantly improved ICHD- migraineurs, 40 healthy controls), serum ionized
diagnosed cyclic vomiting syndrome, a condition magnesium levels were lower between attacks and
hypothesized to be related to deficient mitochon- during acute attacks in cases compared to controls,
drial energy supplies [36]. with odds of acute migraine significantly increas-
ing when serum levels of magnesium were low
Riboflavin Guideline (OR 35.3, 95% CI 12.4–95.2, p = 0.001) [42]. Low
Recommendations ionized magnesium levels have been reported dur-
Evidence for efficacy of riboflavin (studied dose: ing acute menstrual migraine attacks [43].
400 mg daily) was categorized as Level B in the Factors limit simple magnesium blood level
2012 AHS and the AAN guidelines. The Canadian testing to assess for magnesium deficiency [38].
Headache Society guidelines report strong but Of total body magnesium stores, 31% are intra-
low-quality evidence. The EFNS considered the cellular, 67% in the bone, and only 2% in the
evidence for riboflavin as Level C and classified extracellular space, where it could be accurately
it as a third-line option. measured with a blood draw; thus, blood
magnesium levels do not reflect true body stores
[38]. As magnesium is depleted from the blood, it
Magnesium is pulled from the cells in attempts to maintain
adequate levels. A magnesium test in red blood
The essential mineral nutrient magnesium (Mg2+) cells may be more accurate, but it is not available
exists in every cell type and plays a major role in at all institutions and can be costly.
vidence for Treatment of Headache

E Two studies have evaluated oral magnesium in
with Magnesium children with migraine. A randomized, double-
In one study, 81 patients with migraines used blind, placebo-controlled study tested oral magne-
600 mg of trimagnesium dicitrate daily for sium oxide (9 mg/kg/day divided tid with food)
12 weeks versus placebo. Migraine attack fre- versus placebo for 16 weeks among children with
quency was reduced in 41.6% in the magnesium migraine [48]. The magnesium group reported
group versus 15.8% in the placebo group fewer headaches of lower severity (p = 0.0037 and
(p < 0.05). Diarrhea and gastric complaints were p = 0.0029, respectively). There was also a pla-
reported in about a quarter of participants [44]. cebo response in headache frequency that waned
A recent meta-analysis reviewed 21 studies of after 6 weeks. In a second study of 45 children
magnesium for migraine using Cochrane review given 2.25 g of magnesium pidolate twice/daily
criteria. In 11 studies, magnesium was given intra- for 3 months (in an unblinded, open-label design),
venously for acute treatment; in 10 studies, oral treatment improved MIDAS scores, headache
magnesium was used as a preventive [45]. The 10 days (decreased by 69.9%), and use of analgesics
studies of oral magnesium included 789 partici- (65.4% lower) [49]. However, only 22 participants
pants (6 studies in China) and used 6 different forms completed the full 12-month follow-up period.
of the salt and/or combinations, for periods of Unpleasant taste was the only adverse effect noted.
4–12 weeks. Overall findings were positive. Oral Magnesium was recently reclassified from
magnesium decreased frequency and intensity of category A to D during pregnancy based on evi-
migraine (odds ratios [ORs] 0.20 and 0.27). dence that intravenous magnesium sulfate injec-
Intravenous magnesium aborted acute migraine tions may have teratogenic effects on fetal bone
within 14–45 min, 120 min, and 24 h after infusion, growth. Evidence is limited on the safety of daily
respectively (ORs of 1.23, 1.20, and 1.25, respec- oral magnesium in pregnancy; given this new
tively). Only one study [46] used blinding of partici- potential risk and categorization, precaution is
pants, personnel, and outcome assessments. advised for use in pregnancy [50].
However, the results are difficult to interpret because
the treatment group received a combination of ribo- Magnesium Guideline
flavin, magnesium, and feverfew; the “placebo” Recommendations
group received a smaller dose of riboflavin [46]. Evidence for efficacy of magnesium (studied
In 1996, Pfaffenrath et al. reported the results dose: 600 mg trimagnesium dicitrate daily) is
of a randomized, double-blind, multicenter pla- considered Level B by the AHS and AAN guide-
cebo-controlled phase III study of 10 mmol mag- lines. The Canadian Headache Society guidelines
nesium twice daily in patients with 2–6 migraines made a strong recommendation for its use,
without aura per month. The study was stopped whereas the EFNS considered the evidence as a
early due to lack of an effect (goal n = 150, Level C, denoting a third-line option. According
stopped after interim analysis of 69 patients) to the 2015 American Headache Society Evidence
[47]. Response rates were equivocal in the two Assessment, 1–2 g of magnesium given intrave-
groups (28.6% with magnesium, 29.4% with pla- nously as abortive relief of migraine with aura
cebo). No difference was seen in numbers of has Level B evidence. There is no evidence of
migraine days or migraine attacks. Adverse significant adverse reactions with oral magne-
events were noted in 45% of the magnesium sium in those without pre-existing severe renal
group including diarrhea or soft stools (n = 10) disease.
and palpitations (n = 3), thus suggestive that the
form of magnesium may have been poorly
absorbed and patients may not have received full Coenzyme Q10 (CoQ10)
benefit. In addition, more than 50% of partici-
pants in both groups had previously failed one or Coenzyme Q10 (ubiquinone) is a hydrophobic
more prophylactic agents; thus, they may have substance found in all cell membranes that serves
been more refractory to treatment. critical roles in the electron transport chain [39]
and in mitochondrial function [39, 51] by helping rapid improvement, patients may not have felt a
convert fats and sugar into energy. As a free radi- need for continued therapy. The study was also
cal scavenger, it is an antioxidant with numerous limited because baseline headache frequency was
anti-inflammatory properties [39, 52]. CoQ10 based on report, whereas treatment headache fre-
has long been studied for its cardiovascular ben- quency was based on headache diaries. The dose
efits, such as blood pressure reduction, hypothe- used in this study was lower than in the adult
sized to be secondary to improved endothelial studies (only 100 mg daily rather than 100 mg
function. Severe CoQ10 deficiencies are found in tid) and was an add-on to an already effective
mitochondrial diseases (neonatal encephalopathy multidisciplinary clinic approach; CoQ10 as
with nephropathy, Leigh syndrome, lactic acido- monotherapy was not evaluated. Based on evi-
sis, infantile nephropathy, recessive ataxia, cere- dence from an open-label study in 32 adults [58],
bellar atrophy ± retardation) [53], and CoQ10 150 mg daily of CoQ10 reduced average number
supplementation can significantly reduce symp- of days with migraine from 7.34 to 2.95 in the
toms. Ubiquinol was recently approved by the last 60 days of treatment (P < 0.0001). These
FDA as an orphan drug to treat primary CoQ10 findings are supported by a recent study done by
deficiencies. Some hypothesize that migraine Shoeibi et al. [59]. No adverse effects were
may be a disorder of mitochondrial energy defi- reported in either study [58, 59].
ciency [54] and that inflammation present during Some authors suggest testing coenzyme Q10
a migraine leads to depletion of CoQ10 [55]. levels in patients prior to supplementation [4].
One-third of 1550 patients aged 3 to 22 with
vidence for CoQ10 for Headache
E diagnoses of migraine with and without aura,
In a double-blind, randomized, placebo-con- probable migraine, and chronic migraine had
trolled study published in Neurology, CoQ10 CoQ10 deficiency [52]. Once diagnosed, they
100 mg tid improved attack frequency (p = 0.05) were then started on 1–3 mg/kg/day of CoQ10.
and days with nausea after 3 months of treatment Although there was no control group for com-
(p = 0.02) in 42 participants with episodic parison, at follow-up evaluation (mean 97 + _56
migraine with and without aura, compared to pla- days later), headache frequency (46.3% with
cebo. The 50% responder rate for attack fre- 50% reduction; p < 0.001) and headache disabil-
quency was greater for those receiving CoQ10 ity scores both improved significantly (from
than placebo (47.6% CoQ10 vs. 14.4%; p = 0.05). 47.4 ± 50.6 to 22.8 ± 30.6; p < 0.001).
Mean duration, severity, and abortive medication
use did not differ between groups. One patient oQ10 Guideline Recommendations
C
reported cutaneous allergy, but otherwise no Coenzyme Q10 (studied dose 100 mg tid) was
other adverse reactions were noted [56]. given Level C evidence and judged as possibly
A randomized, double-blind, placebo-con- effective by the AHS and AAN guidelines. The
trolled, crossover study (in addition to a multidis- Canadian Headache Society guidelines strongly
ciplinary clinic approach) of 100 mg CoQ10 was encouraged offering it based on low-quality evi-
conducted in 6- to 17-year-old participants with dence but low adverse effects. The EFNS consid-
episodic or chronic migraine with and without ered the evidence for efficacy of coQ10 as Level
aura. Both groups improved from baseline, with- C, denoting a third-line option.
out a difference between coenzyme Q10 and pla-
cebo [57]. Chronic migraine patients taking
CoQ10 did have a greater initial reduction in Melatonin
headache frequency from baseline to week 1–4
compared to placebo. Similarly, episodic Melatonin is a hormone produced by the pineal
migraineurs who crossed over from placebo to gland associated with regulation of the circadian
CoQ10 improved after the first 4 weeks (but rhythm. Melatonin is thought to have anti-inflam-
declined with the opposite crossover). There was matory properties, inhibits both nitric oxide syn-
a high dropout rate; the authors suggest that after thesis and dopamine, and may have a role in
glutamate transmission. Its safety profile for 6 months of 4 mg melatonin resulted in less fre-
short-term use has been established in both quent migraines (p < 0.001) and chronic tension-
human and animal studies, but data are lacking type headaches (p = 0.033) and lower HIT-6
during pregnancy and lactation. Melatonin may scores for both groups (p < 0.001 and p = 0.002,
enhance opioid efficacy; thus, caution should be respectively) [60].
used in prescribing melatonin to patients using Melatonin benefited a small series of patients
opioids. Supplements produced in a lab may be with indomethacin-responsive headaches, both
safer than products made from animal sources, hemicrania continua (n = 11) [63] and idiopathic
which may contain contaminants. Lower doses stabbing headache (n = 3) [64]. The similar
are proposed to have a greater phase-shifting chemical structures of melatonin and indometha-
effect on human circadian rhythms [60, 61]. cin may explain the benefits seen [64]. Other
studies have cited gastric protection with melato-
vidence for Melatonin for Headache
E nin, suggesting it might be beneficial combined
Studies evaluating melatonin for headache are with nonsteroidal anti-inflammatory agents [65].
challenging to summarize given the variety of Although only a few studies have evaluated mel-
headache diagnoses, melatonin dosages, forms atonin for cluster headache, with conflicting
(immediate versus extended release), and dura- results, melatonin is considered a second-line
tion of treatments. In a randomized, double-blind, therapy in cluster headache [66]. The evidence
placebo-controlled trial of amitriptyline 25 mg, that melatonin levels may be low during a cluster
melatonin 3 mg, and placebo for 12 weeks in 196 attack strengthens the hypothesis that melatonin
participants with episodic migraine with and may act on cluster headaches [67]. One study of
without aura [62], the amitriptyline and melato- 20 participants (18 with episodic cluster and 2
nin groups had fewer migraine headache days per with chronic cluster headaches) reported
month compared to placebo. Compared to base- improvement after 14 days of 10 mg of melatonin
line, after 12 weeks, headache frequency was taken once per day in the evening during a cluster
reduced by 2.7 days in the melatonin group, period, compared to placebo [68]. Headache fre-
2.2 days in the amitriptyline group, and 1.1 days quency was reduced in the melatonin group
in the placebo group. Melatonin reduced head- (ANOVA, p < 0.03) although no response was
ache frequency compared to placebo (p = 0.009) seen in the patients with chronic cluster. However,
but not compared to amitriptyline (p = 0.19). As a another study of nine participants (six with
secondary end point, more patients taking mela- chronic cluster, three with episodic headaches)
tonin had >50% reduction in headache frequency did not report a benefit from 2 mg melatonin
versus amitriptyline (p < 0.05) and placebo given during a cluster period [69].
(p < 0.01). Those receiving both melatonin and In an open-label trial of melatonin, 14 of 21
amitriptyline had reductions in migraine duration children with migraine with and without aura and
and intensity and less analgesic use compared to chronic tension-type headache reported a >50%
placebo. Adverse effects were similar in the mel- reduction of headache attack frequency com-
atonin and placebo groups but significantly pared to baseline [70]. One child complained of
higher in the amitriptyline group. In contrast, a excessive daytime sleepiness. Clinical recom-
randomized, double-blind, placebo-controlled mendations in the Journal of the European
crossover study in 48 participants with migraine Paediatric Neurology Society state “there is still
with and without aura found no difference in no definitive consensus about the therapeutic use
migraine attack frequency between extended- of melatonin for headaches in children” [71].
release melatonin 2 mg for 8 weeks and placebo
[61]. However, placebo response was high.
Adverse reactions were mild (fatigue, dizziness, Vitamin D
nervousness, nightmares) and not significantly
different than placebo. One open-label study Vitamin D deficiency is prevalent in the USA
(n = 49; 41 completed study) showed that despite its presence in food sources and exposure
to sunlight. Vitamin D functions as a hormone, aura without headache [79]. Improvement in aura
with receptors in nearly all cells of the body with frequency and duration was seen. Abdominal
many functions, including cell growth, bone complaint and vertigo were reported (n = 3), but
health, immunity, and reducing inflammation overall was well tolerated. Two pediatric studies
[72]. A large cross-sectional population-based (n = 119 and n = 24) using combination products
study (n = 5938) found an interaction with vita- containing ginkgolide B, coenzyme Q10, ribofla-
min D levels and statin’s benefit on migraine, vin, and magnesium in migraine without aura
such that statin use was associated with lower found decreased migraine attack frequency [80,
odds of having severe headaches/migraines only 81]. Another study compared Preparation A
in those with high serum vitamin D levels [73]. (ginkgolide B 80 mg, coenzyme Q10 20 mg,
Based on this observation, a RCT in migraineurs riboflavin 1.6 mg, and magnesium 300 mg) with
was conducted of simvastatin 20 mg twice daily Preparation B (l-tryptophan 250 mg, 5-hydroxy-
plus vitamin D3 1000 IU twice daily vs. placebo. tryptophan [Griffonia simplicifolia], vitamin PP,
Patients continued their current migraine preven- and vitamin B6 1 mg) in 374 school-aged chil-
tative. Those in the treatment group experienced dren diagnosed with migraine without aura [82].
approximately 3 less migraine days per month Both groups showed improvement in headache
compared to placebo (p < 0.001) [74]. duration, pain intensity, disability, and behavioral
Unfortunately, given the intervention involved reactions. Both groups had fewer headaches,
both vitamin D3 and simvastatin, it is unclear especially the Preparation A group. However, the
which treatment had the greatest effect or if both use of combination treatments makes it challeng-
are required. A pediatric study (n = 53) demon- ing to detect which component may be most
strated a decreased frequency of migraine days helpful for migraine.
with supplementation of vitamin D plus amitrip-
tyline, but the study was limited by the lack of
control group [75]. A small case study (n = 3) Combination Treatments
reported the presence of severe vitamin D defi-
ciency mimicking chronic tension-type headaches In a recent RCT, participants (n = 130) were
in children, with resultant improvement/near res- given 400 mg riboflavin, 600 mg magnesium,
olution after vitamin D supplementation [76]. and 150 mg coenzyme Q10, along with a multivi-
tamin (containing 750 mg vitamin A, 200 mg
vitamin C, 134 mg vitamin E, 5 mg thiamin,
Ginkgolide B (Ginkgo biloba) 20 mg niacin, 5 mg vitamin B6, 6 mg vitamin
B12, 400 mg folic acid, 5 mg vitamin D, 10 mg
Ginkgo biloba has been used in herbal medicine for pantothenic acid, 165 mg biotin, 0.8 mg iron,
thousands of years to treat dementia, anxiety, 5 mg zinc, 2 mg manganese, 0.5 mg copper,
asthma, and schizophrenia, although with conflict- 30 mg chromium, 60 mg molybdenum, 50 mg
ing evidence. It is made from leaves from the maid- selenium, 5 mg bioflavonoids) for 3 months [83].
enhair tree originating from China [77]. Ginkgo Reduction in migraine days per month was not
may have an effect through its impact on glutamate significant. However, reductions in migraine pain
[78] and antiplatelet-activating factor [79]. (p = 0.03) and HIT-6 scores (p = 0.01) were seen.
Ginkgo biloba had some benefit as potential In 1 RCT of 49 participants, no differences were
acute abortive for migraine aura in a small seen between the treatment group (who received
(n = 25) open preliminary trial [78]. Another riboflavin 400 mg, magnesium 300 mg, and
open-label trial of Ginkgo biloba terpenes phyto- feverfew 100 mg) and the placebo group (who
some 60 mg plus coenzyme Q10 11 mg plus vita- received placebo containing 25 mg riboflavin)
min B2 8.7 mg was given twice daily for 4 months regarding headache reduction, migraine days,
in 50 women with migraine with aura or migraine migraine index, or triptan dose [46].
Homeopathy efficacy according to the 2012 AHS and the AAN

guidelines, including feverfew (studied dose,
Homeopathic remedies are based on the idea that 50–300 mg bid; 2.08–18.75 tid of MIG-99), ribo-
giving minute amounts of a harmful substance flavin (studied dose, 400 mg daily), and magne-
will trigger the body’s natural healing response sium (studied dose, 600 mg trimagnesium
against the harmful agent. Thousands of different dicitrate daily). Coenzyme Q10 (studied dose
homeopathic remedies/substances are used 100 mg tid) was considered to have Level C evi-
worldwide. Homeopathic treatments are created dence. Melatonin, vitamin D, and Ginkgo biloba
by “alternating steps of diluting and agitating a have limited evidence of potential efficacy for
starting substance; the resulting “potencies” headache. Homeopathy has limited evidence for
quickly reach dilutions beyond Avogadro’s num- use in headache. Despite its Level A evidence,
ber where the probability that one molecule of controversy exists over the concern for hepato-
the starting substance is still present approaches toxicity with Petasites (butterbur); it is therefore
zero [84].” Although homeopathic experts claim not currently recommended [4, 12, 13]. Additional
that many remedies are helpful for migraine, research is needed to further clarify benefits of
there is currently a paucity of evidence-based supplements for chronic daily headache.
research supporting its use. A systematic litera-
ture review found no evidence to support or refute
the use of homeopathy for migraine, tension- onclusions to Parts I, II, and III:
C
type, or cervicogenic headache, [85] and the CAM and Chronic Daily Headache
studies had numerous methodologic problems. A
more recent meta-analysis included four RCTs of Chronic daily headaches are often refractory to
homeopathy and headache [86]; these showed a conventional treatment options, and CAM treat-
positive trend but no statistically significant ben- ments may provide much-needed relief. However,
efit beyond placebo. Despite the lack of evidence, research of CAM treatments specifically for
a survey of 124 Italian children with chronic chronic daily headaches is limited, so we have
headaches demonstrated that 47% use homeopa- reviewed the research evidence for CAM for
thy [6]. Caution should be used with these prod- headache. Most of the studies have significant
ucts, as they have not been evaluated by the FDA methodologic concerns, and larger, more rigor-
for evidence, safety, or effectiveness [86]. ous studies are needed for all CAM modalities.
Studies are limited by small sample sizes, hetero-
geneous interventions, limited headache
Summary: Supplements outcomes, lack of active controls, and short-term
and Chronic Daily Headache follow-up. Despite these limitations, evidence for
mind/body options such as meditation, yoga, tai
The FDA has limited oversight on supplements, chi, and deep breathing is promising, with the
and given potential allegations of poor quality most research to date for mindfulness meditation.
and safety of supplements, consumers need to The strongest evidence for acupuncture is for
look for the “stamp of approval” of third-party chronic migraine, and cost analyses suggest it
testing on bottles to confirm accuracy and quality may have an overall cost benefit. There is some
of the product. Almost one-third of adults with evidence for spinal manipulative therapy for
severe headaches/migraines report using nutra- chronic cervicogenic headache or chronic ten-
ceuticals. Many may seek herb/supplements for sion-type headache, but the potential for major
their supposed natural and safe profiles, although adverse events, such as cervical dissection, limits
side effects also occur with supplements [87]. more widespread recommendation for its use. No
Few studies have evaluated the benefit of nutra- data support the use of massage for any chronic
ceuticals specifically for chronic daily headache. headache conditions. Other complementary ther-
Several supplements have Level B evidence of apies (aromatherapy, homeopathy, daith piercing,
and oxygen administration) have minimal evi- impossible. Participants interested in this type of
dence to support their use for chronic daily head- research may be different from most patients,
ache. The supplements with the strongest level of leading to selection bias. Interventions may not
evidence for benefit for headache (Level B) be easily reproduced, and non-drug treatments
include feverfew, riboflavin, and magnesium, are often not comparable with medical treatments
with CoQ10 having Level C evidence. Additional [88].
evidence is emerging for the potential benefits of Since the research into most CAM therapies
supplemental vitamin D, melatonin, and Ginkgo has really just begun, few studies specifically
biloba. evaluate CAM for chronic daily headache syn-
The research for CAM in general, and for dromes, so extrapolation of the information from
headache, has been limited by methodologic con- headache studies is required. Many studies done
cerns that reduce study quality, leading to chal- in headache evaluating CAM therapies were not
lenges in interpreting and assessing interventions. conducted with well-defined headache research
Treatment modalities are often poorly defined parameters. For example, many studies did not
and heterogeneous in delivery format, leading to clarify if the intervention was assessing episodic
difficulty in understanding what intervention was or chronic headaches. Most did not use ICHD
administered and how to replicate, recommend, diagnostic criteria.
or assess options for patients. Many studies had Despite these limitations and challenges, the
wait-list comparisons without an active control research suggests that many CAM therapies may
group, making it challenging to interpret the be beneficial, with minimal side effects. Patients
effect of the intervention above the placebo with headaches, especially chronic daily head-
effect. Few studies have long-term follow-up. aches, are especially desperate. Although CAM
Most were conducted with the CAM therapy as treatments may be helpful, the placebo rates are
an “add-on” therapy to usual care, making it dif- quite high in many studies. Further, broad recom-
ficult to compare it against usual care treatment mendations of potentially non-therapeutic inter-
options. Side effects are not always reported. ventions may damage the trust instilled in the
Unfortunately, many of the limitations with doctor-patient relationship. Further research is
this research are inherent with this type of critical to having a better understanding of the
research (Table 20.1). Evaluating non-pharmaco- value of these types of therapies for chronic daily
logic treatment options with research standards headache.
created for pharmacologic treatments is difficult. For pregnant or nursing women, CAM thera-
For example, although the “placebo” pill is the pies may be quite helpful at a time when pharma-
standard accepted control for drugs, there is no cologic options are much more dangerous [50].
ideal placebo group for most CAM therapies. Pediatric patients are often open and willing to
Blinding participants to active non-pharmaco- consider CAM therapies to avoid medications.
logic treatment options is challenging, if not Sometimes more traditional treatment options,
even non-pharmacologic options such as bio-
feedback, are difficult for patients due to cost and
Table 20.1 Difficulties with non-pharmacological availability. This point is illustrated with data
research
from the 2007 NHIS analyses that demonstrated
Limited ability to blind participants that <1% of patients with severe headaches/
Difficulty finding a credible control migraines used the well-researched intervention
Small sample sizes
of biofeedback, while 9% used yoga, 17% medi-
Selection bias
tated, and 24% did deep breathing exercises [88].
Behavioral treatments often not comparable with
medical treatments While most CAM therapies have minimal side
Inability to reproduce intervention effects compared to pharmacologic options, the
Reproduced with permission from John Wiley & Sons, potential side effects from CAM are not negligi-
Inc. from the journal Headache [88] ble. The time, energy, and cost associated with
many of these interventions are an important con- Although both were effective, multimodal treat-
sideration in the recommendation and adherence ment was statistically more beneficial than the
to CAM therapies, especially since many of these pharmacologic option in headache outcomes.
treatment options are out of pocket. While sev- CAM in the “real world” takes into account
eral of the cost analysis studies for acupuncture patient preference and considers CAM as an inte-
demonstrated increased costs of the procedure, gral part of every treatment plan, as first line
when the entire condition is considered and qual- rather than last resort [92]. Understanding CAM
ity-adjusted life years taken into account, the therapies is critical for providers to advocate for
value becomes apparent. Even so, the amount of their patients’ health care, as Dr. Rob Cowan
money spent on CAM is tremendous, with an points out, because “we don’t need to embrace
estimated $33.9 billion in out-of-pocket costs every alternative medical system to serve our
spent by US adults [89]. patients, but there exists a wide variety of modal-
Despite the significant amount of research dis- ities which, whether we incorporate them into
cussed in this chapter, there are still many unan- our practices or not, need to be on our radar, and
swered questions about most CAM therapies for which with we need more than a passing famil-
chronic daily headache [90]. Uncertainty persists iarity. Moreover, we need to provide some guid-
as to optimal dosages (frequency, duration, length ance to our patients in these areas if we are truly
of treatment), which types of patients and head- able to be their advocate in healthcare” [92, 93].
aches are most responsive to these interventions, The goal of these chapters is to equip providers
and mechanisms of action [90]. with the knowledge to appropriately counsel
Despite all these limitations and persistent patients on these treatment options and to make
questions, CAM therapies may be a viable treat- patients and providers aware of the possibilities
ment option for adults with chronic daily head- that CAM therapies may offer to those who need
ache. Given the significant risks associated with additional treatment options.
many pharmacologic treatments, especially opi- Chronic daily headache is a challenging con-
oids and the potential for medication-overuse dition to treat, with high associated disability and
headache, CAM treatments may be especially psychological comorbidities. One patient
helpful. The study assessing mindfulness therapy describes her experience with integrative medi-
vs. pharmacologic treatments after medication- cine in an eloquent letter published in Headache
overuse headache withdrawal is especially and concludes by stating “Since I have begun to
encouraging, suggesting that non-pharmacologic incorporate Integrative Medicine, I have started
treatments may be comparable to pharmacologic telling myself to stop waiting until I am 100%
treatments for medication-overuse headache. healthy to live my life. If all I have is 40%, then I
One of the most important aspects of many make sure it is the best 40%” [94]. Hopefully, a
CAM therapies is the opportunity for patients to better understanding of CAM therapies and an
be active in their own treatment plans and to learn integrative medicine approach will give all
techniques that improve their own sense of self- chronic daily headache patients and providers
efficacy. Many CAM therapies may not be most hope to achieve that goal [90].
effective as individual treatments but, as an
approach to care, with patients encouraged to use Acknowledgments Dr. Wells is supported by the
many CAM therapies discussed in this chapter National Center for Complementary and Integrative
Health of the National Institutes of Health under Award
together, using an “integrative” approach. One Number K23AT008406. The content is solely the respon-
study even retrospectively assessed for this possi- sibility of the authors and does not necessarily represent
bility through chart reviews comparing a multi- the official views of the National Institutes of Health. We
modal approach that included osteopathic gratefully acknowledge the editorial assistance of Karen
Klein, MA, in the Wake Forest Clinical and Translational
manipulative treatments, mindfulness, and qigong Science Institute, funded by the National Center for
to standard pharmacologic treatments in 83 ado- Advancing Translational Sciences (NCATS), National
lescents with chronic tension-type headache [91]. Institutes of Health, through Grant Award Number
UL1TR001420. We also thank Mark McKone, Librarian 13.

Mauskop A. Evidence-based guideline update:
at Carpenter Library, Wake Forest School of Medicine, for NSAIDs and other complementary treatments for
his help with the use of Zotero. We are appreciative of the episodic migraine prevention in adults: report of the
help from Nakiea Choate from the Department of quality standards Subcommittee of the American
Neurology at Wake Forest Baptist for her administrative Academy of neurology and the American headache
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Animal Models in Chronic Daily
Headache (CDH) 21
and Pathophysiology of CDH
Xianghong Arakaki, Noah B. Gross,
Alfred N. Fonteh, and Michael G. Harrington
Abbreviations SD Sprague-Dawley

TCC Trigeminocervical complex
5,7-DHT 5,7-Dihydroxytryptamine creatinine tDCS Transcranial direct current stimulation
sulfate TENS Transcutaneous electrical nerve
BAEP Brainstem auditory-evoked potential stimulation
BBB Blood-brain barrier TMS Transcranial magnetic stimulation
BoNT-A Botulinum neurotoxin type A TNC Trigeminal nucleus caudalis
CBF Cerebral blood flow VPM Ventral posteromedial nucleus (of the
CDH Chronic daily headache thalamus)
CGRP Calcitonin gene-related peptide
CM Chronic migraine
CSD Cortical spreading depression
CTTH Chronic tension-type headache Introduction of Animal CM Model
EPs Evoked potentials
FHM Familial hemiplegic migraine Chronic migraine (CM) is a primary headache
fMRI Functional magnetic resonance disorder, characterized by a transformation from
imaging a sporadic or “episodic” state to a more frequent
IM Inflammatory mediator or “chronic” state. This subgroup of episodic
IP Intraperitoneal migraine patients, about 3% per year, evolve
IS Inflammatory soup from having less headache days than non-head-
MOH Medication overuse headache ache days to having more headache days than
NDPH New daily persistent headache non-headache days in any given month of the
NO Nitric oxide year [1]. Therapeutic approaches for CM patients
NTG Nitroglycerin are limited, and less than 50% of the individuals
nVNS Noninvasive vagus nerve stimulation with CM are satisfied with their acute treatment
ONS Occipital nerve stimulation [2]. To explore interventions for CM sufferers,
PAG Periaqueductal gray research that explores neurobiological mecha-
RVM Rostral ventromedial medulla nisms of migraine transformation is critical but
not practical in clinical studies. Animal models
X. Arakaki (*) · N. B. Gross · A. N. Fonteh are ideally suited for this type of investigation
M. G. Harrington and have played crucial roles in our understand-
Neurosciences, Huntington Medical Research
ing of CM pathophysiology, elucidating many of
e-mail: xianghong@hmri.org the mechanisms underlying migraine transition

290 X. Arakaki et al.
to aid in treatment [3]. However, few treatments with reduced threshold for cortical spreading
currently exist for CM, which only bolsters the depression (CSD) [20–22], genes associated with
idea that more valid and reliable animal models migraine trigeminal nociception and pain [23–
for CM are needed. To have positive translational 29], as well as individual rats with migraine traits
significance, these models should mimic the fea- and yet unidentified genetic factors [30].
tures of human CM by having similar mecha- To highlight the importance of animal models
nisms as well as sharing similar responses to in CM research, we will discuss the following
interventions [4]. Therefore, three important pre- aspects: anatomical networks and details of CM
requisites for animal models of CM should be to models induced by repeated nociceptive stimula-
(1) reflect the recurrent activation of the trigemi- tions, clinical manifestations of CM models,
nal nociceptive system shown in all CM patients, electrophysiological mechanisms and non-phar-
(2) model the prominent phenotypic traits such as macological approaches, biochemical mecha-
allodynia/hyperalgesia and photophobia [5], and nisms and pharmacological approaches, genetic
(3) demonstrate positive responses to migraine manipulations, and limitations of animal models.
treatments. Examples of CM animal models are listed in
CM is a heterogeneous condition, and medica- Table 21.1.
tions are effective for some but not all patients.
Multiple models can be used to reveal the diverse
mechanisms underlying this complex condition natomy (Neural Substrate
A
across diverse CM patient populations. Currently, and Their Connections) and CM
there exist a few animal models for CM, although Models from Trigeminal Nociceptive
in their relative infancy, these models are begin- Activation
ning to shed light on this devastating neurologi-
cal condition and treatment options. These Neurogenic Theory of Migraine
paradigms include but are not limited to the fol-
lowing four different categories [5]: (1) repeated Over the past 150 years, many theories have
trigeminal nociceptive stimulation by applying been proposed to explain the pathophysiology
inflammatory soup (IS) or inflammatory media- of migraine. Based on extensive studies of
tor (IM) epidurally via a small craniotomy migraine in animal models, it is widely accepted
applied to the animal’s dorsal skull region [6–11]; that migraine is a neurogenic disorder, originat-
(2) repeated trigeminal nociceptive stimulation ing in the brain, and involves activation and sen-
by a nitric oxide (NO) donor, the most commonly sitization of the trigeminovascular pathways,
used is nitroglycerin (NTG) [12–14]; (3) chronic brainstem nuclei, and diencephalic nuclei [31].
modulation of the endogenous pain-modulating The head pain associated with a migraine attack,
system, such as by serotonin (5-HT) depletion/ including the frontal, temporal, parietal, occipi-
chronic hyperleptinemia [15, 16]; and (4) chronic tal, and upper cervical region, is thought to
state of allodynia/hyperalgesia by genetic manip- result from activation of the trigeminovascular
ulations [17–30]. The first two paradigms to system [31, 32]. Animal studies have also been
model CM are to repeatedly stimulate the noci- instrumental in characterizing the anatomy and
ceptive receptors of trigeminovascular neurons brain circuits that underlie migraine pathophysi-
and produce a chronic pain state [6–14]. Chronic ology, as will be described in detail in the next
modification of pain modulatory pathways section [31, 32].
includes modification of ascending or descending
pain modulatory pathways by altering neu-
rotransmitters such as serotonin level [15, 16]. Neural Circuitry Implicated in CM
Genetic manipulation includes familial hemiple-
gic migraine (FHM)-associated dysfunction of CM is a disabling and complex neurological dis-
channels and pumps [17–19], genes associated order, where multiple sensory pathways, limbic
Table 21.1 Representative animal models for CM
Animal species Approach for CM Migraine outcome References
Male Epidural cannula infusion: 10 miroL inflammatory mediator VPM neurons in CM rats fire faster than sham during mechanical stimulation, which [6]
Sprague- (IM), 15 infusions over 3 weeks (2.5 h before testing). was reduced after occipital nerve stimulation (ONS)
Dawley (SD) Single-unit recording in ventral posteromedial nucleus (VPM)
rats of the thalamus
Male SD rats Epidural cannula infusion: 10 miroL inflammatory mediator Mechanical allodynia occurred in CM, which was reduced after acute ONS Thermal [7]
(IM), 14–17 daily infusions allodynia was not affected by ONS
Male SD rats IS (inflammatory soup) of low intensity and high intensity or Single high IS or repetitive low IS produces reversible cephalic allodynia; repetitive [9]
artificial cerebrospinal fluid (aCSF) through cannula at 2- or high IS causes reversible cephalic and extracephalic allodynia; repeated high IS causes
3-day intervals for 4 times; cranial/extracephalic allodynia (by trigeminal neuronal hyperexcitability and impairs descending pain inhibition and results
von Frey withdrawal thresholds); neuronal excitability in development of central sensitization and cutaneous allodynia, which might facilitate
(single-unit recording and c-Fos) and diffuse noxious inhibitory subsequent migraine attacks and contribute to progression to CM
control (single-unit recording)
Male SD rats IS (contained 1 mM histamine, serotonin, and bradykinin and Repeated dura nociceptive stimulation caused maladaptive neuroplasticity in the brain that [10]
0.1 mM prostaglandin E2 in phosphate-buffered saline is similarly observed in CM patients: long-lasting allodynia; hypersensitivity to Nit
pH 7.4) roglycerin (NTG) (long-lasting decreased mechanical threshold and long-lasting higher
TNC glutamatergic transmission by microdialysis) that is similarly seen in CM patients
Male and Repeated systematic administration of NTG Repeated NTG-induced acute hyperalgesia with each NTG application and progressive [12]
female chronic basal hypersensitivity; known acute medication sumatriptan reduced the acute
C57BL6/J but not chronic hyperalgesia; known preventive medication topiramate inhibited the
mice acute and chronic hyperalgesia
Male and Repeated systematic administration of NTG Repeated NTG-induced acute hyperalgesia with each NTG application and progressive [13]
female mice chronic basal hypersensitivity; known preventive medication propranolol inhibited the
acute and chronic hyperalgesia; daily administration of acute medication sumatriptan
resulted in acute and chronic hyperalgesia similar to that after repeated NTG application,
consistent with medication-overuse headache (MOH)
Male SD rats Repeated systematic administration of isosorbide dinitrate Repeated L-ISDN causes reversible cephalic cutaneous allodynia, H-ISDN causes both [14]
21 Animal Models in Chronic Daily Headache (CDH) and Pathophysiology of CDH
(ISDN), a NO donor at low (L-ISDN) or high (H-ISDN) dose cephalic and extracephalic cutaneous allodynia, measured by von Frey filaments
Wistar rats, Repeated lateral ventricle injection of 5,7-dihydroxytryptamine Serotonin neurons and fibers degenerate; cerebral blood flow (CBF) velocity increased; [15]
both genders creatinine sulfate (5,7-DHT) cortical depolarization wave width extended
SD rats and ICV leptin Number of CSD increased significantly in rats with 7 daily IP leptin injections or in ZF [16]
Zucker fatty intraperitoneal (IP) leptin daily × 7 days; KCl-induced cortical rats. Therefore, the cortex tends to be more susceptible to CSD in chronic
(ZF) rats, spreading depression (CSD) recordings, measure CBF/direct hyperleptinemia
Zucker lean current potential changes/CSD number/CSD duration
(ZL) rats
Mice Knock-in mutation in the CACNA1A gene for alpha 1 subunit Reduced threshold and increased propagation velocity of CSD [17]
of neuronal Cav2.1 Ca2+ channels
Mice Knock-in mutation in the alpha 2 isoform of the ATP1A2 gene Reduced threshold and increased propagation velocity of CSD [18]
291
Mice Knockout mutation in the ATP1A2 gene Light sensitivity, over-activation of amygdala and piriform after conditioned fear stimuli [19]
systems, autonomic networks, and cortical func- Activation of these structures is thought to
tions are involved. The nociceptive innervation of contribute to the perception of pain during

the intracranial vasculature and meninges is migraine (sensory pathways) and also to endo-
mainly through the ophthalmic (V1) division of crine (autonomic networks), cognitive (cortical
the trigeminal nerve but also, to a lesser extent, functions), and affective (limbic systems) symp-
through the maxillary (V2) and mandibular divi- toms that last throughout the migraine “attack.”
sions (V3). There is also neuronal innervation of There is still much debate surrounding the
the dura mater from the cervical dorsal root gan- role of brainstem and diencephalic activation
glia [31]. The axon terminals of nociceptive during migraine. How does regional activation
nerve fibers that innervate the dura mater contain in the brain indicate where migraine may be
the vasoactive neuropeptides calcitonin gene- triggered? Does migraine result from activation
related peptide (CGRP), substance P, and neuro- of the trigeminovascular system, which drives
kinin A, which are released upon stimulation and other symptoms in migraine? These questions
cause vasodilation of dural and pial vessels [31, have received some traction in human imaging
33–35]. The central neural circuitry of the tri- studies where the hypothalamus shows tempo-
geminovascular system includes a central affer- rally—and regionally—specific activation in
ent projection from the trigeminal ganglion that episodic and chronic migraineurs, suggesting
enters the caudal medulla of the brainstem, via that the anterior hypothalamus underlies
the trigeminal tract, which terminates in the tri- migraine initiation and the posterior hypothala-
geminocervical complex (TCC), including the mus is thought to underlie the transition from
dorsal horns of the upper cervical spinal cord episodic to CM [37]. These questions have been
C1–C2, and the caudal division of the spinal tri- under the intense scrutiny of migraine research-
geminal nucleus (TNC). The TCC makes recip- ers in both human and animal studies seeking to
rocal ascending and descending projections with discover more efficacious treatment options for
several brainstem nuclei (periaqueductal gray episodic and chronic migraineurs. Animal stud-
(PAG), rostral ventromedial medulla (RVM)) and ies, however, have the potential to more rapidly
higher brain centers, including reciprocal con- advance our understanding of migraine patho-
nections with the hypothalamus and ascending physiology and drive preclinical drug screen-
projections to the thalamus (ventroposteriomed- ings that will stand a better chance of successful
ial and posterior), which in turn project widely clinical human phase trials.
throughout the cerebral cortex, where somato- Based on recently acquired empirical knowl-
sensory and insular cortices form reciprocal pro- edge of migraine pathophysiology, the most com-
jections with the TNC [31, 36] (Fig. 21.1). mon animal models for CM include either
The severe and throbbing pain in migraine is repeated systemic administration of pharmaco-
thought to result from activation of the nocicep- logical triggers of migraine, such as the NO
tive inputs from intra- and extracranial structures donor NTG [12–14], or repeated epidural admin-
that converge in, and are relayed to higher brain istration of inflammatory substances [6–11]. CM
centers through the TCC. All nociceptive infor- models induced by isosorbide dinitrate (ISDN)
mation from craniovascular structures is relayed will also be mentioned in a later section. Although
through the TCC and via ascending connections other NO donors such as sodium nitroprusside or
to other areas of the brainstem, diencephalon, diethylenetriamine/nitric oxide are being used in
and cerebral cortex, for modulation and interpre- migraine research, they were either used in vivo
tation of pain and other sensory-associated infor- [38] or in an acute mice model [39], which there-
mation. Pain processing is complex and involves fore is not a focus here.
a network of central neural activation primarily NTG, or glyceryl trinitrate (GTN), is a potent
composed of the brainstem nuclei, midbrain, vasodilator that evokes a delayed migraine in peo-
thalamus, hypothalamus, and cortical regions ple who suffer with migraines [40–43], but not in
including the cingulate and insular cortices, non-migraineurs, and has been utilized in multiple
somatosensory cortices, and prefrontal cortex. human experimental paradigms [41]. NTG is an
21 Animal Models in Chronic Daily Headache (CDH) and Pathophysiology of CDH 293
Cerebral cortex
Insular Auditory Visual
Somatosensory
Motor
Hippocampus
Corpus Collosum
Thalamus
Thalamo-cortical
Po PAG Cerebellum
VPM
Cortico-brainstem
Hypothalamus RVM
Amygdala
AH PH
TCC
Brain BBB
Neuron
Pia Mater
BV TNs
Arachnoid Mater
Meninges TG
Dura Mater
TG
Skull
Fig. 21.1 Schematic diagram of the trigeminovascular glion (TG). Pain information is subsequently transmitted to
system depicting principal rodent cephalic pain pathways. the trigeminocervical complex (TCC) and then to several
(Inset) The incipient events of a migraine headache include pain-processing nuclei, some of which have reciprocal
activation of nociceptors that innervate the meningeal blood modulatory connections with TCC (indicated by arrows).
vessels. Activation of meningeal nociceptors leads to the The major brain centers are depicted as mentioned in the
release of vasoactive proinflammatory peptides such as cal- main text. These include the rostral ventromedial medulla
citonin gene-related peptide (CGRP) and substance P (SP) (RVM), the periaqueductal gray (PAG), the amygdala, the
from their terminal nerve endings (colored circles near ter- hypothalamus comprised of the anterior (AH) and posterior
minals), which produce neurogenic inflammation, charac- (PH) nuclei, the thalamus including the ventroposteriome-
terized by vasodilation of meningeal blood vessels (BV), dial (VPM) and posterior (Po) nuclei, and the cerebral cor-
with possible deleterious effects on the blood-brain barrier tex, comprised here of motor, somatosensory, insular,
(BBB), which is depicted by astrocytic end feet (blue) and auditory, and visual cortices. Green dotted arrows indicate
pericytes (green) that directly appose brain capillaries. Pain the main trigeminal pathway from TG to cortex; light
information flows from the meningeal nociceptors via the brown-colored arrows show some modulatory pathways for
trigeminal nerves (TNs) and proceeds to the trigeminal gan- trigeminovascular circuits
organic nitrate with a short plasma half-life ond messenger with diverse effects on signaling
(1–4 min) but longer half-life in lipophilic tissues cascades in the central and peripheral nervous
such as the brain [44]. It is rapidly metabolized tissue [45]. NO donors are known migraine trig-
into NO in mammalian cells via both enzymatic gers in migraineurs, and inhibition of the enzyme,
and nonenzymatic processes. The breakdown NO synthase, has antimigraine effects [46].
metabolite, NO, is a free-radical species that acts NTG-triggered hyperalgesia in rodents has been
as a smooth muscle relaxant and as a neuronal sec- reliably used as a model for sensory hypersensitiv-
ity associated with migraine [47, 48]. The NTG- from different doses of NTG used or difficulties
triggered migraine model has been used in mice in assessing cutaneous sensitivity in mice.
[49] and rats [50], and has been shown to produce An important caveat in the NTG animal model
migraine-associated photophobia and altered men- is that a high dose of NTG (10 mg/kg) is often
ingeal blood flow [51], and prototypic allodynia administered, which is substantially higher than
and hyperalgesia that have been shown to be allevi- the equivalent dose used in human migraine stud-
ated or reversed in rats or mice [14, 30, 52] by the ies [41]. It is possible that this high dose has
antimigraine medications that target the serotonin untoward physiological effects distinct from
system (i.e., triptans) and the CGRP system (i.e., those associated with migraine in humans.
CGRP receptor antagonist, olcegepant) [12, 50]. Despite the possibility for additional physiologi-
In order to better recreate CM, headache cal effects, high-dose NTG-induced hyperalgesia
researchers have adapted the acute NTG model to has been shown to be inhibited by systemic
examine chronic NTG effects on rodent pain sen- sumatriptan and topiramate, indicating that this
sitivity. The intermittent administration of NTG model may be used for screening potential
over several days has been shown to produce migraine prophylactics.
acute hyperalgesia following each NTG injection Another widely used animal model for study-
and a basal hypersensitivity that progressively ing CM is the aforementioned repeated dural
worsens over time [12, 13]. Repeated NTG injec- application of IS. A large body of evidence from
tions evoke mechanical hyperalgesia that was both animal studies and clinical observation sug-
blocked by sumatriptan and long-lasting basal gests that a sterile meningeal inflammation is a
hyperalgesia that was blocked by the migraine key mechanism that underlies the sustained acti-
prophylactic, topiramate. This chronic basal vation and sensitization of meningeal afferents
hypersensitivity was mediated by NO and cGMP during migraine attacks [34, 35]. In experimental
signaling pathways because this NTG effect was animals, activation of meningeal nociceptors
enhanced by the phosphodiesterase-5 inhibitor leads to the release of vasoactive proinflammatory
sildenafil [12]. The observed long-lasting basal substances such as CGRP from nerve endings,
hyperalgesia reported following repeated NTG which produces vasodilation of meningeal blood
injections is consistent with clinical observations vessels, plasma extravasation, and local activation
of people with CM that experience more allo- of dural mast cells and subsequent release of cyto-
dynia, or pain to previously innocuous stimuli, kines and inflammatory mediators [34]. Several
during and between migraine attacks. Additionally, early studies in rodents have shown that a single
women are more susceptible to developing CM, dural application of IS (i.e., histamine, serotonin,
and recent animal studies suggest that female bradykinin, prostaglandin E2) induces activation
rodents are more sensitive to repeated NTG than and mechanical sensitization of meningeal noci-
males: chronic basal hypersensitivity develops ceptors and central trigeminovascular neurons
faster in female mice [12, 53]. These results are [58, 59]. After brief local application of IS to the
noteworthy because NTG-triggered sexual dimor- dura, second-order trigeminovascular neurons in
phism in migraine-associated brain regions is the TCC showed long-lasting increased responses
related to estrogen levels, which further substanti- to innocuous mechanical or thermal facial skin
ates the chronic NTG model as a valid tool for stimulation, and third-order trigeminovascular
studying sex differences in migraine [12, 54]. neurons in the posterior thalamus showed long-
More detailed pharmacological value of this lasting sensitized responses to both cephalic and
model will be discussed later in the biochemical extracephalic skin stimulations [8, 31]. Recently,
mechanism section of this chapter. this single application IS model has been modi-
There are also conflicting reported effects of fied to assess CM, in which various research
systemic administration of NO donors on cutane- groups have developed a rat model of trigeminal
ous sensitivity, including a decrease [52, 55, 56] allodynia that closely mimics clinical observa-
or no change [57]. Those differences might stem tions in CM patients, characterized by chronic
trigeminal allodynia, photophobia, increased sen- CSD and Aura

sitivity to migraine triggers, and similar pain-
relieving responses to migraine treatments [10, Migraine symptoms include aura and severe
60, 61]. Using this rat model to deliver repeated headache. CSD is a slowly propagating depolar-
dural stimulation represents the recurrent episodic ization wave traveling at the speed around 3 mm/
nature of migraine attacks. After receiving five or min across the cortex followed by neuronal activ-
more infusions, similar to repeated NTG injec- ity suppression, which has been considered to
tions, the rats exhibit trigeminal hypersensitivity underlie migraine aura [62] and can potentially
at the baseline measure (prior to subsequent IS activate the trigeminovascular pathway through
application), which represents a transition from trigeminal nociceptors [63, 64].
an episodic to a chronic state of trigeminal sensi- One animal model shows CM manifestation
tivity. After eight to ten IS infusions, the rats tran- using repeated induction of CSD. For example,
sition to a state of chronic trigeminal sensitization, the frequency of CSD increased significantly in
where microdialysis in the TNC showed signifi- rats with seven daily intraperitoneal (IP) leptin
cantly increased levels of the excitatory neu- injections or in ZF rats. Therefore, the cortex
rotransmitter, glutamate, and sensitized behavioral tends to be more susceptible to CSD in chronic
responses that outlast the final infusion by as long hyperleptinemia [16]. This chronic hyperlepti-
as 3 months [10, 61]. nemia may inhibit the serotonergic system [65,
Particularly interesting is the opportunity to 66] and orexin-A secretion [67, 68], resulting in
utilize these CM animal models to investigate a CSD enhancement and therefore increasing corti-
controversial topic in the migraine field, the role cal susceptibility to migraine attacks by increas-
of blood-brain barrier (BBB) permeability during ing long-term potentiation [69] and inflammatory
both the episodic stage (following the second cytokines [70] and facilitating migraine chronifi-
infusion, when dural stimulation only features an cation [16]. Assessment of cortical depolariza-
acute effect on trigeminal sensitivity, but does not tion wave width has also been assessed in a rat
induce long-lasting sensitivity) and the chronic CM model [15].
stage (1 week after the tenth infusion, when the
animals have developed long-lasting trigeminal
sensitivity). It has recently been demonstrated Allodynia and Hyperalgesia
using the sodium fluorescein permeability assay
in many brain regions of the rats that during the The preclinical CM and chronic pain features
chronic stage, astrocyte and microglial activation, resulting from intrinsic neuronal hyperexcitability
BBB permeability, and trigeminal sensitivity include allodynia and hyperalgesia [11]. Allodynia
were increased but only in the TNC. Furthermore, is pain perception to normal tactile stimuli; hyper-
the tetracycline-derived antibiotic with anti- algesia is greater and longer pain perception or
inflammatory properties, minocycline, prevented hypersensitivity to noxious stimuli [71].
these chronic stage changes [61]. CM is a product of progression from epi-
sodic to chronic state. The risk factors associ-
ated with the progression have become an
Preclinical Behavioral increasing focus. The risk factors can reveal
Manifestations of CM Models (Aura/ CM mechanisms and provide knowledge to
CSD, Allodynia/Hyperalgesia, slow down or reverse migraine progression for
and Sensitivity to NTG) migraine management [1]. One of the important
factors being investigated is allodynia [1]. The
There are a few preclinical behavioral features prevalence of cutaneous allodynia is signifi-
that are used for evaluating animal CM model, cantly higher in CM than in episodic migraine
which include aura (CSD), allodynia and hyper- and higher in a migraine group than in other
algesia, and sensitivity to NTG. headaches including other chronic daily head-
aches and episodic tension-type headache [72, [80] and inhibition of descending pain inhibi-
73]. The severity of cutaneous allodynia is also tory controls [9] are also involved.
increased in CM relative to episodic migraine
[72, 74–76]. Cutaneous allodynia is an indica-
tor for CM [77, 78], which was found in more Hypersensitivity to NTG
than 70% CM patients [72, 75]. Thus, allodynia
can be a risk factor for transformation from epi- Besides being used as a CM trigger, NTG adminis-
sodic to CM [1]. Measurements of cutaneous tration has also been suggested for migraine diagno-
sensitivity can therefore help model migraine sis [81, 82]. For instance, repeated migraine attacks
transformation [13]. sensitize the human brain to exogenous NO [83].
Similar to CM patterns in human studies, Similar hypersensitivity to NTG was shown in
repeated dura nociceptive stimulation caused animals. For example, an animal CM model
maladaptive neuroplasticity in the form of long- induced by repeated IS application and low dose
lasting allodynia in the rat brain [10]. Single of NTG induce long-lasting decreased mechani-
high IS or repetitive low IS produces reversible cal threshold and long-lasting higher TNC gluta-
cephalic allodynia; repetitive high IS causes matergic transmission by microdialysis [10].
reversible cephalic and extracephalic allodynia; Greater NTG-induced hyperalgesia and reduced
and repeated high IS causes trigeminal neuronal CSD threshold have been observed in a transgenic
hyperexcitability and impairs descending pain mouse model of familial migraine, with mutation
inhibition, resulting in the development of cen- in the gene encoding casein kinase I delta [20].
tral sensitization and cutaneous allodynia and
potentially facilitating subsequent migraine
attacks and progression to CM [9, 10]. Repeat reatment Assessment Based
T
administration of the NO donor L-ISDN causes on the Symptoms
reversible cephalic cutaneous allodynia;
H-ISDN causes both cephalic and extracephalic Migraine phenotypic traits such as allodynia/
cutaneous allodynia, measured by von Frey fila- hyperalgesia have been used to evaluate treatment
ments [14]. Those findings are consistent with effects. For example, mechanical allodynia but not
migraineurs that do not have allodynia during thermal allodynia in CM was reduced after acute
early migraine stage but develop cephalic and occipital nerve stimulation (ONS), suggesting a
later extracephalic allodynia as migraine attack greater involvement of A-α−/β-fiber than C fibers
frequency increases [1]. [7]. Further details of pharmacological and non-
Animal studies on cutaneous hypersensitiv- pharmacological treatment are discussed below.
ity suggest that (a) the development of initial
allodynia resulted from sensitization of trigem-
inovascular neurons that innervate the menin- Electrophysiological Mechanisms
ges [32]; (b) the cephalic allodynia is related to and Non-pharmacological
sensitization of second-order trigeminovascu- Treatment
lar neurons in the TNC that receive sensory
input from both meninges and the scalp and Repeated nociceptive activation can cause long-
facial skin [79]; and (c) the extracephalic allo- lasting neuroplasticity, eliciting allodynia or
dynia results from sensitization of third-order hyperalgesia [71] that underlies the mechanisms
trigeminovascular neurons in the posterior tha- of migraine progression from episodic to
lamic nuclei that accepts sensory input from CM. The anatomical network described above,
the cephalic and extracephalic skin [8, 32]. especially the trigeminovascular pathway, pro-
Besides the trigeminal pain matrix, the activa- vides a structural basis for studying electrophysi-
tion of descending pain facilitation processes ological mechanisms and developing and
from the rostral ventromedial medulla (RVM) evaluating CM treatment.
Neuronal Hyperexcitability Evoked Potentials (EPs)
In addition to allodynia [30, 52, 79], another Although “lack of habituation” of EPs has been
important approach to study neuronal hypersen- considered as a biological hallmark of episodic
sitivity is to record neuronal excitability directly migraine during the interictal stage, and different
by electrophysiological techniques, such as mea- characteristics of EPs have been reported exten-
suring action potential and bursting activities sively in humans [88], studies about EPs in
using single-unit recording. For instance, in the migraine animal model are still very limited.
rat CM model induced by repeated epidural IM Brainstem auditory-evoked potential (BAEP) mea-
infusion, VPM neurons had higher firing fre- surements in a NTG-induced acute migraine model
quency and bursting activity than those in sham have similar findings in humans: prolonged BAEP
rats from facial mechanical stimulation [6]. later peak (waves 4, 5, and 6) latencies after NTG
Neuronal hypersensitivity underlies the allo- injection are consistent with abnormal monoami-
dynia symptoms. For example, rat trigeminovas- nergic transmission in upper brainstem [89, 90].
cular neurons from posterior thalamus receive This EP approach in animal models has great
convergent afferents from both cranial meninges potential clinical value for CM research, because
and the skin. These thalamic neurons were sensi- the measurements are non-invasive and are transla-
tized for cephalic and extracephalic innocuous tional/reverse translational to clinical CM studies.
and noxious stimulus after activation from dural
exposure to IS [8]. This is consistent with higher
posterior thalamic activation during migraine CSD
shown by fMRI [8]. Thalamic sensitization was
associated with activation of pain-facilitating As mentioned previously, the frequency of CSD
RVM “on” cells and suppression of RVM “off” events was used to monitor migraine progression,
cells [80]. which can be enhanced by chronic hyperlepti-
Botulinum neurotoxin type A (BoNT-A) is nemia [16].
the only approved prophylactic CM medication
[84, 85]. Electrophysiology techniques have
been used to explore the mechanism of BoNT-A reatment Using Electrophysiological
T
effects in dural application of IS [11]: when Approach
applied after dural application of IS, BoNT-A
reversed mechanical sensitization of meningeal The pharmacological CM treatment is challenging
C- but not Aδ-nociceptions; when applied and often refractory because of a limited effect and
before dural IS, BoNT-A prevented meningeal with many intolerable adverse effects [91].
nociceptive sensitization from IS [11]. Further, Medical treatments are less likely to work when
extracranial suture injection of BoNT-A to rats administered after the development of allodynia
inhibited trigeminal nerve nociceptive C-fiber and central sensitization [92]. However, neuro-
responses to meningeal chemical stimulation stimulation used after the development of allo-
through the capsaicin receptor TRPVI agonist dynia and central sensitization [92] has gained
(capsaicin) or a TRPAI agonist (mustard oil) increasing attention as an alternative technique
after 7 days: no effect was seen on C-fiber and has now been widely explored for the treat-
responses or mechanical/chemical responses on ment of CM [93, 94]. Neurostimulation has been
both C- and Aδ-fibers [86]. Those studies pro- applied to the central nervous system for pain
vide mechanistic support for BoNT-A’s prophy- modulation, either invasively (e.g., deep brain
lactic effect on CM, although no CM model was stimulation) [93], minimally invasively (e.g., sub-
involved [85, 87]. This is also a great example cutaneous occipital nerve stimulation) [93–97], or
of animal models used to compliment clinical noninvasively by transcranial direct current stimu-
applications. lation (tDCS), transcranial magnetic stimulation
(TMS), or transcutaneous nerve stimulation gests interaction of hormonal, inflammatory, and

(TENS) [98]. For example, ONS treatment signifi- GWAS variants but not neurotransmitters in
cantly reduced the higher firing and bursting activ- migraine [121]. However, both animal and human
ities of VPM neurons from the CM model induced studies have identified migraine-associated vari-
by multiple epidural IMs, but not from the sham ants regulating neurotransmitter pathways, pain-
rats [6], supporting the gate control by ONS, sensing pathways, synaptic function [122], and
where analgesic effects from nerve stimulation transmembrane remodeling enzymes [123]. In
work during pain states via gate mechanisms [6, FHM2 knock-in mouse model, there is evidence
99]. Another example, noninvasive vagus nerve of a link between female sex hormone cycle, glu-
stimulation (nVNS), was evaluated in patients tamate signaling, and psychiatric behaviors [124].
with CM using stimulation parameters based on
clinical studies [100] and preclinical models of
migraine [101, 102] and provided persistent pro- iscovery of Mechanism-Based CM
D
phylactic effect which was well tolerated and safe Therapy
[103]. In spite of the advantages of neurostimula-
tion treatment, and because of limited knowledge Examining the molecular mechanisms that may
of detailed mechanisms, pharmacological treat- underlie migraine pathophysiology has resulted
ments are still most commonly used in the clinic. in several pharmacological treatment strategies.
Animal models are extensively used to examine
pain syndromes (nociceptive, inflammatory
Biochemical Mechanisms pain, neuropathic pain), and similarities with
and Pharmacological Treatment migraine drug development have recently been
reviewed [125]. For example, migraine medica-
nimal Studies Reveal Molecular
A tions such as triptans [126, 127] were contrib-
Mechanisms uted by studies in animal models of migraine.
This has also recently been exemplified with the
The major hypothesized migraine mechanisms promising new migraine treatment that targets
involve primary CNS [104] changes associated CGRP using monoclonal antibodies where stud-
with neurotransmitters, neuropeptides, receptors ies progressed from preclinical animal studies to
and ion channels, and pumps and result in sus- currently ongoing clinical phase 3 human trials
ceptible individuals who are more sensitive to [128–130]. With several underlying mecha-
changes in physiological and environmental fac- nisms, animal studies suggest that poly-prophy-
tors [105]. Initiation of migraine attacks involves lactic or poly-therapies may be indicated to
CSD and activation of trigeminal nerves. At the manage CM, and these may also impact recog-
molecular level, neurotransmitters and neuropep- nized migraine comorbidities where similar
tides acting on their specific receptors are released pathways are altered. A mouse model for CM
upon nerve activation. Receptor-mediated signal- developed by chronic intermittent administration
ing events that may alter intracellular calcium or of NTG has been used to test preventive thera-
initiate the formation of mediators of inflamma- pies in male and female animals. This model has
tion accompany nerve activation in migraine. been shown and established to screen and test
Several episodic and CM (M/CM) animal models preventive CM treatment [12, 13]. Known acute
that relate to neurotransmitters or neuropeptide medication sumatriptan reduced the acute but
signaling pathways have resulted in preclinical not chronic hyperalgesia [12], consistent with
discoveries of migraine therapies (Table 21.2). sumatriptan unable to prevent migraine progres-
Since migraine pathophysiology involves the sion [131]; known preventive medication topira-
interaction of several molecules (Table 21.2), mate inhibited the acute and chronic hyperalgesia
readouts from animal studies can be used transla- [12]. The acute hyperalgesia and sustained basal
tionally to determine how these molecules affect hypersensitivity induced in the same CM model
humans. A multifocal study by Ghosh et al. sug- were blocked by known preventive medication
Table 21.2 Animal models, potential mechanism, and therapeutic significance in M/CM
Molecules Model and mechanism Migraine clinical significance
Neurotransmitters Rat microdialysis with dural inflammation and quantification of extracellular Increase in glutamate but no change in the excitatory amino acid
Serotonin, glutamate, concentrations of neurotransmitters [106]. Serotonin levels change in animal (aspartic acid) or the inhibitory neurotransmitters, gamma-
GABA, dopamine migraine models [107] aminobutyric acid, or glutamine, suggests that glutamate is
important in allodynia and hyperalgesia [106]. 5-HT receptor
antagonists have clinical utility in migraine [107]
Neuropeptides CSD induced by the application of KCl to the cortex increased CGRP Increased trigeminovascular nociception is associated with CGRP
CGRP, natriuretic Chronic paracetamol treatment enhanced CGRP [108] expression expression [108]
peptide bradykinin Natriuretic peptide P2X3 receptor inhibition
Neuromodulators Increases in rat brain sodium after NTG (IP) is associated with enhanced Specific Na+/K+-ATPase isoforms are targets for brain sodium
Cations (Na+, Ca2+) excitability [56] Localization of Na+/K+-ATPase isoforms in rat brain [109] regulation
NTG mouse model for mechanical hyperalgesia hypersensitivity [110] Sensitive to sumatriptan, hypersensitivity that is prevented by
Enhanced motor nerve Ca2+ influx through mutated Ca2+ presynaptic topiramate [110]
Ca2+v2.1 channels
Mediators of Production of prostaglandins in animal models NSAIDs that prevent prostaglandin production by inhibiting
inflammation Systemic NTG produces hyperalgesia in the rats 4 h after its administration cyclooxygenase are widely used in animal models
Prostaglandins, PAF, [111]. An inhibitor or fatty acid amide hydrolase had antinociceptive effects Pretreatment with endocannabinoid reduced nociception,
endocannabinoids and blocked NTG-induced hyperalgesia [112] hyperalgesia, and neuronal activation [111]
Hormones, estrogen Sex and estrogen influence neuronal activation in NTG-treated rats [54] Gender differences call for customized therapies
Changes in female hormones modulates CSD in mice [113]
Medication (triptan) Lower CSD threshold, reduced Fos expression, deranges 5HT modulating Triptan overuse effects are reversed by topiramate [115]
overuse headache pathways [114]
(MOH)
Receptor-mediated CM rat model of repeated infusion of inflammatory soup increased protein PKC gamma inhibition reduced phosphorylation of GluT1 and
signaling pathways kinase C gamma. PKC gamma activation increased CGRP and Fos [116] allodynia [116]
Involvement of phosphorylated extracellular signal-regulated kinase PTEN and many signaling pathways affected in M/CM are
(p-ERK), CGRP, and cyclooxygenase-2 (COX-2) in pain and nociceptive promising therapeutic targets [120]
21 Animal Models in Chronic Daily Headache (CDH) and Pathophysiology of CDH
pathways [117, 118], brain-derived neurotrophic factor (BDNF),

tropomyosin receptor kinases (TrkB), and c-AMP-responsive element-
binding protein (CREB) [118]. Activation of PI3-K/PTEN pathway [119]
299
propranolol (β-blocker), while valproate had no agonist (triptans) or CGRP receptor antagonist
effect [13]. Amiloride inhibited NTG-induced (gepants) is developed from animal models;
hyperalgesia; memantine was ineffective, while mechanisms of prophylactic medication topira-
administration of sumatriptan did not alter NTG- mate are explored in animal models, leading to its
induced hyperalgesia but resulted in acute and improved prophylactic applications in clinical
chronic hyperalgesia [13]. These studies estab- applications [134]. Those are positive transla-
lish the repeated NTG-induced CM model as a tional examples for CM preclinical studies, in
tool for verifying potential mechanisms and test- addition to reverse translational applications of
ing migraine-preventive therapies. Therefore, biochemical and pharmacological treatment.
animal models can have both translational and
reverse translational values for CM studies.
Medication overuse headache (MOH) typi- Genetic Models
cally occurs in genetically susceptible individuals
suffering from migraine or tension-type head- Four genes implicated in familial hemiplegic
ache. Excessive use of headache medications, i.e., migraine (FHM-1 to FHM-4, reviewed in [135–
triptans or opioids (more than 10 days/ 137]) represent models to investigate the role of
month/>3 months), leads to a gradual exacerba- specific genes in FHM. The next seven murine
tion of episodic migraine frequency, transforming mutants include models that demonstrate a lower
the individual into a chronic headache sufferer. threshold for central sensitization and/or sensory
This condition has recently been examined in ani- nociception that are surrogate analogues for
mal models with repeated administration of migraine. Finally, an inherited cranial nocicep-
migraine-relieving drugs (e.g., sumatriptan) tive trait in SD rats is included; while no gene
which resulted in enduring central sensitization, locus or linkage has been identified, this approach
measured by increased cutaneous allodynia, and has potential to investigate a more natural
increased susceptibility to CSD, similar to that migraine-type predisposition that is distinct from
after repeated NTG application, consistent with transgenic mice models.
MOH [13, 115, 132]. The pathophysiology and FHM-1 is present in about 50% of FHM
mechanisms of MOH are also explored: Fos patients: two mice models have been developed
expression in TNC of sumatriptan-treated rats from the knock-in of human mutations R192Q
was reduced by topiramate, suggesting that the [17] or S218L [138] that are encoded in the α1
underlying mechanism of triptan-induced MOH subunit of the voltage-gated Cav2.1 Ca2+ channel
involved increased activation of TNC [115]; the CACNA1A. The homozygous R192Q mice have a
humanized CGRP antibody (TEVA 48125) has milder phenotype in both humans and mice, and
been shown to reduce NO- and stress-mediated the mice were shown to have a reduced threshold
reinstatement of allodynia in a sumatriptan MOH and increased velocity of CSD, widely considered
model [133]. In addition to the TNC, chronic to be the neurophysiological correlate of the
medication overuse affects several brain regions migraine aura. R192Q mice had gain-of-function
related to headache pathology. In addition to the effects in the CACNA1A channel’s current density
upregulation of CGRP, substance P, and NO syn- and enhancement of neurotransmission at the neu-
thase and increase in the receptive field, the main romuscular junction, and the CSD effects enhanced
mechanism underlying headache chronification circadian phase resetting and potentiated trigemi-
seems to be the derangement of 5-HT-dependent nal nociception [17, 139–147]. These studies
signaling pathways [114]. reveal inflammatory, receptor, channel, signaling,
To summarize, animal models provide knowl- and calcitonin G-related peptide (CGRP) roles in
edge bases for exploring migraine biochemical FHM-1 [17, 139–147]. The S218L mice have a
mechanisms and developing antimigraine phar- more severe phenotype, similar to humans. S218L
macological treatment options. For example, cur- mice have a gene dosage effect where the homozy-
rent rescue medication for CM such as serotonin gous state is often lethal [138, 148].
FHM-2, present in about 25%V of FHM dala and piriform cortex [19]. A dysfunction in
patients, is based on mutations in the α2 isoform the removal of neurotransmitters from synapses
of the ATP1A2 gene for the Na+/K+-ATPase. This could be the underlying cause of neuronal hyper-
isoform is expressed in the brain predominantly activity and of the observed neurodegeneration in
in astrocytes [18] but also in the epithelial cells of the amygdala and piriform cortex. Uptake of glu-
the choroid plexus [109]. Only heterozygous tamate and GABA into crude synaptosome prep-
knock-in or knockout mice are viable, as homo- arations from α2−/− fetuses was impaired
zygous animals die around birth, probably from compared to WT preparations, and consequently,
respiratory failure [149]. both glutamate and GABA levels were increased
Heterozygous knock-in of either of the human in brains from α2−/−fetuses relative to WT litter-
α2+/R887 or α2+/G301R mutations leads to a reduced mates [19]. We suggest this is an interesting ana-
induction threshold and increased propagation logue of the altered amygdala reports in migraine
velocity of CSD [18] resembling the effect of the [19, 54, 151, 152].
human FHM-2 mutations. The varying pheno- Further evidence of a role for the Na+/K+-
type from both of these knock-in mutations has ATPase α2 isoform in the animal migraine ana-
the commonality of altered CSD with a greater logue comes from our recent studies where we
effect in females, which are notable features of found that α2+/− mice have reduced mechanical
migraine. Features of these mice are reminiscent aversive threshold to von Frey hairs and increased
of some other migraine behaviors: α2+/R887 mice c-Fos immunoreactivity in the TNC [153].
had minimal clinical alteration with elevated fear FHM-3 (the voltage-gated sodium channel
response and increased anxiety on SHIRPA pro- SCN1A, Nav1.1) mutations are much less com-
tocol assessment; α2+/G301R mice had depression- monly found in FHM, when these SCN1A mice
like behavior, such as increased immobility have been studied for their prominent epilepsy
compared to WT mice [124] and displayed stress- syndromes thus far. A principal mechanism for
induced anhedonia and increased acoustic startle the effect of SCN1A mutations on lowering the
responses, implying abnormal levels of fear and epilepsy threshold is from loss of function in
anxiety. Females but not males were hypoactive inhibitory neurons, which may illuminate
in the open field test with excessive grooming migraine phenotype studies [154–156].
and compulsive behaviors: female α2+/G301R mice FHM-4 (proline-rich transmembrane protein
buried significantly more marbles compared to 2, PRRT2) mutations are found in the majority of
both WT and male α2+/G301R mice [124]. patients with benign familial infantile epilepsy,
Heterozygous knockout of the ATP1A2 gener- infantile convulsions and choreoathetosis, and
ated α2+/− mice models, which displayed increased paroxysmal kinesigenic dyskinesia but more
fear and anxiety as the main abnormal behavioral recently with FHM [157]. PRRT2 knockout mice
phenotype [19, 149, 150]. Compared to WT lit- have been recently reported [158] and display
termates, α2+/− mice spent less time in the paroxysmal neurological features with increased
illuminated room during the light/dark test, and sensitivity that include jumping in response to
the latency to enter the illuminated room was also sounds that are not displayed in the WT.
significantly higher [19], suggesting increased Additional genetic models that resulted in
fear and anxiety behaviors. We suggest this result reduced CSD threshold or increased CSD include
also represents behavior analogous to the light casein kinase Iδ (CKIδ) [20], neurogenic locus
sensitivity of migraine. In the open field test, α2+/− notch homolog protein 3 (Notch 3) [21], or the
mice were found to be less active compared to ligand-gated cation channel receptor P2X7
WT mice [149], a commonly used indicator of [22]. CGRP receptors are overexpressed and
enhanced fear behavior [149]. c-Fos expression sensitized in a mice model with genetic manipu-
was elevated in the amygdala and piriform cortex lation of the gene nestin/human receptor activity-
in adult α2+/− mice after conditioned fear stimuli, modifying protein-1 (hRAMP1) [23].
indicating neuronal hyperactivity in the amyg- Migraine-susceptible genes associated with tri-
geminal nociception include acid-sensing ion tional circuits that can be important in some
channel 1 (ASIC1) [24] and transient receptor subpopulations with CM.
potential M8 (TRPM8) [25–28]. 6. CM comorbidities are complex and difficult to
Neurofibromatosis type 1 (NF1) is linked to replicate in animal models.
inactivating mutations or homozygous deletion 7. Several potential medications (such as sub-
of the NF1 gene, with numerous effects including stance P antagonists) have failed in clinical
migraine and pain. Moutal and colleagues dem- trials in spite of strong animal model support
onstrate a peptide, t-CNRP1, that mimics the [160, 161].
antinociceptive signaling of neurofibromin, the 8. Some treatment approaches, such as mindful-
NF1 translated protein, and reduces in vivo ness-based training that is effective in CM
responses to noxious stimuli [29]. patients [162], cannot be studied in animal
Genetic effect in rats is recognized but not yet models.
localized. Oshinsky and colleagues [30] reported
individual Sprague-Dawley rats that were inter-
mittently and spontaneously more susceptible to Summary and Conclusion
mechanical trigeminal (periorbital) aversive noci-
ception. This allodynia was reversed by rescue or CM has a complex underlying pathophysiology
prophylactic antimigraine medications and, on the that is not easily unraveled by a single animal
other hand, triggered with NTG or CGRP. They model. Several important animal models involv-
reported that this trait was maintained in breeding. ing NTG sensitization, application of inflamma-
While not yet identified, a rat model of migraine tory agents, or genetic manipulations are revealing
would have great value in further identifying the complex molecular abnormalities that contribute
genetic factors involved in migraine. to the CM mechanisms. Various models reveal
molecules/signaling pathways and putative mech-
anisms with potential therapeutic significance
Limitations of CM Animal Models (Tables 21.1 and 21.2). Animal models have not
always led to successful translation in humans.
While animal models have revealed CM patho- Animal models cannot replace the study and treat-
physiology, identified novel therapeutic targets, ment of migraine. However, their undisputed util-
and estimated treatment effects, there are several ity means that animal models are unraveling
limitations: disease mechanisms and contributing to the devel-
opment of therapeutic tools with translational
1. Pain is a subjective and complicated experi- implications and will eventually guide the dire
ence with sensory, emotional, and cognitive need for personalized therapies [123, 163].
components that are difficult to replicate in
animal models.
2.
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Economic Impact of Chronic
Headaches 22
Anna Pace
Chronic daily headache has been reported to headaches are a common reason for patients to
affect 3–4% of the adult and elderly population seek medical help.
of the world [1]. Chronic daily headache com- There have been two major studies looking at
prises a heterogeneous group of various headache the cost and economic burden of chronic migraine
types, where patients report 15 days or more out in the USA, Europe, and throughout the world.
of every month with headache for at least 3 The first study was the American Migraine
months. The majority of patients with chronic Prevalence and Prevention Study, or AMPP, initi-
daily headache meet the criteria for chronic ated in 2004 and surveyed over 120,000 house-
migraine, and/or medication overuse headache, holds for patients who self-reported chronic
but other headache disorders included in this severe headache [3]. Using ICHD-2 criteria,
group are chronic tension-type headache, chronic patients were categorized as having either epi-
trigeminal autonomic cephalgias, and new daily sodic migraine (EM) or chronic migraine (CM)
persistent headache [1]. based on reported frequency. After this first
Chronic daily headache causes a significant screen, patients were then surveyed regarding
degree of disability in many patients and is an other variables, including primary care visits,
important public health concern, as chronic daily emergency room visits, neurologist or headache
headaches often affect young and middle-aged specialist outpatient visits, pain management vis-
patients at the time of their prime productivity its, medication use, and overnight hospitaliza-
[2]. Primary headaches are prevalent, and even tions. Participants were also surveyed about
the smallest economic loss for a patient suffering “productivity loss,” where patients had to report
from chronic headaches, whether due to increased the number of days in the prior 3 months where
healthcare utilization or due to lost productivity they missed work or school, and how many days
at work or school, can have a significant impact their productivity at work or school, was reduced
on both the patient and the economy. Much of the by more than half, or 50%, on the days they had
literature evaluating the economic burden of headache. Cost assumptions were made based on
chronic daily headache focuses on chronic healthcare and medication use and productivity
migraine and/or medication overuse headache loss based on a PharMetrics Patient-Centric data-
related to chronic migraine, as migrainous base and allowed amounts per diagnosis code [3].
Results showed that those who suffered from
chronic migraine had more primary care visits,
A. Pace neurologist or headache specialist visits, pain
Department of Neurology, Icahn School of Medicine
at Mount Sinai, New York, NY, USA management visits, and ER visits, compared to
e-mail: anna.pace@mssm.edu those with episodic migraine. The mean number

310 A. Pace
of hours lost from work or school due to chronic the UK, France, Spain, the USA, and Canada.
migraine was 85.7 h per person per year, and the Acute medication use was statistically signifi-
mean number of hours with reduced productivity cantly higher in patients with CM only in Italy
due to headache was 256 h per person per year (56.4% in patients with CM vs. 35.5% in patients
[4]. Patients with chronic migraine incurred a with EM), and prophylactic medication use was
mean yearly cost of $7750 per person per year, higher in patients with CM in Spain, the USA,
including both direct and indirect costs, com- and Canada. Direct costs related to chronic
pared to $1757 in costs incurred by those patients migraine estimated by the IBMS are reported to
whose migraines are episodic [3]. The research- be approximately three times that of the direct
ers’ analysis showed that the majority of the total costs related to episodic migraine, with the big-
costs incurred by the patients were due to lost gest difference in costs seen in the UK, where
productive time at work or school (69.6%, or esti- patients with CM incurred a 3.6-fold higher cost
mated $5,392.03 per year, out of $7750) [3]. than patients with EM [5–7].
The second study examining the economic The IBMS researchers found that patients
impact of chronic migraine was the International with CM had an estimated overall productivity
Burden of Migraine Study, which utilized a web- loss of 67.67 days over a 3-month period, whereas
based questionnaire to recruit patients with epi- patients with EM had an estimated productivity
sodic migraine and chronic migraine in North loss of 13.57 days per 3-month period. There is a
America, Germany, France, Italy, Spain, the UK, high rate of disability seen in patients with CM
Australia, Taiwan, and Brazil [5–7]. The two-part throughout the various participating countries,
screen included surveying participants recruited with CM sufferers noted to be less likely to be
through a portal of registered panelists who were employed full time than those with EM, espe-
willing to fill out health surveys and, then based cially in the USA [5–7]. The US data for the
on their responses to the main survey about head- IBMS study showed that total annual cost for
ache and frequency, were categorized as having people with chronic migraine is $8243 compared
either episodic migraine or chronic migraine; a to people with episodic migraine, who incur an
similar distinction was made in the AMPP study annual cost of $2649 [4]. Contrasting to findings
mentioned previously. The second part of the in AMPP, direct medical costs were considered to
administered survey involved a 70-item question- be the majority contributor to total headache-
naire to elucidate healthcare usage, costs, socio- related costs for both those with CM (60%) and
economic information, and disability or quality for those with EM (64.3%) [5–7]. This data, col-
of life related to migraine. Costs were estimated lected over many participating countries, sug-
based on each country’s national formulary sys- gests that the economic burden of chronic
tems with the exception of Italy, which utilized a migraine is a significant worldwide problem.
private site for healthcare professionals to esti- Very few studies have looked specifically at
mate healthcare and medication costs [6]. the economic burden of chronic tension-type
The IBMS researchers showed that those headaches, though one report from a study in
patients with chronic migraine utilized healthcare Turkey compared the economic impact of pri-
resources significantly more than those patients mary chronic migraine as opposed to chronic
who had episodic migraine throughout all of the tension-type headache at university-based hospi-
countries participating in the study. This includes tals [8]. In the study, published in the Journal of
more primary care visits and neurologist outpa- Headache and Pain in 2006, 937 patients were
tient visits, as well as emergency department vis- recruited, and patients were categorized by pri-
its, though inpatient hospitalizations were only mary headache disorder based on ICHD criteria.
found to be higher for patients with CM in the Participants were then surveyed regarding the
UK and not in the other participating countries frequency of headache, frequency of medication
[5–7]. More diagnostic testing was performed for use, and outpatient or hospital visits for headache
patients with CM compared to those with EM in [8]. Costs were estimated based on physician
22 Economic Impact of Chronic Headaches 311
costs for outpatient visits and medication costs in References

relation to monthly average analgesic consump-
tion and preventive medication use. Indirect costs 1. Lanteri-Minet M, Duru G, Mudge M, Cottrell
S. Quality of life impairment, disability and eco-
were calculated based on mean loss of days at nomic burden associated with chronic daily head-
work or efficiency loss, and the minimum wage ache, focusing on chronic migraine with or without
of $14.08 USD was used in the calculations for medication overuse: a systematic review. Cephalalgia.
lost work days [8]. The ratio of total cost per 2011;31(7):837–50.
2. Lanteri-Minet M. Economic burden and costs
headache patient was compared to the GNP for of chronic migraine. Curr Pain Headache Rep.
Turkey per capita to calculate the ratio of costs to 2014;18:385.
average income. Researchers found that patients 3. Munaka J, Hazard E, Serrano D, Klingman D, Rupnow
with migraine (with or without aura) had the MFT, Tierce J, Reed M, Lipton R. Economic burden
of transformed migraine: results from the american
highest mean direct costs, at $250 and $225.60, migraine prevalence and prevention (AMPP) study.
respectively, per year [8]. Patients with chronic Headache. 2009;49:498–508.
tension-type headache had a mean total direct 4. Messali A, Sanderson JC, Blumenfeld AM, Goadsby
cost of $104.80 per year, with medication use P, Buse D, Varon SF, Stokes M, Lipton R. Direct
and indirect costs of chronic and episodic migraine
being the primary driver of costs incurred by in the United States: a web-based survey. Headache.
these patients [8]. Patients with chronic daily 2016;56:306–22.
headache, either tension type or migraine, or 5. Bloudek LM, Stokes M, Buse DC, Wilcox TK, Lipton
patients with both, had the most work days lost RB, Goadsby PJ, Varon SF, Blumenfeld AM, Katsar
Z. Cost of healthcare for patients with migraine in
due to headache, with more days of reduced effi- five European countries: results from the International
ciency per year, compared to episodic headache Burden of Migraine Study (IBMS). J Headache Pain.
syndromes [8]. While the total direct cost for 2012;13:361–78.
patients with chronic tension-type headache is 6. Stokes M, Becker WJ, Lipton RB, Sullivan SD, Wilcox
TK, Wells L, Manack A, Proskorovsky I, Gladstone
lower than that for chronic migraine in this J, Buse DC, Varon SF, Goadsby PJ, Blumenfeld
Turkish population, these results still emphasize AM. Cost of health care among patients with chronic
the significant economic burden of chronic daily and episodic migraine in Canada and the USA: results
headache. from the International Burden of Migraine Study
(IBMS). Headache. 2011;51:1058–77.
Chronic headache is a major public health 7. Blumenfeld AM, Varon SF, Wilcox TK, Buse
problem, not just in the USA but around the DC, Kawata AK, Manack A, Goadsby PJ, Lipton
world. Research has continued to show that RB. Disability, HRQoL and resource use among
chronic headaches, especially chronic migraine, chronic and episodic migraineurs: results from the
International Burden of Migraine Study (IBMS).
take a large economic toll on worldwide health- Cephalalgia. 2011;31(3):301–15.
care systems and especially on patients who suf- 8. Karli N, Zarifoglu M, Ertas M, Saip S, Öztürk V,
fer from them, whether through direct medication Biçakçi S, Boz C, Selçuki D, Oguzhanoglu A, Neyal
use costs, or costs of specialist visits, or indirectly M, Siva A, Irkeçk C, Kaleagasi H, Kansu T, Sarica
Y, Tasdemir N, Uzuner N. Economic impact of pri-
by affecting productivity and efficiency at work mary headaches in Turkey: a university hospital based
or school. study: part II. J Headache Pain. 2006;7:75–82.
From Episodic to Chronic:
A Discussion on Headache 23
Transformation
Anna Pace and Bridget Mueller
“Chronic daily headache” (CDH) encompasses of their headaches. These patients have this pro-
various headache syndromes, including chronic gression over at least 3 months, to result in daily or
migraine, chronic tension-type headache, hemi- almost daily head pain for greater than 1 months’
crania continua, and new daily persistent head- time [1]. The group then subdivides into those with
ache. While there are some patients who initially or without medication overuse: medication overuse
present with a primary chronic daily headache, is defined as involving simple analgesic use >5
most patients begin with episodic headache and days a week, combination analgesic use >3 days a
then progress, or transform, into chronic head- week, or using narcotics at least 2 days a week for
ache over time. Chronic daily headache has been >1 month [1]. For chronic tension-type headache,
reported to affect 3–4% of the population world- which often evolves from episodic tension-type
wide, and patients with CDH represent a signifi- headache, Silberstein et al. proposes criteria to
cant number of referrals to tertiary care centers include an average headache frequency of more
for headache. Chronic daily headache can lead to than 15 days a month with the duration of each
a significant degree of disability in many patients, attack lasting longer than 4 h a day, for 6 months’
especially when affecting young patients in the time [1]. Patients should have a history of episodic
prime of their workforce capabilities. tension-type headache in the past, with an evolu-
According to proposed criteria by Silberstein tion of their headaches increasing in frequency
et al. in 1994, used frequently by headache special- over a 3-month period; headache should involve a
ists, chronic headache can be subdivided into four bilateral pressing/tightening type pain and associ-
entities—transformed migraine (TM), chronic ten- ated with no more than one of nausea, photopho-
sion-type headache (CTTH), hemicrania continua bia, or phonophobia, and no vomiting. CTTH is
(HC), and new daily persistent headache (NDPH) also subdivided into patients with or without medi-
[1]. Transformed migraine is found in patients who cation overuse, as previously described with
previously had a history of episodic migraine but TM. Hemicrania continua is defined as a strictly
have experienced more frequent attacks over time unilateral headache present for at least 1 month,
and whose nausea, vomiting, photophobia, and with continuous pain that may have “jabs and jolts”
phonophobia have become less prominent features superimposed, and may be associated with or with-
out medication overuse. It has no precipitating
mechanisms and is often unremitting [1]. New
A. Pace (*) · B. Mueller daily persistent headache is described as a head-
Department of Neurology, Icahn School of Medicine
ache that is acute on onset and is constant and unre-
at Mount Sinai, New York, NY, USA
e-mail: anna.pace@mssm.edu; mitting, for >15 days a month for at least 1 month,
bridget.mueller@mountsinai.org and patients with NDPH do not have a previous

314 A. Pace and B. Mueller
history of migraine or tension-type headache that and CSF nitrites, as well as subsequent increases in
has increased in frequency or decreased in severity CSF cyclic guanosine monophosphate compounds
over the past 3 months [1]. The focus of the follow- (cGMP), in patients with chronic daily headache
ing discussion will be primarily transformed compared to healthy controls [3]. These findings
migraine and chronic tension-type headache. help support the theory that the release of gluta-
mate and nitrous oxide may play a role in chronic
daily headache development. Substance P and cal-
athophysiology of Chronic
P citonin gene-related peptide (CGRP) were also
Headache found to be elevated in measured CSF samples of
patients with CDH, though the study researchers
Serotonin Receptors did not find a relationship between these levels and
that of the elevated levels of glutamate and nitrites
The pathophysiology of headache transformation [3]. The study investigators propose in patients
is not completely well understood, but there have with chronic daily headache that there is activation
been proposed mechanisms of this headache proof NMDA and other non-NMDA receptors, which
cess. One study published in Headache in 1994 results in the release of glutamate and production
proposed that an upregulation of 5HT-2 serotonin of NO species that contribute to central sensitiza-
receptors may be implicated in transformed tion, with the subsequent release of cGMP correlat-
migraine [2]. This study, which looked at six ing with sustained nociception [3].
patients with transformed migraine and seven
controls, measured the 5HT-2 serotonin receptors
on platelet membranes and found a significant alcitonin Gene-Related Peptide
C
increase in the maximal number of receptors on (CGRP)
the platelets in migraineurs compared to the con-
trol patients [2]. The researchers deduced that, Calcitonin gene-related peptide (CGRP) has also
since there is a significant similarity in receptor been implicated in headache chronification. In a study
characterization between platelet membranes and conducted by researchers in Spain and published in
aminergic neurons, it could be postulated that Neurology in 2013, women with episodic migraine
aminergic neurons would also have higher levels and women with chronic migraine underwent testing
of serotonin receptors. This was suggested to play to determine CGRP levels in the blood interictally
a role in transformed migraine, as patients with between migraine attacks [4]. These patients were
episodic migraine have a decrease in 5HT-2 compared to healthy controls and patients with epi-
receptors on platelets during periods of headache sodic cluster headaches. Results showed that the
freedom. Therefore, the increase in receptors may women with chronic migraine had significantly
contribute to the lack of pain freedom in patients higher levels of plasma CGRP compared to women
with transformed migraine. The researchers also with episodic migraine, women with episodic cluster,
postulated that the increase in serotonergic recep- and women who were in the healthy control group
tors may be due to “serotonergic hypofunction,” [4]. These levels were not affected by rescue medica-
whereby there is a hyposecretion of serotonergic tion use, comorbid psychiatric conditions, vascular
vesicles presynaptically which leads to decreased risk factors, or age [4]. Researchers hypothesize that
serotonin levels over time and results in the upreg- the presence of persistently elevated CGRP levels
ulation of postsynaptic serotonergic receptors [2]. may be a marker for headache chronification.
CSF Glutamate Genetics
Researchers Gallai and colleagues in 2003 found There are suggestions in the literature that there
that there were elevated levels of CSF glutamate may be underlying genetic predispositions to
23 From Episodic to Chronic: A Discussion on Headache Transformation 315
headache chronification, though there have been days per month) [6]. The mothers of the partici-
no concrete studies evaluating specific gene pat- pants were also surveyed with the same question-
terns implicated in chronic daily headache. One naire and divided into the same frequency
study by Cevoli and colleagues in 2008 evaluated categories. Analyses found that if the mother was
family history for chronic headache and family classified as having low-frequency headache, the
history of drug overuse as possible contributors prevalence of low-frequency headaches in the
to headache transformation in patients [5]. One children was 27.3% and the prevalence of inter-
hundred five patients with chronic headache, mediate-/high-frequency headache was 4.8%,
either with tension-type (CTTH), chronic with the prevalence of CDH at 0.6% [6]. If the
migraine (CM), or with medication overuse mother had high-frequency headaches, the preva-
headache (MOH), were interviewed directly by lence of high-frequency headaches in the chil-
investigators about family history of headache, dren was 16.1%, and the prevalence of CDH in
psychiatric disorders, and substance abuse or the children was 1.3% [6]. If the mother had
dependence. Patients were asked to provide CDH, the prevalence of intermediate-/high-fre-
details about their first-degree and second-degree quency headaches in the children was 15.8%, and
relatives regarding timing and onset of headache the children were found to have a 12-fold
and headache frequency, substance use, and his- increased risk of CDH, compared to children of
tory of psychiatric disorders, the latter two being mothers with low-frequency headaches [6].
classified by DSM-IV criteria [5]. Researchers While this study is not able to provide definitive
found that 38.1% of patients with chronic head- evidence that CDH is genetic, the results imply
ache reported a family history of chronic head- some inheritable basis for headache chronifica-
ache, compared to only 13.7% of patients with tion in families [6].
episodic headache reporting a family history of
chronic headache. Patients with chronic head-
ache also reported an increased family history of Quality of Life in CDH
medication overuse and substance abuse than
those patients with episodic headache, but there When looking at quality of life for patients with
was no significant difference noted in family his- episodic migraine versus chronic migraine,
tory of psychiatric disorders when compared Meletiche et al. studied a group of 90 migraineurs
between the two groups. History was not distin- by administering questionnaires including the
guished between first-degree and second-degree Short Form 36 (SF36) and the Migraine Disability
relatives for the participants in the study. Assessment (MIDAS) [7]. These questionnaires
Investigators postulate, due to the high family look to quantify various domains of quality of
history of chronic headache in patients with life in these migraine patients, including assess-
chronic headache, that there may be an underlying social functioning, general health, mental
ing genetic etiology or predisposition that may health, vitality, physical functioning, and bodily
contribute to chronification of headaches [5]. pain. When patients were grouped by ICH-D cri-
Another study in 2010 by Arruda, Bigal, and teria as episodic migraine or transformed
others surveyed 1994 children with headache to migraine (the latter following proposed criteria
determine if maternal headache history and fre- by Silberstein et al. [1]), the researchers found
quency could predict the frequency of headaches that patients with transformed migraines had sig-
in the pediatric participants [6]. Participants, ages nificantly lower scores on seven out of the eight
5–12, were chosen based on their headache fre- tested domains on the SF36 assessment and
quency as reported by their mothers, and divided significantly higher scores on the MIDAS com-
into low frequency (1–4 headache days per pared to patients with episodic migraine [7].
month), intermediate frequency (5–9 headache There is a significant economic burden of
days per month), high frequency (10–14 head- transformed migraine when compared to epi-
ache days per month), and CDH (15+ headache sodic migraine. According to the American
Migraine Prevalence and Prevention Study pies showed improvement in headache frequency,
(AMPP), those migraineurs with transformed duration, and intensity [10]. The effectiveness of
migraines utilize more primary care and neurolo- detoxification was again demonstrated in a con-
gist outpatient visits, visiting emergency rooms trolled open-label trial that randomized chronic
more frequently, and incurred a 4.4-fold higher headache patients to either complete detoxifica-
cost annually compared to patients with episodic tion or restriction to medication 2 days per week
migraine, and this cost includes both direct and [11]. Patients who stopped all acute pharmaco-
indirect costs [8]. Patients with TM had more therapy interventions experienced twice as many
missed days at work or school due to their daily headache-free days per month compared to
pain and were less productive when able to attend patients who decreased medication usage to the
work or school compared to patients with epi- recommended frequency of two to three times
sodic migraine [8]. per week. In addition, 70% of detoxified patients
This important data suggests that chronic reverted to episodic headaches, while only 42%
headache, and specifically transformed migraine, of restricted patients reverted [11].
is a major public health problem [8]. With the Not all drugs are created equal. Barbiturates
report of decreasing quality of life and an and opioids increase the risk of transformation to
increased economic burden in patients with trans- chronic migraine by at least twofold, at any fre-
formed migraine, it is evident that neurologists quency of use [12]. Barbiturates exhibit a dose-
should look to identify risk factors for headache response effect, with the heaviest users
chronification and attempt to prevent this pro- experiencing progression from episodic head-
gression by helping to modify those risk factors. aches to chronic headaches most frequently.
The transformation from episodic headache into These effects persisted after adjusting for head-
a chronic headache disorder likely involves both ache severity. Triptans did not increase transition
an underlying genetic vulnerability and specific to chronic headache. Interestingly, NSAID use
environmental risk factors. Medication overuse, was associated with a decreased risk of headache
obesity, sleep disturbances, stress, depression, progression in patients with low frequency of
and menstrual-related migraines have been headaches and an increased risk of headache
shown to be potent triggers for headache progression in patients with high-frequency
progression. attacks [12, 13].
Risk Factors for Transformation Obesity
Medication Overuse Obesity dramatically increases the risk of epi-

sodic migraines progressing to chronic daily
Patients with chronic daily headache disorders headaches. In a longitudinal population study
are often self-medicating at frequencies that that followed episodic migraineurs over 1 year,
qualify as overuse. Population studies estimate obese migraineurs (BMI > 30) had a five-fold
~30% of patients with transformed migraine is increased risk in headache transformation, while
overusing pain-relieving medication [9, 10]. At overweight individuals (BMI 25–29) had a three-
headache tertiary centers, 80–85% of patients are fold increased risk of headache transformation
overusing medication at time of presentation [14]. The episodic migraineur and episodic
[10]. chronic tension-type headache patient are not
“Detox studies” have shown that medication affected by obesity equally. While even modest
overuse is often a reversible cause of headache weight gain significantly increases the risk of
transformation. In a large retrospective study, developing a transformed migraine, only morbid
patients with chronic migraine and medication obesity increases the risk for progression to
overuse who stopped all acute pharmacothera- chronic tension-type headache [15, 16].
The pathophysiology underlying the associa- relationship between poor sleep and the develop-
tion between obesity and headache transforma- ment of chronic migraine [21]. Interestingly, the
tion is likely multifactorial. It is well established degree of improvement in headache symptoms
that both migraine and obesity share a pro- was proportionate to the number of sleep behav-
inflammatory state. In addition, the hypothala- iors changed, further supporting a causal link
mus and its associated peptides and between poor sleep and the development of a
neurotransmitters including 5-HT, adiponectin, chronic headache disorder.
and leptin play critical roles in headaches and The importance of screening headache patients
energy balance. Interestingly, in addition to for obstructive sleep apnea (OSA) has been high-
migraineurs having increased serum levels of lighted by several studies [22, 23]. A retrospective
leptin and adiponectin compared with healthy study examining the prevalence of OSA in
controls, chronic migraineurs have increased patients with various headache disorders found
leptin and adiponectin compared to episodic 83% of chronic migraine patients without aura
migraine patients [17]. suffered from OSA while 50% of episodic
Studies performed in obese migraineurs who migraineurs suffered from OSA [22]. Overall,
underwent bariatric surgery suggest weight chronic migraineurs without aura were 20 times
reduction is an effective way to decrease head- more likely to have OSA than patients with other
ache frequency in chronic migraine patients. headache types including tension-type and epi-
Three months following surgery, five of the six sodic migraines. The effectiveness of continuous
chronic migraineurs reported at least a 50% positive airway pressure (CPAP) to improve head-
reduction in headache frequency [18]. Additional aches was examined. Almost half of the chronic
studies are needed to replicate these results and migraineurs without aura reported a 50% reduc-
determine if modest weight loss achieved through tion in headache severity and frequency with
behavioral measures also influences headache CPAP, indicating CPAP may be an important tool
frequency in chronic migraineurs. for treating chronic headache disorders [22].
Sleep Acute Stress
Poor sleep is a widespread complaint in patients It is a common complaint heard in the clinic:
with chronic headache. Approximately two- “Stress gives me headaches.” In fact, more than
thirds of patients with chronic migraine suffer 90% of headache patients report that stress affects
from insomnia on a daily or near-daily basis [19]. their headaches [24]. Determining the role of
As measured by the Pittsburgh Sleep Quality acute stress in progression of headaches is com-
Index, higher migraine frequency correlates with plex as experiencing pain can produce stress.
poorer sleep quality. Further, patients with Numerous studies have attempted to parse this
chronic migraine report non-restorative sleep and relationship by establishing temporality of
a higher number of night awakenings compared events. A retrospective study found 44.8% of
to patients with episodic migraine [20]. patients with transformed headache report a
The relationship between sleep and chronic stressful event correlated with transformation
headache presents the classic “chicken or the from episodic to a chronic disorder [25]. Health
egg” question: do headaches interfere with sleep problems accounted for 35.6% of stressful events,
or does poor sleep produce headaches? In a ran- marriage disputes accounted for 13.6% of events,
domized placebo-controlled study, chronic bereavement accounted for 13.6% of events, and
migraineurs who followed behavioral sleep mod- work accounted for 11.4% of events. A smaller
ifications aimed at improving sleep quality and percentage of patients said stress related to edu-
increasing sleep duration were more likely to cation, legal concerns, and immigration preceded
revert to episodic migraine, suggesting a causal worsening of their headaches. Events in this
study were characterized by severity using the screen for stress in their headache patients and
Paykel score [26]. Approximately one-third of consider a multipronged management approach
transformed migraine patients reported a major to help patients reduce stress.
stressful event, characterized as bereavement,
legal concerns, serious illness, change or loss of
job, and retirement, preceding progression. Two- Depression
thirds of patients said minor stressors such as
interpersonal conflict and suboptimal work con- There is extensive literature showing a bidirec-
ditions coincided with headache transformation. tional link between migraine and depression [33].
There are several biological mechanisms Psychiatric comorbidity has been shown to be a
likely underlying the relationship between stress risk factor for headache progression, and, not sur-
and headache. Acute stress activates an opioid- prisingly, living with chronic pain adversely
mediated pain response, which temporarily affects mood. Patients with chronic daily head-
decreases sensation of pain; this may be an evo- ache have higher levels of anxiety and depressive
lutionarily preserved adaptive response permit- disorders than episodic migraineurs. In episodic
ting improved response to a perceived threat. migraineurs, 1 year of depression (as determined
However, recurring stimulation of this pain cen- by PHQ-9 scale) was a significant predictor of
ter can produce central sensitization leading to progression to a chronic headache disorder. This
hyperalgesia [27]. In addition, animal studies effect was present after controlling for sociode-
have shown that chronic stress, but not acute mographic variables, headache frequency, comor-
stress, results in increased sensitivity to pain in bidities, and medications. Further, authors
peripheral nociceptors, which may play an demonstrated a dose-dependent effect of depres-
important role in headache transformation [28]. sion on transformation risk, with the most severely
While acute stress may play a role in headache depressed patients having odds risk of 2.65 and
transformation, therapies focused solely on stress mild depression with an odds risk of 1.77 [34].
reduction have had minimal success in alleviat- As postulated by Lipton and Silberstein, there
ing pain burden and reverting chronic to episodic are several hypotheses to account for the linkage
headache. Only 13% of those suffering from between depression and onset of chronic
chronic headaches reported reduction in head- migraine, including shared risk factors, depres-
ache burden following behavioral therapy, while sion resulting from increasing number of head-
52% of patients with episodic headaches reported ache episodes, and a direct influence of depression
improvement in headache [29]. A combination of on headache progression through sensitization of
pharmacologic and behavioral stress reduction central pain pathways [35].
appears to be more effective than either therapy Chronic stress is a well-established risk factor
alone. Patients with chronic tension-type head- for both depression and chronic migraine.
ache who received behavioral intervention and Chronic stress has been shown to induce neuroin-
antidepressant therapy were significantly more flammation in the brain, which may lead to
likely (64% of patients) to show a clinically sig- hyperalgesia through suppression of the nocicep-
nificant decrease in headache activity than tive threshold [36].
patients who received antidepressant medication There is also evidence that depression may
(38% of patients) or cognitive behavioral therapy result from increasing headache burden. Treating
(35% of patients) alone [30]. chronic migraine with onabotulinumtoxinA pro-
In addition to the direct influence of stress on duced not only a reduction in headache burden but
progression of headache disorders, stress likely also alleviation of depression, demonstrating that
exerts important indirect effects by influencing decreasing headache frequency leads to improved
factors known to contribute to headache progres- psychological outcome even in the absence of
sion. Stress can lead to poor sleep as well as interventions aimed at improving mood [37].
increase the risk for obesity and medication over- Finally, depression may influence headache
use [31, 32]. Clinicians should be encouraged to progression through centrally mediated alterations
in pain sensitization. Imaging studies show that hormonal therapy should be considered in
depressed patients have increased amygdala women not only to reduce MRM but also medica-
activity and neuroplastic changes, which may tion overuse headaches.
contribute to central pain activation and sensiti-
zation [38]. Similarly, rodents with chemically Conclusion
induced chronic migraine show evidence of While the exact pathophysiology of headache
depression and anxiety behaviors as well as transformation is not entirely well understood,
decreased levels of dopamine and serotonin in there have been many studies providing evi-
the frontal cortex [39]. dence that there are several modifiable risk
These hypotheses are not mutually exclusive, factors that can contribute to headache chroni-
and it is probable that, for any specific individual fication. Understanding how risk factors shift
suffering from episodic headaches and depres- an episodic disorder to unremitting, daily or
sion, one or all three of these factors can influ- near-daily headache may lead to novel treat-
ence headache progression. ment and prevention strategies, and help pro-
vide headache patients with an improved
quality of life.
Menstrual-Related Migraines
It has been known for decades that the premen-

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Chronic Daily Headache
and Comorbid Disorders 24
Sara Siavoshi, Carrie Dougherty, and Jessica Ailani
Introduction ease, as well as genetic and pathophysiological

mechanisms for co-occurrence.
Chronic daily headache (CDH), comprised of This chapter will review comorbid disorders
the headache disorders chronic migraine (CM), seen in CDH with a particular emphasis on
chronic tension-type headache (CTTH), new CM. It will discuss mood disorders (depression,
daily persistent headache (NDPH), and hemi- anxiety, childhood maltreatment, and post-trau-
crania continua (HC), has a prevalence between matic stress disorder), musculoskeletal (MSK)
4 and 6% worldwide [1]. In a disease state that disorders (temporal mandibular dysfunction cervi-
will be encountered by most healthcare provid- calgia, and connective tissue disorder), other neu-
ers during their career, it is important not only rological disorders (head injury, epilepsy, and
to understand and identify CDH but also recog- ischemic stroke), and medical disorders (sleep
nize its comorbid conditions. Diagnosis and disorders, obesity, asthma and allergic rhinitis,
treatment of comorbid disorder in CDH can and cardiovascular disease).
impact headache-related disability, health- Most comorbid disorders in CDH are best
related quality of life, and treatment outcomes studied in CM, though they are likely seen in
[2]. Understanding comorbid conditions can CTTH as well. NDPH may share mood and MSK
also lead to insight about shared genetic and comorbidities, but currently there is little evidence
environmental causes of each individual dis- to suggest comorbid conditions in both NDPH
and HC. This may be related to the lower preva-
lence of these disorders in comparison with CM.
S. Siavoshi
Department of Neurosciences, University of
California San Diego, San Diego, CA, USA
C. Dougherty Mood Disorders
Department of Neurology, Medstar Georgetown
Headache Center, MedStar Georgetown University Clinic-based studies show an association between
Hospital, Washington, DC, USA CDH and at least one psychiatric disorder in a
J. Ailani (*) majority of cases [3, 4]. In this section, we will
Department of Neurology, Medstar Georgetown review depression, anxiety, childhood maltreat-
Headache Center, Medstar Georgetown University
Hospital, Washington, DC, USA ment, and post-traumatic stress disorder in per-
e-mail: jessica.x.ailani@gunet.georgetown.edu sons with CDH.

322 S. Siavoshi et al.
Depression most prevalent reported psychiatric disorder in

CDH and is five times higher in migraineurs than
Depression is known to be comorbid with non-migraineurs [3, 14].
migraine. Population studies show that d epression Depression and anxiety affect serotonin and
is diagnosed in 40–47% of people with migraine dopamine signaling, both of which are involved
[2]. Depression is comorbid in non-migrainous in the pathophysiology of various headache
headache as well. Persons with non-migrainous disorders, which may explain their shared
headache are 4% more likely to be diagnosed with co-occurrence in CDH [2].
depression [5]. More frequent migraine headache
is associated with higher rates of depression [6,
7]. Persons with CM are more likely than those Childhood Maltreatment
with episodic migraine (EM) to meet criteria for
depression (41.2–47% vs. 25%) and are two times Childhood maltreatment can refer to sexual,
more likely to have received a diagnosis of depres- physical, or emotional abuse in childhood and
sion [6, 7]. Compared with persons with non- other maltreatment, such as neglect [15]. It is a
migrainous headache, depression risk was public health concern that is often silent [16].
3.83-fold higher in persons with CM [8]. There are close to one million cases of childhood
Depression may be a risk factor for chronifica- maltreatment substantiated per year in the USA,
tion of migraine [9]. This is when persons with but true burden is likely much greater [16]. Rates
EM transition to CM. Increased depression sever- of childhood maltreatment in CDH are reported
ity correlated with an increased risk of chronifi- to be between 27 and 40% [16].
cation, with moderate and severe depression There are unique challenges to evaluating
carrying the highest risk [9]. childhood maltreatment in population and clinic-
Depression can also add further burden to based studies compared to evaluating other mood
chronic headache by impacting employment sta- disorders. Most studies of childhood maltreat-
tus, reducing earnings, and restricting career ment and CDH are retrograde identification of
achievement [10]. maltreatment, which can carry potential bias
Depression does not seem to impact remission related to recollection to painful experiences
of CM to EM; improved mood unrelated to head- [15]. Prospective studies are difficult, as mal-
ache burden did not lead to reduced headache treatment is rarely reported at the time of occur-
frequency [11]. The opposite may be true of rence [15]. This may lead to under- or
impact of headache frequency on mood. A small overrepresentation of disease comorbidity.
study evaluating onabotulinumtoxinA for CM Community studies of childhood maltreat-
found reducing headache frequency also reduced ment are rare. Juang et al. studied childhood
depression [12]. adversities in CDH in young adolescents in pub-
lic schools and found frequencies of physical
abuse and parental divorce were significantly
Anxiety higher in persons with CDH than controls [17].
There are several clinic-based studies evaluat-
Anxiety disorders include general anxiety disor- ing childhood maltreatment in CM. Tietjen et al.,
der (GAD), panic attacks, obsessive-compulsive in a cross-sectional multi-headache clinic (11
disorder, and specific phobias. Anxiety disorders sites) study, reported that childhood maltreat-
are more prevalent in CM than EM and are also a ment was significantly associated with CM and
risk factor for disease chronification [6, 7, 9]. A transformation of migraine. Emotional abuse in
study done by Guidetti et al. found that over time childhood was associated with earlier-onset
anxiety disorders were predictive of either headache as well as continuous daily headache,
unchanged or worsening headache in 70% of severe headache-related disability, and migraine-
migraineurs [13]. General anxiety disorder is the associated allodynia [18].
24 Chronic Daily Headache and Comorbid Disorders 323
The relationship between childhood maltreat- Temporal Mandibular Dysfunction

ment and CDH is likely due to alterations in brain
physiology caused by early stress that trigger a CM patients are more likely to have tenderness at
change in the pain matrix. In childhood maltreat- the temporomandibular joint and on masticatory
ment, early-life stressors can cause long-term muscles relative to EM and controls without
changes to the hypothalamic-pituitary-adrenal headaches [22]. Bevilaqua-Grossi et al. demon-
(HPA) axis function and regulation. This dys- strated that cutaneous allodynia occurs more fre-
function has been associated with CM [16]. quently in EM patients with TMD than those
Early-life stress can also cause changes in a range without, and thus TMD was proposed as a risk
of neurotransmitters involved in migraine (dopa- factor for transformation to CM [23]. A cross-
mine, serotonin, GABA-A), as well as increase sectional survey study found that individuals with
release of pro-inflammatory cytokines [16]. TMD are significantly more likely to have CDH,
with more symptoms of TMD imparting greater
risk [24]. A subsequent controlled study in clinic
Post-traumatic Stress Disorder confirmed that TMD is strongly associated with
both migraine and CDH, but not episodic tension-
Post-traumatic stress disorder (PTSD) occurs as a type headache (ETTH), and that increasing TMD
result of being exposed to extreme traumatic expe- severity is associated with increasing headache
riences that cause feelings of helplessness and fear frequency [25]. Sleep bruxism is also associated
[19]. Persons with PTSD will emotionally re- with CM, but not EM or ETTH [26].
experience the event, avoid stimuli, have a negative
mood or poor cognition, and have symptoms of
overstimulation [15]. Prevalence of PTSD is Cervicalgia
between 1 and 8% in the population [15]. Studies
evaluating the correlation between PTSD and CDH Neck pain accompanies chronic migraine (CM)
find the lifetime prevalence of PTSD in persons so frequently that it is difficult to conceptualize
with CDH to be 19.2% compared to 4.5% in per- the two as separate conditions. A prospective
sons without headache [20]. Clinic-based studies study of 113 migraineurs, nearly half of whom
have found a greater frequency of comorbid PTSD were chronic, found that neck pain occurs more
and depression in CDH compared to EM [19]. frequently in migraine than nausea, a defining
PTSD is related to serotonergic function and associated symptom [27]. The prevalence of neck
may also cause dysregulation of the HPA axis pain increases with migraine chronicity [27].
[15]. This may explain the coexistence of PTSD Neck-related disability and pain thresholds dem-
in patients with migraine. onstrate similar trends. Florencio et al. reported
that individuals with CM were at a significantly
increased risk for cervical disability relative to
Musculoskeletal Disorders episodic migraineurs [28]. Patients with trans-
formed migraine (TM) have significantly lower
Muscle tension was long thought to be involved in pain thresholds in the neck both between and dur-
the pathophysiology of tension headaches [21]. ing migraine than their EM counterparts [28].
While this has been disproven, many patients with Neck pain in migraine is likely a manifestation
CDH experience comorbid MSK disorder. This of allodynia due to activation of upper cervical
may be related to the trigeminal cervical complex afferents in the trigeminal nucleus caudalis (TNC)
and its descending pathway through C1–C3 trigger- [29]. Allodynia is a known risk factor for the
ing pain in the upper neck and related areas [21]. In development of chronic migraine [30]. These stud-
this section, we will review CDH and comorbid ies support the notion that neck pain is implicit in
temporal mandibular dysfunction (TMD), cervical- the pathophysiology of chronic migraine and not a
gia, and connective tissue disorders. separate co-occurring condition.
onnective Tissue Disorders and Pain

C Neurological Disorders
Disorders
Headache is the most common neurological dis-
Pain disorders, including musculoskeletal pain, order and affects both the central and peripheral
fibromyalgia, and joint hypermobility syndrome nervous system. It is therefore not surprising that
(JHS; type III Ehlers-Danlos syndrome), are other neurological disorders can be found more
comorbid with migraine [31–34]. often in patients with CDH. In this section, we
The Nord-Trøndelag Health Study found the will review CDH and comorbid association with
prevalence of both migraine and non-migrainous head injury, epilepsy, and stroke.
headache was increased in persons with muscu-
loskeletal symptoms lasting for ≥3 months, com-
pared to persons without musculoskeletal Head Injury
symptoms. The prevalence of chronic headache
(headache on >14 days per month) was 4.6 times Several studies have suggested that head injury
higher in persons with musculoskeletal symp- and whiplash are risk factors for the development
toms than in those without such symptoms [33]. of CDH [39–44]. In some instances, CDH occurs
Marcus and colleagues reported that out of in direct relationship to head trauma and is then
100 fibromyalgia patients evaluated, 76 reported characterized as post-traumatic headache (PTH).
headache. Of the 76 patients with headache, 48 The Frequent Headache Epidemiology Study, a
(63%) received a diagnosis of migraine, either in population interview survey, found that head and
isolation or combined with tension-type head- neck injury account for 15% of CDH [45]. The
ache [34]. same study also noted that in CDH there is a
Castori and colleagues assessed the preva- higher frequency of lifetime incidence of history
lence of headaches in 21 patients with JHS from of head trauma, in which the onset of headache
a group of 40 individuals with suspected heredi- was not temporally related to the injury [45]. The
tary connective tissue disorder. Of the 21 patients lifetime risk of CDH increased with the number
with JHS, 18 (86%) reported recurrent headaches of head/neck injuries [45].
[35]. Bendik and colleagues assessed the preva- The literature on PTH has shown that head-
lence, frequency, and disability of migraine in aches following head injury exhibit increased
female patients with migraine compared to a con- prevalence of CDH than headaches that are not
trol population. Of the 28 patients with JHS, 21 associated with head trauma [46, 47]. In a cross-
(75%) had migraine compared with 43% of con- sectional study of soldiers returning from combat
trols [31]. Migraine was more prevalent, fre- deployment, 27% of subjects with PTH experi-
quent, and disabling in female JHS patients as enced CDH, as compared to 14% of subjects with
compared with controls [31]. non-traumatic headaches [47]. A subsequent study
Central sensitization may mediate migraine, by the authors similarly showed that 20% of
musculoskeletal pain, and fibromyalgia [36, 37]. patients with headache following deployment-
Central sensitization arises when central pain related concussion met criteria for CDH [47]. This
pathways develop lower thresholds for activa- is noted in the civilian population as well with
tion. This may result from dysregulated pain- 46% of patients with mild TBI reporting a head-
producing mechanisms. It is not known, however, ache frequency of 15 days per month or more [47].
whether central sensitization is secondary to The theoretical mechanisms by which head
ongoing painful input or whether it is a primary injury can precipitate or potentiate headache fre-
disease mechanism [38]. JHS, like migraine, quency include post-injury inflammation,
may be mediated through mechanisms involving increased neuronal and glial excitability, and
autonomic dysfunction or dysregulated cytokine enhanced release of calcitonin gene-related pep-
signaling. tide from trigeminal afferents [47].
Epilepsy cardiovascular death [70]. The CAMERA-2

study also found no association between
There are several studies that have shown white matter abnormality progression and
migraine to be comorbid with epilepsy [48–53]. triptan therapy [71].
Both epilepsy and migraine are thought to arise, 6.
Migraine is associated with an increased
in part, due to neuronal hyperexcitability—the prevalence of patent foramen ovale (PFO)
proposed point of convergence for these comor- [72]. Evidence for this is inconsistent.
bid disorders. Based on this insight, many of the Despite evidence in support of these various
treatments for both disorders target neuronal hypotheses, the precise mechanism leading
hyperexcitability [54]; however not all antiepi- to comorbidity of ischemic stroke and
leptic drugs provide effective prophylaxis for migraine remains unknown.
migraine. While there is a risk of ischemic stroke in
patients with migraine with aura, a clear increased
risk of ischemic stroke has not been seen in
Ischemic Stroke patients with CDH. For patients with CDH, isch-
emic stroke risk counseling should be provided to
Persons with migraine have been shown to be at patients who have concurrent migraine with aura,
increased risk for ischemic stroke [55–66], and especially women.
there is a relationship between stroke and
migraine with aura [56, 57, 59, 61, 63–65], par-
ticularly in women [56, 57, 63, 64]. Several stud- Medical Disorders
ies have also shown an increased incidence of
white matter abnormalities in migraineurs with Patients with frequent headache will often expe-
aura [67, 68]. It has been suggested that pro- rience disruptions of routine functions, such as
thrombotic states, some of which predispose to sleep. Some patients with particular medical con-
stroke, are risk factors for transformation from ditions may be at a higher risk for frequent head-
EM to CM [69]. aches, such as patients who have thyroid
Six hypotheses have been proposed to explain disorders, who are obese, or who have asthma or
the mechanisms by which migraine may lead to allergies. This section will review CDH and
ischemic stroke: comorbid sleep disorders, obesity, asthma and
1. Migraine directly causes ischemic stroke. allergies, and cardiovascular disease.
2. Migraine-specific physiology disrupts vas-
cular lesions, which can lead to an ischemic
stroke (e.g., vomiting during a migraine Thyroid Disorders
leads to carotid or vertebral artery dissec-
tion which then acts as a source for ischemic In the Fernald Medical Monitoring Program
stroke). (FMMP), patients with a self-report of “frequent”
3. Migraine is associated with a higher preva- headache disorder had a 21% increased risk of
lence of an unfavorable cardiovascular risk developing new-onset hypothyroidism, while
profile. those with self-report of “frequent” possible
4. Migraine and ischemic stroke are linked migraine showed an increased risk of 41%. Age
through shared genetic mechanisms. was found to be a predictor of hypothyroidism, as
5. Anti-migraine medications, such as triptans HRs progressively increased from the youngest to
and ergots, are vasoconstrictors which the oldest participants [73]. In a clinic-based study,
increase the risk of ischemic events. This the correlation between age and hypothyroidism
theory is contradicted by a 2004 study that was found to be stronger in CM than in EM [74].
showed that triptan usage was not associ- In a prospective study of 102 adults with
ated with an increased risk of stroke, MI, or hypothyroidism, 30% of those that endorsed
headaches with onset after the first symptoms of during attacks [81]. The hypothalamic suprachi-
hypothyroidism also reported resolution of head- asmatic nuclei that control circadian rhythms are
ache symptoms after initiation of thyroid hor- integral to sleep patterns [80]. Finally, the hypo-
mone therapy [75]. thalamus has extensive connections with the lim-
One theory of shared pathophysiology is that bic system, the pineal gland, and brainstem nuclei
upregulation of the immune system in headache involved in the sleep-waking cycles and pain
disorders provokes an attack on the thyroid gland. modulation [82].
This is supported by a study that shows interictal
periods of elevated CRP and altered proportions
of T lymphocytes in migraineurs [76]. Obesity
Like many comorbidities of migraine, obesity is

Sleep Disorders more prevalent in persons with CM than in those
with EM [68]. Like many other comorbidities,
Findings from the National Comorbidity Survey- obesity has been demonstrated to be a risk factor
Replication Study demonstrated a significant for progression from EM to CM [83]. The link
association between frequent severe headache between obesity and migraine has been investi-
and sleep disorders. Compared with persons gated in a number of population-based studies [6,
without headache, those with frequent severe 83, 84]. Bigal and colleagues found that higher-
headache reported more difficulty initiating and BMI patients experienced a greater frequency of
staying asleep, early morning awakening, and migraine attacks. In the normal-weight group,
daytime fatigue. Migraine, specifically, was asso- 4.4% had 10–15 headache days per month,
ciated with an increased risk of sleep disorders increasing to 5.8% of the overweight, 13.6% of
[77]. The correlation between sleep disorders and the obese, and 20.7% of the morbidly obese
migraine may be affected by migraine frequency. group. Body mass index was also a predictor of
A study of 332 patients, assessed using the headache severity. A significantly higher propor-
Pittsburgh Sleep Quality Index (PSQI), found tion of overweight, obese, and morbidly obese
that patients with more migraine days per month persons reported severe headaches compared
had higher PSQI scores, indicative of poorer with persons in the normal-weight group. Finally,
sleep [78]. obese and morbidly obese patients experienced
The relationship between migraine and more headache-related disabilities, including
obstructive sleep apnea was evaluated in a cross- more missed workdays, and their headache pain
sectional population-based study, and results was more frequently exacerbated by physical
were not statistically significant. There was, how- activity [85].
ever, a statistically significant relationship An analysis of data from the American
between migraine and excessive daytime sleepi- Migraine Prevalence and Prevention (AMPP)
ness [79]. study of 120,000 US households found that high-
The Nord-Trøndelag Health Study of 297 par- frequency headaches (10–14 days per month)
ticipants showed a strong association between occurred in 7.4% of overweight persons, 8.2% of
severe sleep disturbances and chronic headaches, obese persons, and 10.4% of morbidly obese per-
with CM being more strongly associated than sons, compared with 6.5% of persons in the nor-
EM. Sleep maybe a precipitant as well as a pallia- mal-weight group. Headache-related disability
tive agent for migraine [80]. Shared neurophysi- was associated with BMI as well. Compared with
ologic mechanisms in sleep disorders and migraineurs in the normal-weight group, over-
migraine include involvement of the hypothala- weight, obese, and morbidly obese subjects were
mus and the neurotransmitters, serotonin and significantly more disabled [86].
melanin [80]. Migraines are thought to be trig- Significant BMI reduction has been demon-
gered in the hypothalamus, as it is highly active strated to benefit headache frequency. Bond and
colleagues demonstrated a reduced frequency of have higher headache frequency and a higher
headache in persons with CM in a small study of level of disability [91].
severely obese individuals who underwent bariat- In a small clinic-based study of 76 persons
ric surgery. Twenty-four patients with migraine diagnosed with allergic rhinitis, immunotherapy
were assessed before and 6 months after bariatric (allergy shots) decreased the frequency and dis-
surgery. The mean number of headache days was ability of migraine headaches by 52% and 45%,
reduced from 11.1 preoperatively to 6.7 postop- respectively, in those migraineurs who were
eratively, after a mean percent excess weight loss younger than 40 years of age [92].
of 49.4%. Reduction in pain severity was also Several large population-based studies have
observed, and the number of patients reporting found an increased risk of asthma in migraineurs
moderate to severe disability decreased from [93–96]. Findings from the 2005 AMPP study
50.0% before surgery to 12.5% after surgery [87]. indicate that persons with CM are more likely to
Migraine and obesity may in fact be biochem- have asthma than those with EM. Self-report of a
ically linked [85]. Obesity is a pro-inflammatory physician diagnosis of asthma occurred in 24.4%
state. Several inflammatory mediators, such as of respondents with CM compared with 17.2% of
interleukins and calcitonin gene-related peptide respondents with EM [68]. Martin and colleagues
(CGRP), which are important in migraine, are reported that the risk for CM increased by 2.1-
also increased in obese persons [88]. Adiponectin, fold in episodic migraineurs with asthma as com-
a protein hormone secreted by fat cells, may pared to those without asthma [97].
modulate pain during migraine. Adiponectin lev- Mast cells play an important role in both
els are increased in obesity; and at low and abnor- migraine and asthma or allergic rhinitis. The
mal levels, adiponectin is nociceptive. Similarly, dura mater is highly innervated by pain fibers
orexins modulate both pain and metabolism, and and densely populated by mast cells [98]. Animal
dysfunctional orexin pathways may be a risk fac- studies suggest that mast cell degranulation in
tor for both migraine and obesity [88]. the dura could activate trigeminal nociceptors,
Obesity is a modifiable risk factor for head- contributing to migraine pathogenesis. Animal
ache chronification. Prevention and treatment studies further show that plasma protein extrava-
should be considered as part of CDH treatment. sation, including extravasation of neurotransmit-
ters involved in pain mechanisms, is increased in
pre-sensitized animals upon exposure to an aller-
Allergic Rhinitis and Asthma gen [99]. It is also possible that allergic disorders
may indirectly contribute to the onset of
The relationship between migraine and non- migraine. Allergic disorders may modulate
migrainous headache and hay fever, a form of comorbidities and possible precipitants of CDH
allergic rhinitis [89], was assessed in the Head- such as sleep, depression, or anxiety. It has also
HUNT study, a cross-sectional population-based been proposed that the comorbidity with
study. Persons with both migraine and non- migraine may be due to immune system dys-
migrainous headache were more likely to have function in migraineurs. The clinical manifesta-
hay fever than those without headaches. This tions of allergic rhinitis include itching, runny
effect was greater in individuals with more than nose, and mucous secretion. This response is
14 days of headache per month [90]. Buse and mediated in part by the release of histamines in
colleagues demonstrated that the rates of aller- response to an inciting allergen [100]. Since his-
gies and hay fever are higher in persons with CM tamines have been implicated in the pathogene-
than in those with EM (59.9% vs. 50.7%) [68]. sis of migraine headaches, and the nasal passage
The AMPP study found that 66.8% of 5849 is in close proximity to the central nervous sys-
migraineurs had rhinitis (most commonly mixed tem, it has been hypothesized that allergic rhini-
rhinitis). Those with rhinitis were more likely to tis may trigger migraine headaches [92].
Comorbid asthma in migraine may affect angina. Women with migraine with aura have
treatment choices. Beta-blockers can trigger been found to have an increased risk of cardio-
bronchospasm in patients with asthma [101]. vascular events including angina and myocardial
Nonsteroidal anti-inflammatory drugs (NSAIDs) infarction (MI) [118, 119]. The results of the
may worsen asthma, especially in persons with AMPP and IBMS studies showed that cardiovas-
nasal polyps and exercise-induced asthma [102]. cular diseases and risk factors are significantly
more likely to be associated with CM than with
EM [7, 68]. Furthermore, heart disease, angina,
Irritable Bowel Syndrome and Other and stroke were more prevalent in those with CM
Gastrointestinal Disorders than in those with EM. Compared to those with
EM, respondents with CM had a higher fre-
Various population-based studies have found quency of high blood pressure (33.7% vs. 27.9%)
migraineurs to be two to three times more likely and high cholesterol (34.2% vs. 25.6%) [68].
to develop IBS. Migraine and IBS have been The mechanisms that link migraine to isch-
observed to be comorbid conditions [103–107]. emic vascular disease and its risk factors are
Lau et al. found this effect to be more pronounced unknown. Migraine with aura has been associ-
as headache frequency increased [103]. ated with several risk factors for heart disease
Celiac disease, an autoimmune disorder of the including unfavorable cholesterol profiles, ele-
small intestine, has been reported to be comorbid vated blood pressure, history of early myocardial
with migraine [108–110]. A small study also infarction, and both CHD and early-onset CHD
found weak evidence that a gluten-free diet might [116].
reduce migraine frequency [108]. Potential theories explaining cardiovascular
Aberrant autonomic dysfunction may pose a disease risk in migraineurs include both intrinsic
link between migraine and GI disorders. This and extrinsic mechanisms. Intrinsic mechanisms
mechanism is supported by studies that show may include changes in vascular reactivity, endo-
delayed gastric emptying during interictal thelial disturbance, and platelet dysfunction.
migraine periods [111, 112]. Another theory for Altered platelet aggregation in migraineurs com-
shared migraine and GI pathogenesis is that of bined with changes in blood flow may predispose
the “gut-brain axis,” a term that represents the to ischemic disease [117]. An insufficiency or
bidirectional relationship between the gut dysfunction of endothelial precursor cells
microbiome and brain function and links altera- (EPCs), which are programmed to renew the
tions in GI flora to neurological disorder like endothelium, is a possible mechanism of vascular
migraine [113]. pathology in migraine [117]. However in con-
Oral administration of migraine medications trast, Oterino and colleagues showed that a higher
may have limited effectiveness in the context of number of activated EPCs were found in
delayed gastric emptying, nausea, and vomiting migraineurs as compared to controls. This was
associated with migraine and should prompt con- explained by the mobilization of EPCs after vas-
sideration of alternative delivery routes [114]. cular injury in migraine [120]. Additionally, ele-
vated prothrombotic or vasoactive peptides have
been observed in migraine including prothrombin
Cardiovascular Diseases factor 1.2, factor V Leiden, serotonin, and von
Willebrand factor [118].
Population-based studies demonstrate that Sedentary lifestyle and medication effect are
migraine is significantly associated with cardio- extrinsic mechanisms of cardiovascular disease
vascular risk factors, including an unfavorable risk in this population. However, in the Women’s
cholesterol profile, elevated blood pressure, and Health Study, the increased risk of vascular
diabetes [68, 115–117]. Both men and women events remained even after correcting for external
with migraine with aura have increased risk of cardiovascular risk factors [121]. Specifically in
regard to risk associated with migraine medica- 7. Blumendfeld A, Varon S, Wilcox TK, Buse D,
Kawata AK, Manack A, Goadsby PJ, Lipton
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over 63,000 migraine patients found no associa- database in Taiwan. J Headache Pain. 2012;13:311–9.
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Neurostimulation
in the Management of Chronic 25
Migraine
Derrick Alan Shumate and Frederick G. Freitag
Introduction tions. Deep brain stimulation techniques have

been employed in the management of various
There are effective and tolerable acute and pre- movement disorders including Parkinson’s dis-
ventive management strategies for migraine and ease [5], essential tremor [6, 7], medically refrac-
chronic migraine. Many patients benefit from tory dystonia [8], and Tourette syndrome [9, 10].
non-pharmacologic strategies such as biofeed- Posterior hypothalamic deep brain stimulation
back and cognitive behavioral therapy. In tertiary has been examined as a potential treatment for
headache centers, the use of both pharmacologi- refractory cluster headaches, chronic paroxysmal
cal and non-pharmacological interventions is hemicranias, and intractable short-lasting unilat-
commonplace. Therapies such as onabotulinum- eral neuralgiform headache with conjunctival
toxinA injections [1, 2] and topiramate [3, 4] injection and tearing [11–15]. More recently, the
have been shown to be effective for the manage- ventral tegmentum has been considered a poten-
ment of chronic migraine along with other thera- tial site for stimulation in cluster headache [16].
pies including tricyclic antidepressants and Implantable vagus nerve stimulation has been
beta-blockers; however, patient preference, lack shown to be effective in the management of epi-
of response, and intolerance often preclude the lepsy [17–20], depression [21–23], and headache
use of established pharmacotherapies. Among and other pain disorders [24–26].
the potential non-pharmacologic treatments for We will discuss noninvasive vagal nerve
chronic migraine, there is developing substantial stimulation in the management of migraine later
interest in the role of neurostimulation. in this chapter. Neuromodulation is being
The term “neurostimulation” encompasses a employed as potential therapies in several head-
variety of treatments, utilizing both invasive and ache disorders. We examine in this chapter spe-
noninvasive methods. They are used in the man- cific stimulation modalities for the treatment of
agement of a diverse group of both painful and migraine including occipital nerve stimulation
non-painful neurological and psychiatric condi- (ONS), single-pulse transcranial magnetic stim-
ulation (sTMS), repetitive-pulse transcranial
magnetic stimulation, transcranial direct current
stimulation (tDCS), transcutaneous supraorbital
D. A. Shumate · F. G. Freitag (*)
nerve stimulation, transcutaneous vagal nerve
Neurology, Medical College of Wisconsin,
Milwaukee, WI, USA stimulation (VNS), and sphenopalatine gan-
e-mail: ffreitag@mcw.edu glion stimulation.

336 D. A. Shumate and F. G. Freitag
I mplantable Occipital Nerve medications with reductions of −5.9 vs. −2.6

Stimulation and − 5.9 vs. −4.8, respectively.
In the ONSTIM feasibility study [33], patients
The basis for the utilization of percutaneous with chronic migraine who experienced at least a
occipital nerve stimulation in the management of 50% reduction in headache within 24 h of a
migraine has its roots in the work of Weiner and greater occipital nerve block were randomized to
Reed who proposed ONS might be an effective receive one of three treatments: adjustable
means by which to manage intractable occipital implanted occipital nerve stimulation, preset
neuralgia [27]; however, after review of the cases stimulation, or medical management. Multiple
from the study and resultant diagnostic scrutiny, efficacy measures were evaluated at 3 months,
functional neuroimaging was recommended and including reduction in headache days per month
performed. Eight of the 13 patients underwent and decrease in overall pain intensity compared
positron emission tomography (PET) with find- to baseline values. The percent reduction in head-
ings consistent with those changes seen in ache days per month was 27.0 ± 44.8% for the
migraine [28]. There were significant changes in adjustable stimulation group, 8.8 ± 28.6% for the
regional cerebral blood flow (rCBF) in the dorsal preset stimulation group, and 4.4 ± 19.1% for the
rostral pons, anterior cingulate cortex (ACC), medical management group. The reduction in
cuneus, and left pulvinar, correlating to pain and headache intensity was 1.5 ± 1.6 for the adjust-
stimulation-induced paresthesia scores. The acti- able stimulation group, 0.5 ± 1.3 for the preset
vation pattern in the dorsal rostral pons is the stimulation groups, and 0.6 ± 1.0 for the medical
same as that seen in chronic migraine. management group. However, analysis showed
Early case series [29] showed a reduction in no statistically significant improvement in the
headache days from 75.6 to 38.1 for a 90-day adjustable stimulation group over baseline when
period and an improvement of 88.7% in the compared to the preset stimulation and medical
Migraine Disability Assessment (MIDAS) scores management groups. Lead migration was the
with implanted peripheral nerve stimulation at most common adverse event and occurred in 12
C1 through C3. Open-label studies by Dodick of 51, or 24%, of patients. Incision site complica-
et al. [30] and Schwedt et al. [31] suggested tions were another adverse event reported in 4%
implanted occipital nerve stimulation may be an of patients.
effective tool for the management of chronic In the St. Jude study [34], Silberstein et al.
migraine showing significant improvement randomized 57 patients in a 2:1 manner to either
across multiple efficacy measures including active occipital nerve stimulation or sham proto-
headache frequency, pain intensity, MIDAS col. Patients underwent implantation if they
scores, and Headache Impact Test-6 (HIT-6) and experienced at least a 50% reduction in pain or
Beck Depression Inventory-II (BDI-II) scores. paresthesia in the area of pain during a trial phase.
One hundred and thirty-two patients who suf- The primary endpoint was defined as the differ-
fered from chronic migraine were enrolled in the ence in the percentage of responders who
Precision Implantable Stimulator for Migraine, achieved a ≥ 50% reduction in daily visual ana-
or PRISM, study [32] in which a 12-week blind- log pain scale scores. The active ONS group
ing phase was then followed by an open treat- demonstrated a 17.1% reduction versus 13.5%
ment phase. Implantation was pursued if the with sham protocol, which was not statistically
preceding 5–10-day stimulation trial with exter- significant; however, differences between the two
nal leads was successful at alleviating pain. The groups in 40%, 30%, and 20% reduction were
reduction in headache days per month was not significant. There was a significant difference in
statistically significant at 12-week follow-up; reduction of number of headache days, reduction
however, there appeared to be a trend toward in MIDAS scores, and patient reports of pain
more benefit in those patients without medication relief. Persistent implant site pain was the most
overuse versus those who had been overusing commonly reported device-related adverse event.
25 Neurostimulation in the Management of Chronic Migraine 337
Dodick et al. [35] conducted a multicenter, events were common with 42.8% reporting lead
double-blinded, sham-controlled study of the migraine and 14.2% infection in the latter study.
effectiveness of ONS that included analyses of
125 patients with intractable chronic migraine as
well as an intent-to-treat (ITT) population of 157 ranscutaneous Supraorbital Nerve
T
patients after a 2-week blind period followed by Stimulation
a 50-week open period. The number of headache
days was significantly reduced by 7.7 (±8.7) days Transcutaneous supraorbital nerve stimulation
in the intractable chronic migraine group and may be effective for the prevention of migraine.
reduced by 6.7 (±8.4) days in the intent-to-treat In a study of 67 migraine patients, Schoenen
group. Reduction in headache intensity, MIDAS et al. [41] observed a greater reduction in
scores, and Pain and Distress (PAD) scores and migraine days per month, from 6.9 to 4.8, in the
direct patient reports of improvement in quality group treated with 20 min of stimulation daily for
of life and pain relief were also significantly 1 month with Cefaly®, a novel transcutaneous
improved. Adverse events were common and supraorbital nerve stimulation device, versus
reported by 70.7% of patients. Two hundred and sham in which migraine days were reduced from
nine adverse events were reported in total. Among 6.5 to 6.2 days. Post hoc statistical analysis of
them were 38 cases of persistent pain or numb- data from the aforementioned study [41] sug-
ness, 5 wound site complications, 11 infections, 8 gested that those patients who suffered from
battery failures, 29 lead migrations, and 7 lead more migraine attacks at baseline may have
breakages or lead fractures. experienced a greater reduction in migraine days
The reduction in pain intensity and attack fre- [42]. The patient satisfaction rate, among a popu-
quency seen in some patients may be attributable lation of both episodic migraine and chronic
to activation of central pain modulation centers migraine sufferers, was 54% [43]. This may sug-
similar to that seen on FDG-PET results of gest a greater role for such technology in chronic
patients with cluster headache that have under- than episodic migraine, but to date, there are no
gone peripheral occipital nerve stimulation [36]. studies to support such a supposition.
All patients compared with controls in the trials It is hypothesized that transcutaneous supraor-
demonstrated several areas of hypermetabolism bital nerve stimulation, as with occipital nerve
including the ipsilateral hypothalamus, midbrain, stimulation, likely owes its beneficial effects in
and ipsilateral lower pons. After ONS all areas migraine to modulation of central pain centers. It
normalized except for the hypothalamus. The appears to be well tolerated and effective in
perigenual anterior cingulate cortex (PACC) was migraine prophylaxis with a possible tendency
hyperactive in ONS responders compared to non- toward greater benefit in those suffering from
responders. ONS may also provide pain relief via more frequent headache attacks. Additional
modulation of the trigeminocervical complex as translational and controlled clinical studies, spe-
trigeminal nociceptive fibers are in proximity to, cifically in the chronic migraine population,
and intertwined with, those from the C2 level [37, could be revealing.
38]. Implanted occipital nerve stimulation will
likely maintain a limited role in the management
of refractory chronic migraine as implantation Transcranial Stimulation Methods
and device-related adverse effects are common
[33, 35] and insurance coverage is uncommon. The effects of TMS can be divided into two types
Of note, two smaller unblinded studies by depending on the mode of stimulation: a single-
Reed et al. and Hann [39, 40] have suggested that or paired-pulse TMS. sTMS causes neurons in
combined implanted supraorbital nerve and the neocortex under the site of stimulation to
occipital nerve stimulation may benefit those suf- depolarize and discharge an action potential. If
fering from chronic migraine; however, adverse used in the primary motor cortex, it produces
muscle activity, referred to as a motor evoked patients were randomized to receive active TMS,
potential (MEP), which can be recorded on elec- and another six were randomized to sham proto-
tromyography. If used on the occipital cortex, col. Migraine attack frequency was reduced by
“phosphenes” (flashes of light) might be per- 53% in the active treatment group and by 7%
ceived by the subject. In most other areas of the with sham. In a randomized, double-blind, sham-
cortex, the participant does not consciously expe- controlled study of 100 patients, 60 of whom suf-
rience any effect, but his or her behavior may be fered from chronic migraine. Misra et al. [50]
slightly altered (e.g., slower reaction time on a observed a 78.7% reduction in headache fre-
cognitive task), or changes in brain activity may quency in those patients who received three treat-
be detected using sensing equipment. ments of high frequency over the left frontal
Repetitive TMS (rTMS) produces longer-last- cortex on alternating days versus a 33.3% reduc-
ing effects, which persist past the initial period of tion with sham protocol. Headache severity was
stimulation. rTMS can increase or decrease the also reduced with active versus sham treatment
excitability of the corticospinal tract depending by 76.6% versus 27.1%, respectively. All patients
on the intensity of stimulation, coil orientation, reported some discomfort related to TMS, but no
and frequency. The mechanism of these effects is serious adverse events were reported. Conversely,
not clear, though it is widely believed to reflect in a small study, Conforto et al. [51] randomized
changes in synaptic efficacy akin to long-term seven chronic migraine patients to receive 23 ses-
potentiation (LTP) and long-term depression sions of rTMS over the left dorsolateral prefron-
(LTD). tal cortex and found active TMS to be less
The transcranial stimulation techniques, effective than sham.
including single-pulse transcranial magnetic
stimulation, repetitive-pulse transcranial mag-
netic stimulation, and transcranial direct current Single-Pulse Transcranial Magnetic
stimulation, likely influence migraine through Stimulation
normalization of cortical hyper-reactivity which
is thought to be present in migraine sufferers as Clark et al. [52] conducted an open-label study,
evidenced by defective habituation [44–46] which examined the tolerability and efficacy of
across multiple sensory modalities [47], includ- single-pulse transcranial magnetic stimulation
ing nociceptive inputs [48], observed in multiple for the acute management of migraine in 41
evoked potentials studies of patients with patients suffering from migraine without aura,
migraine. Repetitive-pulse transcranial magnetic migraine with aura, and probable migraine. One
stimulation may also reduce migraine attack fre- to three trials of two pulses were applied over
quency through the upregulation of inhibitory the area of perceived pain in those patients with
input, thereby restoring habituation [44]. In the migraine without aura and over the visual cortex
following section, we will discuss recent clinical in patients who suffered from migraine with
data pertaining to, and possible utility of, the var- aura. Reduction in pain intensity was used as the
ious methods. primary outcome measure and was reduced by
75% for up to 20 min poststimulation. Thirty-
two percent of subjects reported no headache
Repetitive-Pulse Transcranial recurrence for up to 24 h after one treatment.
Magnetic Stimulation Additional treatments appeared to convey ben-
efit as 24-h headache freedom was observed in
Brighina et al. [49] examined the potential effec- 29% of those who received two treatments and
tiveness of daily high-frequency repetitive tran- 40% of those who received three treatments.
scranial magnetic stimulation for the prevention This particular TMS paradigm appeared to be
of both episodic migraine and chronic migraine. well tolerated without any serious adverse
Stimulation was delivered over the left dorsolat- events. Dizziness, drowsiness, and feeling tired
eral prefrontal cortex. Six chronic migraine were reported.
Lipton et al. [53] conducted a randomized, potential treatment for migraine. Antal et al. [55]
double-blind, sham-controlled study of the conducted a randomized, sham-controlled trial of
effects of single-pulse transcranial magnetic 26 patients with migraine with aura (14) and
stimulation in which 164 patients who suffered migraine without aura (12). Attack frequency and
from migraine with aura used a portable device to attack duration were not significantly reduced in
administer either a single magnetic field pulse or either the real stimulation or sham protocol
sham treatment over the area of the visual cortex group. Similarly, Rocha et al. [56] did not observe
without 1 h of aura onset. Patients treated up to a reduction in migraine frequency, intensity, or
three attacks of migraine with aura over a duration in their randomized, sham-controlled
3-month span. Pain freedom at 2 h was the pri- trial in which patients received 12 20-min cath-
mary outcome measure and was observed in 39% odal stimulation sessions over the visual cortex.
of those who received active TMS versus 22% in Conversely, Dasilva et al. [57] examined the
the sham group. Sustained headache freedom at potential effectiveness of anodal stimulation over
24 and 48 h were secondary outcome measures the contralateral motor cortex and cathodal stim-
and were both superior with active treatment ver- ulation over the contralateral orbitofrontal area of
sus sham protocol at 29% versus 16% and 27% 13 chronic migraine patients with some promis-
versus 13%, respectively. ing results. Ten 20-min sessions of 2 mA stimula-
In their open-label study, Bhola et al. [54] tion were administered over a 4-week span in the
examined the effectiveness of single-pulse mag- active group, whereas those patients in the sham
netic transcranial stimulation delivered via the protocol also received 2 mA stimulation but only
portable Spring® TMS device for the acute treat- for 30 s. Improvements in both headache dura-
ment of migraine. One hundred and ninety tion and pain intensity were observed in the
patients, including 59 with either migraine with- active tDCS group.
out aura or migraine with aura and 131 with In a randomized, sham-controlled study,
chronic migraine who had found previous acute Auvichayapat et al. [58] observed a statistically
pharmacotherapies ineffective, intolerable, or significant reduction in migraine frequency,
medically contraindicated, participated in the intensity, and the number of acute medications
study. Patients were instructed to treat individual utilized in 37 patients with episodic migraine
migraine attacks with 2 consecutive pulses fol- who administered either active anodal tDCS
lowed by additional “as needed” pulses at 15-min treatment or sham therapy over the motor cortex
intervals to a maximum of either 16 single pulses for 20 min daily for 20 days consecutively.
or 8 double pulses. There was no limit on the Treatment was well tolerated without any
number of attacks treated or the days of utiliza- reported serious adverse events.
tion. The specific stimulation parameters mir- Repetitive transcranial magnetic stimulation
rored those in the study by Lipton et al. [53]. may prevent migraine attacks; however, the avail-
Fifty-nine percent of patients reported a reduc- ability and portability of the delivery system may
tion in migraine days after 12 weeks. Sixty-two be prohibitive. Single-pulse transcranial mag-
percent reported reduced or alleviated pain with netic stimulation, such as with the Spring® TMS
stimulation. device, may have a role in both acute and preven-
tive treatment of migraine and is portable.
ranscranial Direct Current

T
Stimulation Transcutaneous Vagus Nerve
Stimulation
Transcranial direct current stimulation is thought
to potentially provide relief from migraine by As mentioned earlier in this chapter, vagus nerve
normalization of cortical hypersensitivity. stimulation has been utilized in the management
Cathodal transcranial direct current stimulation of epilepsy and depression for several years.
which is inhibitory has also been studied as a The complete mechanism by which vagal nerve
stimulation may acutely abort or prevent migraine pain freedom were lower in the chronic migraine
attacks has not been elucidated. VNS may in part group versus high-frequency migraine.
owe its therapeutic effect to its synapses within Silberstein et al. [65] conducted a random-
the trigeminal nucleus caudalis and the ability to ized, sham-controlled study of noninvasive vagus
inhibit glutamate release from within this struc- nerve stimulation in 59 patients suffering from
ture [59], thereby potentially limiting propaga- chronic migraine with a mean headache fre-
tion of pain messaging. quency of 21.5 days per month. Patients adminis-
One small case series demonstrated the poten- tered three stimulation sessions daily in which
tial benefit of implantable vagus nerve stimula- they received two 90-s bursts of stimulation to
tion in six patients with either refractory chronic the right vagus nerve. At 2 months, the average
cluster or migraine [60]. Nesbitt et al. [61] uti- reduction in headache days per month was
lized a portable noninvasive VNS device for both −1.4 in the active VNS group versus −0.2 days
the acute management and prevention of head- with sham protocol. Fifteen patients randomized
ache attacks in eight patients with episodic clus- to active treatment completed an 8-month open-
ter headache and 11 patients with chronic cluster label period with a significant reduction in head-
headache. Forty-seven percent of attacks were ache days of −7.9 per month from baseline.
aborted within an average of 11 ± 1 min initiating Similarly, efficacy improved over time in studies
treatment. The average attack frequency was of VNS in depression and epilepsy [66, 67].
reduced from 4.5 per 24 h to 2.6 per 24 h. Gaul Adverse effects were similar between groups.
et al. [62] conducted a prospective, randomized,
controlled study (PREVA study) of adjunctive
transcutaneous vagus nerve stimulation versus Sphenopalatine Nerve Stimulation
standard-of-care treatment alone in 114 chronic
cluster headache sufferers and found that the Sympathetic hypoactivity and parasympathetic
number of attacks per week was significantly activation are cardinal features of some primary
reduced in the adjunctive vagus nerve stimulation headache disorders including cluster headache
group versus standard-of-care treatment alone at and the trigeminal autonomic cephalalgias, but
−5.9 vs. −2.1 attacks/week, respectively. Patients increased parasympathetic activity may also be
also experienced improvement in quality of life observed during the ictus of a migraine attack.
measures and a reduction in the use of abortive This is likely due to the presence of parasympa-
pharmacotherapies. thetic efferents, originating in the superior sali-
In an open-label study by Goadsby et al. vatory nucleus, projecting from the
[63], 30 patients with either migraine without sphenopalatine ganglion (SPG) to the meningeal
aura or migraine with aura utilized transcutane- blood vasculature, lacrimal gland, and nasal
ous vagus nerve stimulation for the acute man- mucosa. Activation along this pathway may
agement of migraine. Stimulation was delivered result in the propagation of neurogenic inflam-
in two 90-s bursts to the right vagus nerve. mation and ultimately headache through the
Thirty-eight percent of patients with attacks of release of vasoactive peptides [68, 69].
mild severity and 22% of patients with moder- Various SPG blockade methods have been
ate-to-severe pain experienced pain freedom at shown to be potentially effective at aborting clus-
2 h. Barbanti et al. [64] conducted another open- ter headache attacks including application of 4%
label study of transcutaneous vagus nerve stim- lidocaine intranasal droplets [70], 4% lidocaine
ulation for the acute management of intranasal spray [71], intranasal application of
high-frequency migraine and chronic migraine. cocaine or lidocaine using a cotton-tipped appli-
56.3% of patients in the active VNS group expe- cator [72, 73], and supra-zygomatic SPG block-
rienced pain relief at 1 h, 64.6% had pain relief ade with alcohol [74]. Case series as well as
at 2 h, and 35.4% and 39.6% were pain-free at 1 prospective and retrospective studies have also
and 2 h, respectively. Two-hour pain relief and suggested that patients with refractory cluster
headache may benefit from radiofrequency abla- additional translational and controlled clinical
tion of the sphenopalatine ganglion [75–80]. studies, specifically in the chronic migraine
Migraine has also been a potential target of SPG population, are needed to confirm.
blockade using intranasal lidocaine [81–83] with Transcranial magnetic stimulation methods
relatively rapid onset of relief. may prevent migraine through normalization
In a randomized, double-blind, placebo-con- of cortical hyper-reactivity, which is thought
trolled trial, Cady et al. [84] demonstrated the to be present in migraine sufferer, and by
potential effectiveness of SPG blockade in the upregulation of inhibitory input. Repetitive
management of acute headache attacks in patients transcranial magnetic stimulation is possibly
suffering from chronic migraine utilizing 0.3 ml efficacious for the prevention of migraine
of 0.5% bupivacaine delivered via the Tx360® attacks; however, the availability and portabil-
device. The active treatment group demonstrated ity of the delivery system may prohibit wide-
statistically significant reduction pain scores at spread utilization at this time. Single-pulse
15 min, 30 min, and 24 h versus placebo (saline). transcranial magnetic stimulation may have a
In a small open-label study of 11 patients with role in both acute and preventive treatment of
either episodic or chronic migraine, Tepper et al. migraine and is portable.
[85] sought to determine if electrical stimulation Sphenopalatine ganglion blockade meth-
of the SPG could abate an intractable migraine ods have been shown to possibly be effective
attack. Ten patients underwent stimulation. Two for the management of both cluster headache
patients achieved pain freedom, three reported and migraine; however, SPG neurostimulation
pain reduction, and five denied any change in trials in chronic migraine are limited and
headache severity. include one small open-label study. Additional
studies are needed.
Conclusion
Chronic migraine is prevalent, frequently dis-
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Postsurgical Headaches and Their
Management 26
Michael Doerrler and José Biller
Anatomy throbbing, or burning pain. A-delta fibers are

thought to transmit sharper pain sensations [2].
To understand the pathophysiology of postsurgi- Most of the sensation from the face and head
cal headaches, it is important to define the pain- is conveyed by the trigeminal sensory afferent
sensitive structures of the skull and brain. Much nerves. These fibers terminate in the trigeminal
of the anatomy of sensitive structures in the head brainstem nuclear complex (TBNC) [3]. The
was identified by Harold Wolff, Bronson Ray, TBNC is divided in the principal sensory nucleus
and Wilder Penfield in the mid-twentieth century and the spinal trigeminal nucleus. These fibers
[1]. The brain parenchyma is shown to lack the enter the brainstem in the sensory root of the tri-
capacity to sense pain. However, many structures geminal nerve. The ascending fibers terminate in
surrounding the brain do have this ability. These the principal nucleus, and the descending fibers
structures include the basal dura; meninges; make up the trigeminal spinal tract. The termina-
venous sinuses; cranial nerves V, IX, and X; tion of these fibers is topographically organized,
upper cervical nerves; dural arteries; carotid with the mandibular afferents terminating in the
arteries; vertebral arteries; basilar artery; circle of dorsomedial medullary dorsal horn (MDH) [3].
Willis; and proximal portions of the major intra- The ophthalmic fibers terminate in the ventrolat-
cranial vessels [1, 2]. Studies show the major eral MDH. Most nociceptive fibers from the face
contributors to intracranial nociception are tri- and head appear to terminate in the subnucleus
geminal afferents. These nerve fibers primarily caudalis rat models, but this still remains to be
sense mechanical, thermal, and chemical fully defined in a human model [3].
stimulation. TBNC fibers largely (60–80%) project to the
Further contributing to the nociceptive system contralateral thalamus. They cross and ascend
are the afferent nerve fibers which primarily enter with the medial lemniscus. This conglomeration
the trigeminal ganglion and dorsal root ganglion of of medial lemniscus and trigeminothalamic fibers
the upper cervical roots. The fibers involved projects to the ventro-postero-medial nucleus of
include small unmyelinated C fibers, lightly the thalamus (VPM) [3]. Only a small percentage
myelinated A-delta fibers, and silent nociceptors, of the neurons in the VPM respond to nociceptive
which respond only to extreme stimuli [2]. C fibers stimulation. These neurons primarily exist in the
have been associated with slow-building aching, outer regions of the VPM. These neurons appear
to receive fibers from the caudal aspect of the
TBNC. These caudal nociceptive TBNC projec-
M. Doerrler (*) · J. Biller
Department of Neurology, Loyola University Chicago tions also go to the posterior thalamus and the
Stritch School of Medicine, Maywood, IL, USA internal medullary lamina. The thalamus and the

346 M. Doerrler and J. Biller
TBNC appear to be the primary drivers in noci- modulate the intensity and scope of noxious
ceptive stimulation as there are few cortical neu- stimulation. It is also hypothesized that input
rons capable of responding to nociceptive events from the thalamus behaves similarly. Fibers from
[3]. The neurons that do respond in the cortex are the TBNC also project to the periaqueductal gray,
primarily for spatial localization and facilitating a known site of enkephalin production and pain
cortical arousal. modulation [3] (Fig. 26.1).
The trigeminothalamic system of nociception Nociception in this system can also be a
does, however, have multiple opportunities for peripheral process, transmitted by small unmy-
pain modulation. Projections from the somato- elinated afferents in muscle groups dissected dur-
sensory cortex and other cortical input appear to ing the procedure. The suboccipital musculature
Somesthetic cortex
(postcentral gyrus,
parietal lobe)
Thalamus, nucleus
ventralis posterior
Trigeminal lemniscus
Trigeminal ganglion
Mesencephalic nucleus
(proprioception) Opthalmic branch of V
Pons Maxillary branch of V

Main sensory nucleus of V
(mainly touch)
Mandibular branch of V
Medulla
Spinal cord
C2
Spinal nucleus of V
(mainly pain and
temperature)
Fig. 26.1 The trigeminal brainstem nuclear complex, as pathway [3]. Reproduced with permission from Biller J,
illustrated in this image, is the pathway thought to be a Gruener G, Brazis PW. DeMyer’s The Neurologic
major driver of postsurgical headaches. Nuclei send infor- Examination. 7th ed. New York, NY: McGraw-Hill; 2017
mation to the VPM via the anterior trigeminothalamic
26 Postsurgical Headaches and Their Management 347
the forehead. The skin and galea are elevated

and skin clips are placed. The incision is then
carried through the pericranium, temporalis fas-
cia, and muscle line. The temporalis muscle is
then stripped from the zygomatic process of the
frontal bone to gain further access to the tempo-
ral fossa, the pterion, and the greater wing of the
sphenoid [5]. With the skull exposed, four burr
holes are made in the skull. A drill is then used
to cut the interposing bone between the burr
holes. Once the bone is fractured by the drill, it
can be removed from the rest of the skull. The
underlying dura is now exposed and can be
incised. The dura is incised in a semicircular
fashion, reflected, and retracted, exposing the
Sylvain cistern underneath [5].
After the intracranial procedure is complete,
the dura is replaced and reconnected with simple
interrupted sutures. Gelfoam is then placed over
the dural incision to act as a seal and prevent sub-
galeal accumulation and CSF hypotension [6].
The bone flap is then replaced and connected to
Fig. 26.2 Suboccipital musculature in relation to the the skull by means of microplates. The tempora-
occipital bone. These muscles are frequently reflected lis muscle, temporal fascia, and galea are all
during suboccipital procedures. Surgical procedures in
this area are much more likely to be associated with post-
closed separately [6]. Finally the skin is closed
operative headaches [4]. Source: Plate 387, Gray’s and the surgical site cleaned and dressed.
Anatomy of the Human Body (1918) For craniectomy, the bone flap is left off.
Depending on the underlying pathology, proce-
(particularly the capitis muscles and levator scap- dure can vary where they might be expanded by
ulae) is more frequently associated with short- the placement of a dural graft.
term and long-term pain when compared to
supratentorial procedures [4] (Fig. 26.2).
Postsurgical Headaches
Craniotomy Technique Acute Headaches
While the location and reason may vary, the pur- Postsurgical causes for headache can be multifac-
pose of a craniotomy remains the same: to expose torial. Headaches related to surgery can be ini-
a variable amount of intracranial structures to tially subdivided into acute (occurring within
allow visualization and intervention. It is beyond <48 h of surgery) and chronic (new-onset head-
the scope of this text to provide a “how-to” for ache in the postoperative period lasting greater
this procedure, but a basic understanding of than 2 months). In the acute setting, up to 60% of
which structures are disturbed is important. As an post-craniotomy/post-craniectomy cases suffer
example, a fronto-temporo-sphenoidal craniot- from surgery-related pain. The pain is more com-
omy will be detailed; the principle remains the monly described as superficial, rather than deep
same throughout the skull. pain. This indicates that the acute pain experi-
With the patient supine, an incision is made enced by patients is more likely to be somatic pain
from the zygoma to above the hairline, down to rather than visceral pain [7]. The likely etiology of
the pain is injury to the scalp musculature and departments in 2005 shows that 48% of services are
associated soft tissue structures. The suboccipital prescribed on an as-needed basis [10]. The other
and sub-temporal routes are associated with the finding was that all centers used opioids with vari-
highest incidence of acute postoperative pain [7]. able therapies, as there is no standardized protocol
This is likely due to insult to the muscle groups in for post-craniotomy analgesia [10].
these regions [7, 8]. However, some studies show
a higher level of pain using a frontal approach. Opioid Medications
There is some suggestion that location is not as The opioid class is the mainstay of postoperative
important as the amount of tissue injury and the pain and has many side effects. Commonly, it can
sub-temporal and suboccipital approaches have cause decreased level of consciousness and respira-
more tissue to injure [8]. Cerebrospinal fluid tory depression. Increased cerebral blood flow and
(CSF) leakage can also account for some pain that by extension increased intracranial pressure also
patients experience. These headaches are usually occur [10]. In addition, their use can blunt the clini-
orthostatic in nature and resolve when lying flat. cal significance of the neurologic examination. Use
of these medications has been associated with pro-
longed ICU stays and ICU complications.
Acute Postcraniotomy Headache [9]
Diagnostic criteria: Acetaminophen with Codeine
Codeine-based analgesia has been widely used
A. Headache of variable intensity, maxi- for post-craniotomy pain control. It has a lower
mal in the area of the craniotomy, ful- risk of respiratory depression and sedation. It
filling criteria C and D also preserves pupillary light reflexes better than
B. Craniotomy performed for a reason other opioid medications [8, 10]. The main draw-
other than head trauma back of the medication is sub-optimal pain con-
C. Headache develops within 7 days after trol. However, this appears to be mediated by
craniotomy individual demethylation processes and is highly
D. One or other of the following: variable [10]. Other concerns about its use are
1. Headache resolves within 3 months common to all opioids, including constipation,
after craniotomy dependence, and addiction.
2. Headache persists but 3 months have
not yet passed since craniotomy Tramadol
Tramadol is an analgesic medication that acts on
Note: 1. When the craniotomy was for head opiate and non-opiate pathways. It is a μ-opiate
trauma, code as 5.1.1 acute post-traumatic receptor agonist but also acts to increase CNS
headache attributed to moderate or severe levels of serotonin and noradrenaline [8]. It is
head injury. less effective than morphine and has fewer side
effects. There is no ceiling effect and depression
of respiratory function is rare [8]. When com-
pared to other opioids for postoperative analge-
Treatment sia, it decreases length of stay and overall
Historically, surgeons presumed craniotomy hospitalization costs [11]. The main drawbacks
patients would not feel much pain due to the poor include nausea and vomiting after bolus and a
innervation of the dura and underlying brain tissue. small increase in seizure risk [8, 10].
As a result, analgesia was given on an “as-needed”
basis and there are still many questions that remain Morphine PCA
[8]. Presently, the main forms of acute pain control A morphine PCA affords the patient some control
consist of local analgesia in the form of a scalp over the levels of analgesia, while also allow-
nerve block and systemic analgesia, commonly an ing a baseline of pain control as well. This
opioid medication. A survey of UK neurosurgical gives the patient some psychological relief while
simultaneously decreasing the total morphine Dexmedetomidine

requirement for the patient. Jellish et al. found that Dexmedetomidine (trade name, Precedex) is a
in 2 years of using a dosage of 1.5 mg with an highly selective α-2 agonist which has been shown
8-min lockout (4 h max dose no greater than 40 g), to have antinociceptive effects through binding of
there were no incidences of respiratory depression these receptors both centrally and peripherally. It
or re-intubation related to analgesic use [12]. decreases pain scores up to 24 h postoperatively
compared to placebo [4]. It also decreases postop-
onsteroidal Anti-inflammatory Drug
N erative nausea and vomiting. Dexmedetomidine is
(NSAID) Medications associated with decreased morphine use compared
In the acute postoperative period, NSAID use is to placebo. Hemodynamic stability, a significant
controversial. They do decrease pain without the postoperative concern, is improved compared to
systemic side effects of opioid medications; how- placebo [4]. Dexmedetomidine can cause brady-
ever they do inhibit the cyclooxygenase pathway cardia, and, in some cases, bradycardia secondary
(COX-1 and COX-2). This inhibition of the to dexmedetomidine has been confused for a
COX-1 pathway can cause a clinically significant Cushing’s reflex (also known as vasopressor
defect in the hemostatic system [10]. This response to increased intracranial pressure charac-
increases the risk of intracranial hematoma and terized by increased blood pressure, irregular
other potential sites for bleeding [8]. Preoperative breathing, and bradycardia). There is a theoretical
diclofenac has been shown to decrease pain scores risk of delayed emergence from general anesthe-
postoperatively [4]. In a study comparing keto- sia, but some studies found no significant differ-
profen to acetaminophen, it was found that those ence between dexmedetomidine and placebo [4].
on ketoprofen have decreased oxycodone needs
compared to the acetaminophen group [4]. It also
has the potential to cause renal insufficiency. Due Chronic Headaches
to these risks, neurosurgeons have shied away
from their use for acute postoperative pain relief. Chronic headaches are known complications fol-
lowing craniotomy/craniectomy. These head-
Local Anesthetics aches are defined as occurring postoperatively,
The goal of local anesthesia is to block the nerves lasting greater than 2 months and not attributable
supplying the superficial tissues. This is achieved to any other cause. The incidence of chronic post-
by preventing nociceptive nerves from depolar- craniotomy headaches has been estimated
izing and sending signals to the spinal cord and between 12% and 34% [7]. These headaches can
brain. The most challenging aspect of local anes- present as chronic persistent head pain, tension
thesia is to localize the appropriate nerves for headaches, orthostatic headaches, headaches
blockade and to apply the block without causing with nuchal rigidity, local pain syndromes, or
unintended motor and sensory compromise [8]. even headache syndromes similar to migraines or
Blockade is not without its drawbacks. The most trigeminal autonomic cephalalgias. The exact
important drawback is the ephemeral nature of incidence of these subtypes is not fully defined.
the block, typically lasting only a few hours. Some studies show that in acoustic neuroma
However, 0.75% ropivacaine can last up to 48 h resection, postoperative headache incidence is
[7]. Potential risks include systemic toxicity with 46.7% for tension-type headaches, occipital neu-
repeated administrations, hematoma, infection, ralgia 16.6%, trigeminal neuropathy 16.6%, neu-
and, rarely, intra-arterial/subarachnoid injection ropathy of the intermedian nerve 10%, and
[8]. These blocks can be done preoperatively to cervicogenic headache 10% [13].
diminish the effects of intraoperative stimulation The exact cause of chronic post-craniotomy
on the circulatory system and postoperatively. In headaches is unclear but believed to be
one study preoperative blocks decreased pain multifactorial. Contributing causes include nerve
scores up to 12 h postoperatively, and morphine entrapment, persistent dural traction, CSF leak-
use was decreased in the first 24 h [4]. age, scar tissue formation, aseptic meningitis,
persistent musculoskeletal dysfunction, and even gesics including acetaminophen, NSAIDs, or opi-
central sensitization [7, 8, 14]. It has been hypoth- oids. While this may be effective in some patients,
esized that post-craniotomy headaches lie on the it can result in rebound headaches if the medica-
spectrum of post-traumatic headaches, with the tions are taken frequently. Cervicogenic headaches
surgery as trauma [15]. There is an increased may respond to trigger point injections [7].
headache incidence in sub-tentorial cranioto- Botulinum toxin type A (Botox) injections could
mies/craniectomies, in particular suboccipital be a potential avenue of therapy; however, some
[8]. Aside from location, approach and technique small studies have not shown benefit [7]. For other
seem to play a role. In regard to vestibular neuropathic pain, mainstay treatments such as tri-
schwannoma resection, bone flap replacement cyclic antidepressants, gabapentin, carbamazepine,
has a much higher incidence of headache (94% and duloxetine are tried based on patient’s medical
replaced vs. 27% not replaced). Duraplastic clo- comorbidities. Lamotrigine is reportedly effective
sure has a much lower incidence of headaches in trigeminal nerve pain disorders and may be of
than with direct dura closure (0% vs. 100%) [7]. clinical value in patients suffering from chronic
Drilling of the internal auditory canal and the use post-craniotomy headaches [7]. However, it is not
of fibrin glue also may have an association with considered a first-line agent. Patients with migraine-
increased incidence of postsurgical headaches like symptoms can be treated similarly to migraines,
[7]. The multitude of potential contributing fac- but in post-craniotomy/trauma patients, sodium
tors for chronic postsurgical headaches means valproate has been shown to be effective [8].
that effective treatment can be a difficult road to Opioids are used but are typically ineffective in
travel. However, most patients have some chronic neuropathic pain as there is a downregula-
response to a combination of pharmacologic and tion of μ-receptors as the disease state progresses,
non-pharmacologic therapies. making the opioids less effective. Tramadol, a
weak opioid agonist, can be effective as it also acts
on serotonin and norepinephrine uptake [7]. There
Chronic Postcraniotomy Headache [9] have been instances were ketamine has been used
Diagnostic criteria: for refractory post-craniotomy pain. It acts as an
NMDA receptor antagonist. Its use is limited as the
A. Headache of variable intensity, maxi- medication is foul tasting and has side effects of
mal in the area of the craniotomy, ful- hallucinations and feelings of unreality [7].
filling criteria C and D Local allodynia can be treated with a variety of
B. Craniotomy performed for a reason topical anesthetics or nerve blocks [8]. Most of these
other than head trauma act as sodium channel blockers (e.g., lidocaine) to
C. Headache develops within 7 days after reduce the spontaneous firing of peripheral nerves.
craniotomy While pharmacologic therapy alone can be
D. Headache persists for >3 months after effective, non-pharmacologic therapies can be
craniotomy added to increase the odds of a favorable out-
come in appropriate patients [8]. These therapies
Note: 1. When the craniotomy was for head include TENS, acupuncture, radiofrequency
trauma, code as 5.2.1 chronic post-trau- ablation, cryoablation, and physical therapy.
matic headache attributed to moderate or
severe head injury.
Hemicrania Continua
Treatment Hemicrania continua was originally described by

As the exact mechanism of postsurgical headaches Drs. Sjaastad and Spierings as a steady, non-parox-
is unclear, the treatment is often geared to the syn- ysmal, moderate to severe headaches that responded
drome that the symptoms most resemble. Patients reliably to indomethacin [16]. The pain these
will often be given or self-treat with systemic anal- patients suffer is always unilateral and does not
alternate, unlike the typical migraine phenotype. Scalp Neuralgias

These headaches have also been described some-
times as being associated with ipsilateral autonomic Neuropathic pain can form at the site of craniot-
symptoms (lacrimation, rhinorrhea, etc.). A small omy or craniectomy most likely due to localized
case series done by Gantenbein et al. in 2015 trauma, gliosis, nerve entrapment, and localized
described three patients with hemicrania-like syn- sensitization [22]. Diagnosis of scalp neuralgias is
dromes. While resistant to most NSAIDs, they had primarily clinical. The pain will be isolated to a
full relief on indomethacin [15]. These patients had specific superficial nerve distribution. The most
different surgical approaches for different underly- common scalp neuralgias are supraorbital and
ing pathologies; it was felt that they shared common occipital. The supraorbital can become entrapped
underlying pathophysiology through the cervico- by the frontalis muscle, and the occipital nerve
trigeminothalamic pathway [15]. In these patients, may become entrapped by the semispinalis capitis
MR imaging should be performed to exclude other muscle [23]. Another possible cause of neuralgia
structural causes of secondary hemicrania continua. in patients with occipital neuralgia and postsurgi-
These causes include carotid artery (ICA) dissec- cal anatomy would be a close proximity of the
tion, pineal mass or cyst, pituitary mass, ipsilateral occipital nerve and the occipital artery [23].
mass, unruptured ipsilateral intracranial aneurysm, The treatment for this can be localized,
and posterior fossa infarctions [17–20]. When eval- through nerve blocks, lidocaine patches, and in
uating these patients for postoperative hemicrania some cases nerve release procedures. The treat-
continua, the differential may also include side- ment can also be systemic through typical neuro-
locked chronic migraine or other trigeminal auto- pathic pain agents including GABAergic agents,
nomic cephalalgias [21]. tricyclic antidepressants, and the like.
Hemicrania Continua [9] CSF Hypotension Syndrome

Description: Persistent strictly unilateral
headache responsive to indomethacin. This is a pattern of headaches that can occur in
Diagnostic criteria: the post-craniotomy/craniectomy setting as a
result of imperfect dural healing or gaps in the
A. Headache for >3 months fulfilling cri- dura postoperatively. These headaches com-
teria B–D monly are worsened upon standing, but there
B. All of the following characteristics: have been reports of worsening upon lying as
1. Unilateral pain without side shift well. Associated symptoms include photophobia,
2. Daily and continuous, without pain- phonophobia, meningismus, nausea, vomiting,
free periods loss of hearing, blurred vision, double vision, and
3. Moderate intensity, but with exacer- in rare extreme cases depressed level of con-
bations of severe pain sciousness [24]. Spontaneous CSF hypotension
C. At least one of the following autonomic is either idiopathic or associated with systemic
features occurs during exacerbations connective tissue diseases, such as Marfan syn-
and ipsilateral to the side of pain: drome and Ehlers-Danlos syndrome, or malfor-
1.
Conjunctival injection and/or mations of the dura [24]. Postsurgical CSF leak
lacrimation can be attributed to any number of reasons,
2. Nasal congestion and/or rhinorrhea including dural dehiscence, size of the dural
3. Ptosis and/or miosis defect, surgical approach, and dural friability
D. Complete response to therapeutic doses limiting repair [25]. In vestibular schwannoma
of indomethacin (also known as acoustic neuroma) resection, there
E. Not attributed to another disorder appears to be increased need for surgical repair
of the trans-labyrinthine approach compared to
the retrosigmoid approach, but there was no dif- Initial management is typically conservative
ference in incidence of the rate of leaks [25]. It is including hydration, salt tabs, bed rest, and caf-
uncommon for spontaneous CSF leaks to cause feine. However, should conservative manage-
CSF rhinorrhea, but more common in a surgical ment fail, intervention may be required. If a
scenario. This is particularly true for the trans- spinal source is suspected, blood patching or
labyrinthine approach [25]. fibrin glue may be used [24]. However, in the
Diagnosis includes a thorough history and postsurgical CSF hypotension, surgical repair
physical examination MRI, and lumbar puncture may be required if conservative measures do not
(LP) (Fig. 26.3). A brain MRI should be per- work. Surgical management can include re-
formed with and without contrast, and depending approximating the dural edges, grafting with
on the location of the surgery, spinal imaging autogenic tissues (fat or muscles), or grafting
may also be needed. MR brain findings can with allogenic dural matrix.
include diffuse uninterrupted smooth pachymen-
ingeal enhancement, sagging of brain structures
(especially midline), subdural fluid collections, Headache Attributed to Low Cerebrospinal
pituitary enlargement, and decreased ventricle Fluid Pressure [9]
size [24]. Should spinal imaging be needed, MRI Diagnostic criteria:
may show extra arachnoid/dural fluid collection
or dural enhancement. If a spinal source of the . Any headache fulfilling criterion C
A
hypotension is suspected, however, the gold stan- B. Low CSF pressure (<60 mm CSF) and/
dard is myelography. or evidence of CSF leakage on
imaging
C. Headache has developed in temporal
relation to the low CSF pressure or CSF
leakage or led to its discovery

ICHD-3 diagnosis
Medication Overuse Headaches
In treating patients with chronic headaches, one

must resolve not to do further harm by causing
more headaches. Almost any pharmacologic
treatment for headaches increases the risk of
developing medication overuse headache (MOH).
However, some medications are more prone to
causing this than others. MOH are defined as
chronic headaches (>15 days per month) that
develop as a consequence of taking analgesic
medication too frequently [26]. Often, these
patients will note an increase in headache fre-
quency, sometimes to the point of being a daily
persistent headache. They will worsen when not
Fig. 26.3 MR brain post-contrast sequence in a patient
with CSF hypotension. Note smooth continuous dural taking the abortive medication, but will never truly
enhancement be headache free. For patients seeing primary care
services, MOH is most commonly caused by

over-the-counter (OTC) analgesics. Patients Medication Overuse Headache [28]
being seen in secondary and tertiary medical set- Diagnostic criteria:
tings (commonly the postsurgical population) are
most often afflicted by MOH caused by centrally A. Headache occurring on ≥15 days per
acting agents. For all chronic headache patients month in a patient with a pre-existing
in the United States, 23% are though to suffer headache disorder
from MOH. About 50% of patients with 15 or B. Regular overuse for >3 months of one
more headaches per month have MOH [26]. Not or more drugs that can be taken for
all patients with headaches on medication acute and/or symptomatic treatment of
develop headache and the exact pathogenesis is headache
unclear. Some feel that it is due to the difference C. Not better accounted for by another
in mechanism of medication, pathology of under- ICHD-3 diagnosis
lying headaches, or some as of yet undescribed
pathway. In the general migraine population, dif-
ferent medications convey different risks of head-
ache progression. Opioid medication use ther Postsurgical Syndromes
O
increased risk in patients using it more than Associated with Headaches
8 days out of a month. Barbiturates increased risk
in patients exposed greater than 5 days out of a rontotemporal Brain Sagging
F
month [27]. NSAIDs were protective of head- Syndrome
ache progression in patients suffering from less
than 10 days of headache out of the month but Patients can present with behavior typical of
increased risk in patients suffering from more behavioral variant of frontotemporal dementia
frequent headaches [27]. It is unclear what the (bvFTD) but can lack the obvious imaging
frequency of postsurgical patients with chronic changes, as well as have other findings on imag-
headaches suffer from MOH or if they suffer it in ing as well to suggest a different clinical entity.
a similar manner as patients in the general This syndrome has been called frontotemporal
population. brain sagging syndrome (FBSS). It typically
As MOH is a heterogeneous disorder, there is presents with an insidious decline in cognition
no international consensus on treatment. and behavior, daytime somnolence, and head-
However, the mainstay is removal of the over- aches [29]. They have cognitive decline in a simi-
used agent [26]. Commonly patients experience a lar manner as bvFTD, but do not have the typical
withdrawal 2–10 days after discontinuation of patterns of atrophy and have sagging of midline
medication. This typically manifests as a worsen- structures associated with CSF hypotension.
ing of the headaches, nausea, vomiting, sleep dif- Typical behavioral symptoms included are
ficulties, and anxiety. Duration of withdrawal disinhibition and apathy with concomitant onset
appears to vary depending on the overused drug of daytime sleepiness. Some patients can have an
with triptans being about 4 days and analgesics orthostatic component to their headache. In one
being about 10 days [26]. A suggested strategy is case series, only one of eight patients had verified
to withdraw the offending agent, to provide phar- CSF hypotension [29]. On MRI they were found
macologic and non-pharmacologic support for to have a range of findings including sagging of
withdrawal symptoms, and to prevent relapse of the brainstem and cerebellum and trans-tentorial
MOH. In one study, simply giving the patient herniation of medial temporal lobe and corpus
information about overuse headaches cut the callosum (Fig. 26.4). Pachymeningeal enhance-
occurrence by 42% [26]. There is currently no ment, subdural fluid collections, and atrophy
consensus whether to bridge a patient on prophy- were uncommon. These patients were found to
lactic medication during detoxification. have decreased frontal and temporal metabolism
Fig. 26.4 A sagittal T1 MR brain showing an example of

midline structure sagging in a patient with CSF
hypotension
on PET scan. Notably this hypometabolism

resolved after leak repair [29].
A variety of therapies were tried in these
Fig. 26.5 MRI brain FLAIR sequence showing paradox-
patients including corticosteroids, direct dural
ical herniation of a patient with a chronic right hemicrani-
repair, and blood patching. Some patients tran- ectomy who had worsening of left-sided weakness during
siently improved, but ultimately all declined periods of prolonged standing
despite therapy [29]. It is felt that this disease
process could represent a chronic CSF leak that after the hemicraniectomy without subsequent
could either be spontaneous or iatrogenic. It is replacement of the bone flap.
thought that this is a treatable disease process and The pathophysiology of the syndrome is felt
bears further research. to be caused by persistent atmospheric pressure.
A contributing component could be over-shunt-
ing by a VP shunt [31]. It may even have an
Syndrome of the Trephine orthostatic component. Untreated, SoT can prog-
ress to a paradoxical herniation causing further
The syndrome of the trephine (SoT) also known neurologic dysfunction, coma, and death [31].
as motor trephine syndrome, sunken brain and The treatment is replacement of the bone flap or
scalp flap syndrome, or sinking skin flap syndrome reduction of shunt flow volume.
is a rare syndrome involving a persistent cranial
vault defect after large craniectomy (Fig. 26.5). It
was first described in 1977 by Yamaura et al. [30]. Carotid Endarterectomy-Related
These patients principally present with severe Headaches
headaches, mental status changes, focal deficits,
or seizures. Uncommonly these patients can pres- There is a headache entity seen in patients that
ent with dysautonomia. These symptoms include undergo carotid endarterectomies. It is classified as
paroxysmal changes in heart rate, respiratory rate, a unilateral and ipsilateral headache that begins
temperature, blood pressure, and diaphoresis [31]. within 1 week of a carotid endarterectomy. It typi-
Autonomic symptoms portent a worse outcome cally will resolve within 1 month. It also cannot be
compared to its absence. The onset of this syn- attributed to any other pathology besides the
drome is typically late (months to over a year) surgery [32]. It can have an extremely variable
presentation that has had descriptions outside of the References

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Chronic Daily Headache
Classification 27
Maggie W. Waung and Morris Levin
Introduction Goals of Classification
Chronic daily headache affects approximately Many aspects of chronic daily headache classifi-
3–5% of the population [1–3], extracting signifi- cation have drawn heated debate, and we will
cant morbidity and healthcare costs. Despite the attempt to draw attention to the most salient
highly negative impact of chronic daily headache debates for the reader. A number of these conten-
on global health, relatively little is understood tions arise from different viewpoints on the goals
about the underlying mechanisms of headache of classification. For some, the major agenda of
chronification and maintenance. The limited headache classification is to allow rigorous epi-
mechanistic understanding of long-standing demiological characterization in order to facili-
headache poses significant challenges to the clas- tate quality research, enable the study of
sification and diagnosis of chronic headache. pathophysiology, and guide targeted treatment
This chapter discusses goals and pitfalls of head- discovery. However, another goal for headache
ache classification, provides a brief history of classification is more practical, to allow clini-
chronic daily headache classification, and sum- cians a guide for diagnosis and treatment of their
marizes the current knowledge of the major headache population. While these goals are not
chronic daily headache categories. Chronic head- always in opposition, there can be conflict when
aches of long duration will be presented, with classifications are overly stringent for research
attention given to chronic daily headache in chil- purposes versus overly broad or simplistic for
dren and the elderly. ease of diagnosis.
It has been proposed that a valid classification
should reflect underlying biological mechanisms,
demonstrate consistent clinical characteristics,
and predict treatment response [4]. Functional
classifications also tend to be relatively straight-
M. W. Waung (*) forward and easy to apply [5]. In examining the
Department of Neurology, University of California history of headache classification, it becomes
San Francisco, San Francisco, CA, USA clear that the back-and-forth between researchers
e-mail: Maggie.Waung@ucsf.edu
and clinicians in the iterative shaping of disease
M. Levin classification is critical for promoting the ongoing
Department of Neurology, UCSF Headache Center,
University of California San Francisco, discovery and understanding of headache mecha-
San Francisco, CA, USA nisms. Hopefully, discussion of the insights and

358 M. W. Waung and M. Levin
criticisms of chronic daily headache classification The ICHD-II criteria for chronic migraine
will illuminate the progress we have made in our were deemed to be overly restrictive, as Bigal
understanding of the basic mechanisms of chronic et al. demonstrated by classifying 638 CDH
headaches but also shine a spotlight on areas that patients over 20 years, with only 9 patients fulfill-
need further research and understanding. ing the ICHD-II criteria for transformed migraine
compared to 158 using the S-L criteria [13]. The
authors of this comparative study went on to argue
History of CDH Classification that the rarity of chronic migraine under the
ICHD-II criteria would hamper clinical trials in
Classification of chronic daily headache has a this group. The ICHD-II criteria for chronic head-
history of confusing taxonomy and nomencla- aches were further criticized due to their focus on
ture. In the early 1980s, Mathew et al. [6] drew a classification of attack phenomenology for a
connection between patients with daily head- snapshot in time and for not taking into account
aches and a history of episodic or menstrual- the progressive clinical course of patients, whose
related migraine and coined the term “transformed symptoms may develop insidiously over several
migraine.” At the time, it was generally believed years [14]. Many chronic migraine patients often
that daily headaches were more related to “mus- have several headache types, and many headaches
cle contraction headache” or tension headache. In did not fit the criteria for migraine, begging the
the early 1990s, the idea of transformed migraine question, “Why call it ‘chronic migraine’ when
[7] became associated with chronic daily head- the majority of headaches are usually tension-
ache as patients with episodic migraine devel- type?” [15]. In 2006, a proposal was put forth to
oped more severe and more frequent headaches. ignore the classification of specific attacks in the
These transformed headaches were either related diagnosis of chronic migraine with the justifica-
or unrelated to excessive drug use. tion that “most attacks of migraine without aura
By the mid-1990s, Manzoni et al. divided initially develop and go through a phase that phe-
chronic daily headache into chronic tension-type, nomenologically fulfills criteria for tension-type
chronic migraine, and migraine with interparox- headache before the headache gets worse, and
ysmal headaches, as headaches on at least 6 days early intake of triptan may abort the attack before
a week for at least 1 year [8], while the Silberstein typical characteristics of migraine develop.”
and Lipton (S-L) criteria defined chronic daily The 2006 ICHD-IIR diagnostic criteria
headache as headache lasting at least 4 h per day defined chronic migraine as:
for at least 15 days per month for at least 1 month,
with a history of transformation [9]. Silberstein 1. Headache on ≥ or equal to 15 days per month
et al. further subcategorized chronic daily head- for ≥3 months.
ache into transformed migraine, new daily persis- 2. Occurring in patient with at least five attacks
tent headache, chronic tension-type headache, fulfilling criteria for migraine without aura.
and hemicrania continua [10]. 3. On ≥8 days per month for ≥3 months, head-
Although discussion of chronic daily headache has fulfilled criteria for pain and associ-
ache classification was ongoing, it was not ated symptoms of migraine without aura, or
included in the first edition of the International patient has been successfully treated with an
Classification of Headache Disorders (ICHD-I) ergot or triptan and no medication overuse and
criteria published in 1988 [11]. Not until 2004 not attributed to another causative disorder.
with the publication of ICHD-II [12] did chronic
migraine replace transformed migraine as head- In 2010, a multiaxial classification for CDH was
aches lasting for greater than 3 months. In addi- proposed largely based on the structure of classifi-
tion to chronic migraine, definitions emerged for cation for psychiatric diseases [16]. This classifica-
chronic tension-type headache, new daily persis- tion addresses some of the criticisms arising from
tent headache, hemicrania continua, and medica- chronic daily headache and medication-overuse
tion-overuse headache. headache classification and attempts to break down
27 Chronic Daily Headache Classification 359
complexities of CDH into different axes for a more toxinA as “≥15 days per month with headache last-
comprehensive assessment of headaches. The pro- ing 4 h a day or longer,” further complicating
posed classification envisioned six different com- chronic migraine classification for the clinician.
ponents of CDH classification: ICHD-III (beta edition) was published in 2013 [17]
and will be used in this chapter for further discus-
Axis I: main headache category sion of the chronic daily headache subtypes.
Axis II: subtypes
Axis III: associated conditions
Axis IV: contributory factors and triggers (includ- CDH Differential Diagnoses
ing medication overuse)
Axis V: functional impairment Chronic daily headache affects up to 4.7% of the
Axis VI: pain severity adult population [2] and can be classified into
two major categories, primary or secondary
In the same year, the US Food and Drug headaches (Table 27.1).
Administration (FDA) approved a definition of In this chapter, we will discuss the major pri-
chronic migraine for prescribing onabotulinum- mary and secondary chronic headaches of long
Table 27.1 Primary and secondary causes of chronic daily headache

Primary causes Secondary causes
Chronic migraine with and without aura Medications and toxins
Chronic tension-type headache Persistent toxin exposure
Chronic cluster headache Medication-overuse headache
Hemicrania continua Posttraumatic head or neck injury
New daily persistent headache Post-craniotomy headache
Cervicogenic headache
Chronic subdural hematoma
Headache due to past ischemic stroke
Headache due to past nontraumatic intracranial hemorrhage
(subarachnoid, intracerebral, or acute subdural hemorrhage)
Headache due to vascular malformations (unruptured saccular aneurysm,
arteriovenous malformation, dural arteriovenous fistula, cavernous
angioma, encephalotrigeminal or leptomeningeal angiomatosis)
Headache due to past cervical or vertebral artery dissection
Cerebral venous thrombosis
Cerebral arteritis (primary central nervous system or systemic)
Headache due to past reversible cerebral vasoconstriction syndrome
Idiopathic intracranial hypertension (pseudotumor cerebri)
Spontaneous cerebrospinal fluid leak
Intracranial hypotension following lumbar puncture, trauma, or
durotomy
Solid brain parenchymal tumor (primary, metastatic, lymphoma)
Skull-based tumor (primary, metastatic)
Meningeal neoplastic disease
Neurosarcoidosis
Chronic viral or other meningoencephalitis (HIV, malaria, EBV)
Headache due to systemic infection in the absence of meningitis or
meningoencephalitis
Intracranial abscesses (bacterial, fungal, cysticercosis)
Hypophysitis
Chronic sinusitis
Adapted with permission from Levin [18]
HIV human immunodeficiency virus, EBV Epstein-Barr virus
duration. We will not address the short-lasting for at least 1 month to establish frequency of
headaches that may also develop into chronic symptoms. The phenotype of individual head-
forms such as chronic paroxysmal hemicrania, aches can vary within the same patient [19], and
chronic short-lasting unilateral neuralgiform migraine features such as throbbing pain, nausea,
headache attacks with cranial autonomic symp- photophobia, and phonophobia are less promi-
toms (SUNA), and chronic short-lasting unilat- nent in patients with chronic migraine compared
eral neuralgiform headache attacks with to episodic migraine [20, 21].
conjunctival injection and tearing (SUNCT).
Epidemiology
hronic Migraine with and Without
C
Aura Chronic migraine affects 1–3% of the global pop-
ulation [22, 23], which is more common than other
Chronic migraine is the most common chronic neurological disorders including epilepsy or
daily headache, classified as pain and associ- Parkinson’s disease. The ratio of female to males
ated symptoms of migraine without aura for 15 with chronic migraine mirrors the gender distribu-
or more days per month over 3 months or lon- tion in episodic migraine (approximately 2.5 to 3:1
ger, without medication overuse. As mentioned female to male) [23]. The age distribution of
above, it was first included in the ICHD-II in chronic migraine skews slightly older compared to
2004 under complications of migraine. episodic migraine with peak prevalence in the fifth
decade [23]. In the United States, chronic migraine
disproportionately affects individuals with low
ICHD-III Beta: Diagnostic Criteria household incomes while having no increased
A.
Headache (tension-type-like and/or prevalence for any particular race and ethnicity
migraine-like) on ≥15 days per month after adjusting for socioeconomic factors [23].
for >3 months [2] and fulfilling criteria
B and C
B. Occurring in a patient who has had at Risk Factors
least five attacks fulfilling criteria B–D
for 1.1 migraine without aura and/or The American Migraine Prevalence and
criteria B and C for 1.2 migraine with Prevention (AMPP) study found several risk fac-
aura tors for chronification of headache, including
C. On ≥8 days per month for >3 months, lower socioeconomic status, obesity, snoring,
fulfilling any of the following [3]: comorbid pain, head or neck injury, stressful life
1. Criteria C and D for 1.1 migraine events, high caffeine intake, overuse of certain
without aura medications [24], and persistent frequent nausea
2. Criteria B and C for 1.2 migraine [25]. In the Chronic Migraine Epidemiology and
with aura Outcomes (CaMEO) study, episodic migraine
3. Believed by the patient to be
patients with comorbid pain were also more
migraine at onset and relieved by a likely to develop chronic migraine [26]. The
triptan or ergot derivative presence of anxiety, depression, and allodynia
[27] also correlates with an increased risk of
ICHD-III diagnosis migraine chronification.
In patients with episodic migraine, approxi-
mately 2–3% of patients convert to chronic
migraine per year [28]. Interestingly, ineffective
Other Features treatment of episodic migraine was associated with
a higher risk of chronic migraine, suggesting that
A diagnosis of chronic migraine excludes ten- adequate treatment of episodic migraine may pre-
sion-type headache and requires a headache diary vent headache chronification, although refractory
episodic migraines may be a marker of impending Structural MRI studies looking at cortical surface
chronic migraine [29]. Other than reducing medi- area, cortical thickness, and regional volumes
cation overuse, so far there is no definitive data demonstrate changes in multiple brain regions,
demonstrating that modification of risk factors can including several known to be involved in pain
influence the natural history of chronic migraine. processing such as the anterior cingulate, the
medial orbital frontal cortex, the insula, and the
temporal pole. Principle component analysis of
Comorbidities structural imaging data enabled the development
of a set of anatomical classifiers to differentiate
AMPP Data—Psychiatric and pain disorders between chronic and episodic migraine patients
associated significantly more often with CM than [38]. Furthermore, the anatomical differentiation
EM include (Table 27.2): between chronic and episodic migraine using this
model is most accurate when using a threshold 15
headache days per month [38], further supporting
Pathophysiology the current definition of chronic migraine.
A few studies have utilized MRI to character-
The underpinnings of chronic migraine are ize alterations in iron homeostasis in the brain-
thought to involve both central and peripheral stem of patients with chronic migraine. Increased
mechanisms, with central nervous system altera- iron deposition in the periaqueductal gray posi-
tions supported by advanced imaging studies and tively correlates with the duration of migraine
CSF studies, while peripheral changes may be [34] and increased deposition of iron in the basal
implicated by serum biomarker studies. Central ganglia can differentiate between chronic vs. epi-
changes in cortical and subcortical structure, sodic migraineurs [39]. Resting-state functional
metabolism, functional connectivity, and noci- connectivity of areas involved in pain such as the
ceptive pain processing have been documented in periaqueductal gray and anterior insula correlates
chronic migraine patients compared to healthy with the frequency of attacks [40] and duration of
controls and episodic migraine patients [32–37]. chronic migraine [33].
Table 27.2 Comorbid conditions with increased prevalence on chronic migraine compared to episodic migraine
patients
Associated with Odds ratio 95% confidence interval
Comorbidities CM (%) EM (%) p value
Arthritis 33.6 22.2 1.71 1.43–2.05 0.001
Chronic pain disorders 31.5 15.1 2.49 2.08–2.97 0.001
other than migraine
Anxiety 30.2 18.8 1.80 1.51–2.15 0.001
Depression 30.2 17.2 2.00 1.67–2.4 0.001
Bipolar disorder 4.6 2.8 1.56 1.06–2.31 0.024
Obesity 5.0 21.0 1.24 1.03–1.50 0.020
Circulation problems 17.3 11.4 1.51 1.21–1.87 0.001
Heart disease 9.6 6.3 1.43 1.08–1.90 0.012
High blood pressure 33.7 27.8 1.23 1.03–1.47 0.021
Stroke 4.0 2.2 1.65 1.09–2.52 0.019
Allergies or Hay fever 59.9 50.7 1.47 1.25–1.73 0.001
Asthma 24.4 17.2 1.53 1.27–1.84 0.001
Bronchitis 19.2 12.9 1.54 1.25–1.89 0.001
Chronic bronchitis 9.2 4.5 1.99 1.49–2.65 0.001
Emphysema or COPD 4.9 2.6 1.73 1.18–2.54 0.005
Sinusitis 45.2 37.0 1.39 1.18–1.63 0.001
PTSDa 42.9 9.5 0.023
Data compiled from [30] and [31]a
Neurophysiological studies illustrate altera- chronic migraine may be more dependent on envi-
tions in the brainstem and cortical areas of patients ronmental or epigenetic factors. A European candi-
with chronic migraine. Laser-evoked potentials date genome-wide association study looking for
(LEPs) that elicit nociceptive brain responses via genetic factors associated with migraine chronifi-
activation of Aδ and C thermal nociceptors may cation did not find any significant associations [49],
be increased at baseline in chronic migraine though clearly more genetic studies are needed.
patients [36] and lead to increased activation of
the rostral anterior cingulate cortex compared to
episodic migraine patients, which correlates with Chronic Tension-Type Headache
migraine frequency [37]. Visual evoked potentials
measured via magnetoencephalography demon- Classification
strated increased occipital cortex excitability in
interictal chronic migraine patients, which are The classification of tension-type headache is
similar to visual processing changes seen in controversial, mainly because the current classifi-
patients with episodic migraine during an attack cation lumps a heterogeneous group of patients
[41]. Furthermore, hyperexcitability of the occipi- together whose headaches do not necessarily
tal cortex in chronic migraine patients was dem- reflect common neurobiological underpinnings.
onstrated using magnetic suppression of The clinical features of tension-type headaches
perceptual accuracy with transcranial magnetic are characterized by the absence of migraine-like
stimulation (TMS) [35]. features, and not based upon positive attributes or
Several small studies have examined a variety unique defining characteristics. However, a few
of molecules related to inflammation and pain neurophysiological, imaging, and genetic studies
processing, revealing altered molecular signal- point toward potential distinguishing features of
ing pathways in chronic migraine compared to chronic tension-type headache.
healthy controls. Patients with chronic migraine
have interictal elevation of serum CGRP com-
pared to EM patients [42]. Other biomarkers
reported to be elevated in serum or CSF of
ICHD-III Beta: Diagnostic Criteria
chronic migraine patients include tumor necrosis
factor-α [43], corticotrophin-releasing factor A. Headache occurring on ≥15 days per
[44], orexin-A [44], taurine, glycine, and gluta- month on average for >3 months (≥180
mine [45]. Lower levels of glial cell line-derived days per year), fulfilling criteria B–D
neurotrophic factor and somatostatin were found B. Lasting hours to days or unremitting
in chronic migraine patients compared to age- C. At least two of the following four
matched controls [46]. The melatonin metabolite characteristics:
6-sulfatoxymelatonin is elevated in urine of 1. Bilateral location
patients with chronic migraine compared with 2. Pressing or tightening (non-pulsat-
patients with episodic migraine and healthy con- ing) quality
trols [47], perhaps indicating aberrant hypotha- 3. Mild or moderate intensity
lamic signaling. Recently, adipokine dysfunction 4. Not aggravated by routine physical activ-
has been implicated in both episodic and chronic ity such as walking or climbing stairs
migraine, as levels of adiponectin, resistin, and D. Both of the following:
leptin were found to be elevated in chronic 1. No more than one of photophobia,
migraineurs compared to healthy controls [48]. phonophobia, or mild nausea
While the inheritability of episodic migraine is 2. Neither moderate or severe nausea
well accepted, genetic factors that may or may not nor vomiting
predispose to chronic migraine are not well estab- E. Not better accounted for by another
lished. It is possible that while episodic migraine ICHD-III diagnosis
has a strong genetic influence, the development of
Other Features ache precipitated by alcohol, over-matured

cheese, chocolate, and physical activity [60].
Aside from eliminating secondary causes, it is Risk factors for developing TTH include poor
important to distinguish chronic tension-type self-rated health, inability to relax after work, and
headache from chronic migraine, although this sleeping fewer hours per night [61].
can be challenging. Patients with chronic ten-
sion-type headache have been noted to exhibit
increased pericranial tenderness compared to Comorbidities
migraine [50, 51] and increased pain sensitivity,
which positively correlates with CTTH duration Chronic tension-type headaches have been linked
[52]. Pain intensities in extracranial muscles, to depression [62] and vitamin D deficiency [63].
such as the trapezius, also demonstrate changes
in the pain response curve and increased sensitiv-
ity in patients with chronic tension-type head- Pathophysiology
ache compared to healthy controls [53]. One
study has also found that patients with CTTH are High-quality studies addressing the pathophysi-
more likely to drink alcohol on a daily or near- ological mechanisms underlying chronic tension
daily basis [54], which may be a helpful distin- headache are lacking or produce conflicting
guishing factor from chronic migraine. Patients results among different research groups.
with chronic daily headache can technically ful- Clinical features of prominent cranial muscle
fill the criteria for both chronic tension-type tenderness led to the hypothesis that muscle-
headache (>15 headaches per month fulfilling related factors may contribute to tension-type
criteria for tension-type headache) and chronic headache. Electromyography (EMG) of pericra-
migraine (>15 headache days with >8 headaches nial muscles demonstrates higher activity on aver-
fulfilling criteria for chronic migraine), and these age in CTTH patients compared to healthy
patients are given the diagnosis of chronic controls; however neither elevated EMG activity
migraine headache only [17]. [64] or hardness of muscle [65] correlates with
pain severity. Furthermore, onabotulinumtoxinA
injections into pericranial muscles, while decreas-
Epidemiology ing electromyographic activity in pericranial
muscles, do not relieve headaches [66]. There is
Chronic tension-type headache occurs in 2–3% no elevation of inflammatory mediators (prosta-
of population-based studies [55–57]. There is a glandin E2, ATP, glutamate, or bradykinin) in ten-
slightly higher incidence of CTTH in women der points of patients with TTH compared to
compared to men (5:4 [3], 5:2 [50]), and the aver- healthy controls, suggesting that tender points are
age age of onset of TTH is higher than in not areas of ongoing inflammation [67].
migraine, ranging from 25 to 30 years in cross- Neurogenic inflammation also does not appear to
sectional epidemiologic studies [58]. The preva- play a key role in CTTH, as plasma concentra-
lence of chronic tension-type headache peaks tions of CGRP [68], substance P, neuropeptide Y,
between ages 30 and 39 and decreases slightly and vasoactive intestinal peptide are not different
with age [59]. in patients with CTTH compared to healthy con-
trols [69, 70].
Central sensitization plays a role in the trans-
Risk Factors formation of ETT to CTTH. Patients with CTTH
have generalized decreases in mechanical pain
Triggers reported most frequently for TTH are thresholds [71] and higher pain ratings with supra-
fatigue and stress, either mental or physical. Only threshold electrical stimulation [72] throughout
migraineurs had episodes of tension-type head- their body compared to ETT patients or healthy
controls, suggestive of a defect of central pain specific treatments and outcome data for patients
modulation. Differences in brainstem reflexes, with chronic tension-type headache.
such as decreases in the R2 amplitude of the noci-
ceptive-specific blink reflex [73] and abnormal
trigemino-cervical reflexes [74] are observed in Chronic Cluster Headache
patients with CTTH compared to ETTH. EMG
studies also support a role for altered descending Cluster headache is characterized by severe, uni-
modulation of pain. Altered pain-induced inhibi- lateral retro-orbital/temporal pain lasting for
tion of voluntary muscle activity in the temporalis 15 min to 3 h, usually associated with cranial
muscle in CTTH patients [75] indirectly impli- autonomic parasympathetic features. Chronic
cates inhibitory interneuron deficits. Glyceryl cluster headache is defined as cluster headache
trinitrate produces an immediate headache without attacks without periods of remission.
pericranial sensitivity followed by a typical ten-
sion-type headache hours later [76], similar to
migraine. Nitric oxide synthase inhibitors decrease Classification
muscle hardness in patients with CTTH, perhaps
through inhibition of central sensitization. ICHD-III beta: cluster headache attacks occur-
Structural studies using voxel-based mor- ring for more than 1 year without remission or
phometry demonstrate decreases in brain regions with remission periods lasting less than
involved in pain processing such as the dorsal 1 month
rostral and ventral pons, the anterior cingulate
cortex, and the insula, in CTTH as compared to
healthy controls or MOH patients [77]. These Diagnostic Criteria
changes correlated positively with increasing A. Attacks fulfilling criteria for 3.1 cluster
headache duration. headache and criterion B below
Genetic studies examining the inheritance of B. Occurring without a remission period
chronic tension-type headaches indicate that or with remissions lasting <1 month,
first-degree relatives have a two- to fourfold risk for at least 1 year
of developing CTTH compared to the general
population, suggesting a genetic component that
likely follows a multifactorial inheritance pat-
tern [78, 79]. Other Features
Bouts of pain in chronic cluster headache occur

Prognosis anywhere from every other day up to eight times
a day with a periodicity. Cluster headaches fre-
Poor outcome was associated with baseline quently peak in the early morning, midafternoon,
chronic TTH, coexisting migraine, not being or late evening and can occur nocturnally out of
married, and sleeping problems [61]. Overall, sleep [80, 81]. While patients with migraine
there is a general sense that the course of chronic headaches prefer lying down in a dark room dur-
tension-type headache is not as severe or pro- ing their headaches, patients with cluster head-
tracted as chronic migraine. In-depth epidemio- ache tend to be restless and agitated and describe
logical studies for chronic tension-type headache pacing around. Pain in cluster headache is often
have been scarce in part due to lack of consensus described as excruciating, with a boring, non-
on its definition. throbbing quality [82]. Furthermore, patients
Clearly, the mechanisms underlying chronic with chronic cluster headache may have a persis-
tension-type headache are not well understood, tent baseline headache between cluster attacks,
and this may reflect insufficiency in the nosology which can be confused for chronic migraine or
of this entity. This gap is reflected in the lack of hemicrania continua.
Individuals with CCH are more likely to report Comorbidities

radiation of the pain to the upper teeth, jaw,
cheek, ear, and shoulder. Rhinorrhea and osmo- Unlike chronic migraine, which is associated
phobia are more commonly reported features in with higher rates of depression and anxiety com-
CCH compared to episodic cluster headache. pared to episodic migraine, little is known about
Shifting of the affected side within the same bout the medical and psychiatric comorbidities of
of headaches is infrequent but occurs with higher cluster headache, much less chronic cluster head-
frequency in patients with chronic compared to ache. Some studies have demonstrated an
episodic cluster headache [81]. increased rate of mood disorders and depression
Chronic cluster headache can be chronic at in patients with chronic cluster headache [80,
outset (primary) or arise from episodic cluster 88]. A recent pilot study suggests a lower rate of
headache (secondary). Primary CCH represents anxiety and depression in chronic cluster head-
about 2/3 patients, while secondary CCH reflects ache patients compared to historical healthy con-
1/3 of patients with CCH. Notable triggers of trols [89]. More detailed and comprehensive
chronic cluster headache bouts include stress, multicenter studies are needed to better charac-
alcohol, and weather changes [80]. Light expo- terize the medical and psychiatric comorbidities
sure, crossing multiple time zones, and head related to chronic cluster headache.
trauma are also reported triggers of cluster
headaches.
Pathophysiology
Epidemiology The trigeminovascular system is thought to play

a key role in cluster headache pathophysiology.
The prevalence of cluster headache is 124/100,000 in In particular, autonomic features of cluster head-
population-based studies [83]. In a clinic-based ache are thought to arise via activation of the tri-
study, 4% of patients with episodic cluster headache geminal parasympathetic reflex through the
(ECH) converted to chronic cluster headache superior salivatory nucleus (SSN), which sends
(CCH) over a period of 16 years [84]. In another efferent projections via the sphenopalatine gan-
study, 13% of ECH converted to CCH over 10 years glion (SPG) to meningeal nociceptors. Activation
[85]. The mean age of onset of chronic cluster tends of meningeal nociceptors leads to subsequent
to be higher than with episodic cluster headache (37 activation of the trigeminal nucleus caudalis,
vs. 28). There is a striking male predominance of which facilitates trigeminal pain and further per-
chronic cluster headache, with the male to female petuates activation of the SSN. In support of this
ratio for chronic cluster headache ranging from 4:1 theory, low-frequency stimulation of the SPG can
[86] to as high as 15:1 [83]. provoke cluster-like attacks in patients with clus-
ter headache, while high-frequency stimulation
successfully treats these provoked attacks [90].
Risk Factors Functional brain PET imaging of patients with
episodic cluster headache has highlighted a region
Later onset of cluster headache, the presence of in the posterior hypothalamus that is active during
sporadic attacks, a high frequency of cluster peri- attacks but quiescent interictally [91], and MR
ods, and short-lived duration of remission peri- brain imaging studies have confirmed structural
ods are risk factors predicting the transition from changes in the same area in chronic cluster patients
episodic to chronic cluster headache [87]. [92]. In animal studies, the hypothalamus is capa-
External and lifestyle factors such as head trauma, ble of modulating sensory pain activity both in the
cigarette smoking, and alcohol intake have also trigeminal nucleus caudalis [93, 94] and through
been proposed to have a negative effect on the direct connections to the SSN [95]. The circadian
clinical course of cluster headache, but have not periodicity of cluster headaches implicates changes
been proven [87]. in hypothalamic signaling to the brainstem as
potential markers or causative factors in the devel- paroxysmal hemicranias by the presence of con-
opment of cluster headache bouts. Furthermore, tinuous, background headache without fluctuating
there is evidence of decreased CSF hypocretin-1 in periodicity. Although controversial [102, 103],
episodic and chronic cluster headache patients HC is generally accepted as a trigeminal auto-
compared to healthy controls [96]. Finally, a large nomic cephalalgia (TAC) and was included as
case series of patients with chronic cluster head- such in the ICHD-III beta criteria. Opponents
ache treated with deep brain stimulation in the against the classification of hemicrania continua
hypothalamus demonstrated a greater than 50% as a TAC argue that cranial autonomic symptoms
clinical improvement in a majority of patients. should not be viewed as prominent features of this
Thus far, there are limited studies differentiat- headache subtype [102].
ing the pathophysiology of chronic compared to
episodic cluster headache. In addition to the
clinical differences between chronic and epi- Classification
sodic headache noted above, there are indica-
tions of alterations in biochemical pathways,
such as tyrosine metabolism [97], in chronic Diagnostic Criteria
cluster that have distinct profiles compared to A. Unilateral headache fulfilling criteria

patients with episodic cluster headache. In con- B–D
trast to migraine, lack of habituation of the tri- B. Present for >3 months, with exacerba-
geminal nociceptive system has not been tions of moderate or greater intensity
consistently demonstrated in chronic cluster C. Either or both of the following:
headache [98], but there may be evidence of lat- 1. At least one of the following symp-
eralized central facilitation of trigeminal noci- toms or signs, ipsilateral to the
ception, as measured via electrically evoked V1 headache:
pain-related evoked potentials. In patients with (a) Conjunctival injection and/or
episodic cluster headache, this facilitation occurs lacrimation
at the level of the brainstem, while in chronic (b)
Nasal congestion and/or
cluster headache patients, there are additional rhinorrhea
changes in the evoked potentials corresponding (c) Eyelid edema
to supraspinal facilitation at the thalamic or cor- (d) Forehead and facial sweating
tical level [99]. (e) Forehead and facial flushing
(f) Sensation of fullness in the ear
(g) Miosis and/or ptosis
Prognosis 2. A sense of restlessness or agitation or
aggravation of the pain by movement
Limited longitudinal data exists for chronic clus- D. Responds absolutely to therapeutic

ter headache; however 33% of chronic cluster doses of indomethacin1
patients remit to episodic cluster [85]. E. Not better accounted for by another
ICHD-III diagnosis
1. In an adult, oral indomethacin

Hemicrania Continua should be used initially in a dose of
at least 150 mg daily and increased
First described in the 1980s [100, 101], hemicra- if necessary up to 225 mg daily. The
nia continua is characterized as a persistent, dose by injection is 100–200 mg.
strictly unilateral headache with ipsilateral cranial Smaller maintenance doses are often
autonomic features that is absolutely sensitive to employed.
indomethacin. It is distinguished from chronic
Other Features Epidemiology
Chronic background pain in hemicrania conti- Given the rarity of the disease, the prevalence of
nua is punctuated by exacerbations of variable hemicrania continua has been difficult to assess
frequency (as opposed to CPH and CH where and only a few hundred cases have been pub-
duration of attacks is more stereotyped). Pain lished in the literature. However, one headache
intensity can fluctuate, though in general the center diagnosed 34 new cases of HC over a
pain is described as more moderate, and 3-year period, suggesting the disorder is more
patients with HC are able to continue working, common than once thought [108]. One relatively
though work quality may be impacted. Eye large prospective case series looking at chronic
itching or foreign body sensation in the eye daily headache found the prevalence of HC to be
and facial and cheek swelling are commonly 0.8% [109]. There is a slight skew toward female
reported. Most patients follow an unremitting predominance for HC, with a male to female
subtype (60–80%), though some patients begin ration ranging from 1:1.8 to 1:2.8, and the pooled
with a remitting headache punctured by breaks mean age at onset is 40 years old, but the range of
of headache freedom lasting anywhere from reported HC cases includes patients from age 5 to
1 day to several weeks. 77 [110].
Pain is commonly located predominantly in Hemicrania continua is often misdiagnosed
the V1 distribution, including temporal, frontal, with a mean time to diagnosis ranging from 5 to
orbital, or retro-orbital regions [104, 105] with 12 years. Factors contributing to misdiagnosis
spreading of pain to other regions during exac- include a paucity of autonomic symptoms, over-
erbations [104]. Side-switching of pain [106] use of analgesics, and atypical aggravating fac-
can occur and rare reports of bilateral pain tors [111]. Another potential contributing factor
[107] sensitive to indomethacin have been is missing the presence of background pain in the
reported. Background pain is typically of mild history, as patients can tend to focus on exacerba-
to moderate intensity with dull and pressure- tions. Instead, hemicrania continua is often con-
like characteristics, but throbbing and stabbing fused with migraine, cluster headache, dental
background pain is also reported. Exacerbations pain, and sinus headache [111].
are often described as throbbing and/or stab- Evaluation for secondary causes of headache
bing. Lacrimation is the most commonly with head imaging, as with all TACs, should be
reported cranial autonomic symptom, and nasal performed. There are numerous secondary causes
congestion, conjunctival injection, and ptosis of HC including head injury [112], postpartum
are most commonly reported cranial autonomic [113], post craniotomy [114], venous malforma-
symptoms. Agitation during attacks as well as tion [115], ipsilateral brainstem infarction [116],
worsening of headache with movement can be leprosy [117], pituitary adenoma [118], osteoid
features. osteoma [119], nonmetastatic lung cancer [120,
There can be overlap with migrainous fea- 121], internal carotid artery dissection [122], and
tures, as many patients report photophobia, with pineal cyst [123]. Furthermore, secondary HC
a lesser extent reporting phonophobia. The may be responsive to indomethacin, so a positive
Indotest is used diagnostically in hemicrania con- indomethacin response should not be used as a
tinua, as HC patients respond absolutely to ade- rationale to forgo imaging studies.
quate levels of indomethacin, and the
reappearance of pain upon indomethacin with-
drawal is a positive confirmatory test. An addi- Pathophysiology
tional placebo control has been proposed to be
added to the Indotest to ensure the specificity of Responsiveness to indomethacin suggests a
indomethacin as an effective treatment. specific underlying mechanism, but delineation
of this mechanism has been elusive. PET stud- Classification

ies have demonstrated significant activation in
the contralateral posterior hypothalamus (simi-
lar to cluster headache) in patients during head- Diagnostic Criteria
aches compared to without headache on A. Persistent headache fulfilling criteria B
indomethacin, as well as ipsilateral dorsal ros- and C
tral pons (similar to migraine) and ipsilateral B. Distinct and clearly remembered onset,
ventrolateral midbrain and bilateral pontomed- with pain becoming continuous and
ullary junction [124]. unremitting within 24 h
C. Present for >3 months

Prognosis ICHD-III diagnosis
Most patients relapse with withdrawal of indo-

methacin; however 42% of patients could reduce
their effective dose by more than 50% [125]. Other Features
Headache in NDPH is generally described as

New Daily Persistent Headache mild to severe intensity, with variable pain loca-
tion, and often associated with migrainous fea-
New daily persistent headache (NDPH) was tures of vomiting, nausea, photophobia, and
first described in a case series by Vanast in phonophobia.
1986 [126]. Previously used terms for NDPH While NDPH has a clear history of onset that
include chronic headache with acute onset and distinguishes it from CM and CTTH, it is not
de novo chronic headache. New daily headache clear whether NDPH is a distinct entity or
is characterized by a persistent headache, daily whether it is a syndrome that encompasses a
from its onset, which is clearly remembered. number of disorders [127]. It is important to
Patients can often recall the exact date, time, exclude secondary causes, particularly sponta-
and what they were doing at the time. The pain neous intracranial hypotension, as well as
lacks characteristic features and may be venous sinus thrombosis, intracranial hyperten-
migraine-like and tension-type-like or have sion, carotid or vertebral artery dissection, men-
elements of both. ingitis, sphenoid sinusitis, posttraumatic
NDPH was first included in the ICHD-II headache, and cervical facet syndrome. As such,
classification; however this initial definition patients should receive thorough head and neck
excluded migrainous features, including moder- imaging, including MRI with and without con-
ate or severe nausea or vomiting, and patients trast, MRV, and MRA.
could have no more than one of photophobia,
phonophobia, or mild nausea. In ICHD-III, the
definition of NDPH was revised to allow inclu- Epidemiology
sion of migrainous features. Patients with head-
aches that fulfill both criteria for NDPH and CM The 1-year population prevalence of NDPH is
(or CTTH) are given the default diagnosis of anywhere from 0.03% [128] to 0.1% [2], and
NDPH. In contrast, patients that fulfill criteria there is a slight female predominance [129].
for both NDPH and hemicrania continua are Median age of onset of NDPH is in the 20s for
given the diagnosis of HC. women and in the 50s for men [129, 130].
Risk Factors patients [134]. Up to 76% of NDPH patients can

experience persistent headache for more than
NDPH often follows a preceding viral illness, 2 years, with only about 14% of patients achiev-
and EBV infection can be associated with ing headache remission [134]. NDPH with a
NDPH. Suggested predisposing factors include migrainous phenotype may portend a worse out-
cervical joint hypermobility or a stressful life come compared to NDPH patients without
event [131]. migrainous features [130].
Comorbidities Medication-Overuse Headache
NDPH patients have a higher prevalence of anxi- Medication-overuse headache is listed by the
ety [132], depression, somatization, and pain World Health Organization as the 20th leading
catastrophization compared to healthy patients or cause of morbidity worldwide [135]. The cate-
patients with chronic low back pain [133]. gory of medication-overuse headache is intrinsi-
Medication overuse is documented in over 1/3 of cally controversial and poses several challenges
NDPH patients [130, 134]. to classification. Whether medication overuse is
the root cause or manifesting symptom of wors-
ening headaches is not known and highly debated.
Pathophysiology Thus far, discontinuation of acute medication has
not been shown conclusively to produce improve-
The underlying mechanisms of NDPH are not ment of headaches in a controlled study. Similarly,
well understood, which may reflect the notion Scher and colleagues proposed that proving the
that NDPH is an umbrella term for many distinct existence of MOH would require the randomiza-
entities. Because NDPH is often linked to a pre- tion of patients with episodic headaches to either
ceding viral infection, it is postulated that CNS limited or frequent use of acute medications in
immune activation may play a role in the patho- order to document the development of worsening
physiology of NDPH. To support this idea, Rozen headache with medication overuse [136]. Neither
and Swiden found elevated levels of the proof these studies is feasible in the United States.
inflammatory cytokine TNFα in the CSF from 19 Observational studies suggest that withdrawal of
out of 20 patients with NDPH [43]. medications can lead to reduction of headaches
in a subset of patients, although it is not clear
whether this reduction in headaches reflects
Prognosis reversion to the mean or an intervention effect
(either placebo or medication withdrawal itself).
In general, the prognosis for NDPH is poor. The first formal definition of medication-over-
Although the majority of patients with NDPH use headache (MOH) appeared in the ICHD-II
described by Vanast achieved complete headache criteria and included typical headache features
remission over 2 years, other case studies have associated with the specific medications used.
demonstrated that NDPH can persist for years The idea of medication-specific clinical subtypes
and become refractory to treatment. A subset of was challenged, as differential headache features
patients with NDPH, more often those who have did not bear out with rigorous clinical data col-
had symptoms for less than 6 months, can have a lection. The number of days of medication over-
self-limited course, and a relapsing remitting use and the overall length of time of medication
form has also been described in a minority of overuse are also not based on formal evidence,
although certain medications do seem to have a Classification

higher propensity toward medication overuse,
such as the barbiturates, opioids, and combina- Headache occurring on 15 or more days per
tion analgesics. month developing as a consequence of regular
In 2005, a revision for the definition of MOH overuse of acute or symptomatic headache medi-
was developed based on constructive criticism cation (on 10 or more or 15 or more days per
given at the International Headache Research month, depending on the medication) for more
Seminar in Copenhagen in March 2004. This revi- than 3 months. It usually, but not invariably,
sion included “(i) elimination of the headache
characteristics for each MOH subtype; and (ii) a
new subform that takes into account patients over- Diagnostic Criteria
using medications of different classes but not any A. Headache occurring on ≥15 days per
single class (combination of acute medications)” month in a patient with a preexisting
[137]. In the 2006 ICHD-II revised criteria, the headache disorder
requirement for medication withdrawal was dis- B. Regular overuse for >3 months of one
pensed for the diagnosis of medication-overuse or more drugs that can be taken for
headache. These revised criteria (ICHD-IIR) were acute and/or symptomatic treatment of
published in 2011. Critics of the revised criteria headache [1]
felt that although the criteria may be more appli- C. Not better accounted for by another
cable to clinical application, they may hamper rig- ICHD-III diagnosis
orous research on the basic mechanisms of MOH,
and the definition of MOH in large-scale epide-
miological studies may make results more difficult
to interpret. resolves after the overuse is stopped.
Another limitation of the ICHD-II definition General comment: In the criteria set out below
of MOH required two clinic visits and at least for the various subtypes, the specified numbers of
2 months of medication withdrawal before the days of medication use considered to constitute
diagnosis could be given. For example, if medi- overuse are based on expert opinion rather than
cation overuse was present, then a diagnosis of on formal evidence.
probable chronic migraine and MOH were given.
If headache improved after medication with-
drawal, then MOH was confirmed. In the most Epidemiology
recent proposed criteria for headache disorders,
the ICHD-III beta, patients meeting criteria for The prevalence of medication-overuse headache
chronic migraine and medication-overuse head- in the general population is close to 2% [139–
ache should be given both diagnoses. After drug 141] with a male to female ratio of 1:3 [141, 142]
withdrawal, the patient can be re-diagnosed and peak prevalence in the fifth decade [141].
accordingly, either as episodic migraine with
medication-overuse headache or chronic
migraine. Risk Factors and Comorbidities
While medication-overuse headache is often
thought of as a secondary headache, there is debate There is an increased prevalence of active smokers
as to whether MOH is a complication of migraine and obesity in patients with medication-overuse
and thus should be characterized under primary headache [142]. MOH is also associated with
headache disorders, specifically as a complication increased frequency cardiovascular comorbidities
of migraine. Medication overuse in itself is not such as hypertension, diabetes, and a history of
sufficient to cause or exacerbate headache, and myocardial infarction [142]. The prevalence of
there is clinical evidence that MOH occurs pre- MOH is higher in individuals with lower educa-
dominantly in the background of migraine [138]. tion level and lower annual income [141].
Pathophysiology intracranial pathology, infection, disrupted

homeostasis, or disorders of the cranium, cervi-
Animal studies point toward medication overuse as cal spine, temporomandibular joint, and eyes.
a condition with discernible features and changes These secondary headaches tend to improve with
in neural circuitry. For example, upregulation of amelioration or treatment of the underlying dis-
CGRP and neuronal nitric oxide synthase (nNOS) order and will not be discussed here.
in trigeminal ganglia dural afferents occurs with
both prolonged triptan and chronic opioid exposure
[143, 144]. Intriguingly, subthreshold pain hyper- ersistent Headache Attributed
P
sensitivity can be unmasked even after cessation of to Traumatic Injury to the Head
medication exposure with either stress or adminis-
tration of a NO donor [144]. Furthermore, imaging By definition, persistent headache attributed to
studies in humans demonstrate functional meta- traumatic injury to the head or chronic posttrau-
bolic and connectivity differences between patients matic headache (PTH) begins within 7 days of
with chronic migraine and medication overuse trauma or after consciousness is regained after
[145, 146]. Clinical data indicates that MOH may trauma; however this cutoff is controversial, as
require an underlying migraine (or other primary new headaches have been reported to arise even
headache) phenotype [138, 147], arguing against a 3 months after TBI [152]. These criteria were
purely independent neurobiology. modified from the ICHD-I diagnostic criteria,
A number of genetic polymorphisms related to which allowed for a time interval of up to 14 days.
dopaminergic signaling and addiction pathways Similarly, the time landmark of 3 months delin-
have been associated with medication-overuse eating between acute and chronic PTH may be
headache; however none of these associations have arbitrary [153]. Patients who experience worsen-
been replicated or validated in an independent ing of a primary headache directly after head
cohort of medication-overuse patients [148]. While trauma are also given both a diagnosis of chronic
these studies suggest a possible genetic predisposi- migraine (or tension-type headache) and persis-
tion toward development of medication-overuse tent PTH according to ICHD-III, and this was
headache, better designed studies are required. amended from the ICHD-II criteria, which main-
tained patients in this category under preexisting
Prognosis
The prognosis of medication-overuse headache is Diagnostic Criteria

linked to successful detoxification from medica- A. Any headache fulfilling criteria C and D.
tions. There is an estimated 20–40% relapse rate B. Traumatic injury to the head has
after medication detoxification within the first occurred.
year [149–151]. C. Headache is reported to have developed
within 7 days after one of the following:
1. The injury to the head
Persistent Secondary Headaches 2. Regaining of consciousness follow-
ing the injury to the head
Persistent secondary headaches are most com- 3. Discontinuation of medication(s) that
monly a result of traumatic injury to the head and impair ability to sense or report head-
neck. ICHD-III separates out posttraumatic headache following the injury to the head
ache into three major categories based on the D. Headache persists for >3 months after
mechanism of trauma: injury to the head, injury the injury to the head.
attributed to whiplash, and injury attributed to E. Not better accounted for by another
craniotomy. Secondary headaches may also arise ICHD-III diagnosis.
due to cranial or cervical vascular disorders,
migraine exacerbated by headache attributable to of chronic PTH arising from mild compared to
head injury. moderate/severe TBI [152, 162].
Classification omorbidities and Risk Factors

C
in PTH Chronification
Description: headache of greater than 3 months’
duration caused by traumatic injury to the head There is a 30% prevalence of PTSD in patients
with chronic posttraumatic headache [163], and
this tends to be higher in combat-related injuries.
Other Features In deployed military personnel, PTSD symptoms
were correlated with PTH severity [164].
Chronic PTH does not have any unique clinical Depression, anxiety, and cognitive complaints
features. The most commonly reported are also associated with PTH [165].
characteristics of persistent headache due to TBI Risk factors for developing chronic PTH
are migraine or tension-type headache features include insomnia, multiple concussions, and
[154, 155], though characteristics of other pri- lower socioeconomic status [164, 166]. Older age
mary headaches have been reported. Headaches (>60 years) may be protective against PTH [154].
are not necessarily localized to the site of head
injury. PTH is often accompanied by post-con-
cussive symptoms such as dizziness, tinnitus, Pathophysiology
photophobia, phonophobia, blurred vision,
decreased smell, fatigue, impaired attention, A large component of acute pain after head or
decreased concentration, slowed mental process- neck trauma is often attributed to musculoskele-
ing, impaired memory, and irritability. These tal injuries, but trauma to the head can also result
post-concussive symptoms are not distinctive for in cortical contusions or diffuse axonal injury due
post-concussive syndrome, and most are indistin- to shearing forces [167]. Injury to white matter
guishable from migraine. tracts can be observed with diffusion tensor
imaging as changes in fractional anisotropy (FA)
that can persist for up to 6 months after traumatic
Epidemiology brain injury [168]. Decreased FA in the splenium
and increased FA in the genu of the corpus cal-
Posttraumatic headache occurs in 30–90% of losum are associated with patients with TBI who
patients after TBI, and 18–22% of patients con- develop PTH [169].
tinue to experience PTH headache after 1 year On a cellular level, the physical impact of con-
[156, 157]. In population-based surveys, the cussion in animal models causes sudden stretching
prevalence of PTH is found to be 0.2% [140]. of neuronal membranes, leading to unregulated flux
People with pre-injury history of headache are of ions across channels and excessive release of
more likely to develop PTH [158]. In the civilian excitatory neurotransmitters. Increased excitatory
population, the most common modes of head activity in cells trying to restore resting membrane
injury are motor vehicle accidents, falls, occupa- potential leads to increased energy demand with
tional accidents, and sports injuries. Blast injury decreased oxidative capacity from stunned mito-
from combat zones is the most common source of chondria. This metabolic cascade of events renders
TBI leading to persistent headache in military neurons vulnerable to cell death, particularly in
personnel [159]. Some studies demonstrate that response to repeated injury [170, 171], which may
posttraumatic headaches are paradoxically more be a mechanistic explanation for why cumulative
likely to occur after mild TBI [160, 161]. head injury over time predisposes individuals to the
However, other studies have found similar rates development of posttraumatic headache.
Impairment of cerebral vascular autoregula- 12–36 months and more likely to be delayed for
tion can also occur after brain injury, and higher younger children [178]. CDH may significantly
cerebral vasoreactivity, as measured by transcra- impact the quality of life in this age group, lead-
nial Doppler coupled to end-tidal CO2, correlates ing to frequent absenteeism from school and can
with increased severity of posttraumatic head- also affect sleep [177]. Diagnosis and manage-
aches [172]. ment of headaches in this age group can be chal-
Factors playing a role in PTH chronification lenging for a number of reasons. There are no
include central sensitization from axonal injury of specific CDH criteria for children, and many of
pain-inhibiting structures of the brainstem and the treatments used in adults for CDH are either
abnormal cortical processing [153]. Underscoring not effective or not well-tolerated in children.
persistent alterations in central pain processing
mechanisms, quantitative sensory testing in
chronic PTH patients demonstrates mechanical Clinical Features
hyperalgesia and allodynia over the cranium [173]
and changes in conditioned pain modulation, also As with adults, chronic migraine and chronic ten-
known as diffuse noxious inhibitory control, which sion-type headaches are the most frequent subtype
is lower in patients with chronic PTH [174]. A of headache in children [179]. Clinical features of
recent MRI study demonstrates differences in migraine headache in children may differ from
brain structure in patients with persistent PTH adults, in that headaches may be of shorter duration,
compared to patients with chronic migraine [175], headache location is more likely to be bilateral, and
likely indicating unique pathophysiology of PTH. photophobia and phonophobia are more likely to be
inferred by behavior [17]. Headache location tends
to be more frontal and temporal, with a subset
Prognosis describing facial migraine pain. On the other hand,
exclusive occipital pain is rare in children and
While most patients with PTH improve with time, should prompt further diagnostic investigation.
up to 23% of patients continue to have headache In young children, recognized variations of
at 1 year after injury [152]. Patients who continue migraine include cyclical vomiting syndrome,
to have frequent headaches at 1 year may continue abdominal migraine, benign paroxysmal vertigo,
to have chronic PTH after 5 years [176], though vestibular migraine, benign paroxysmal torticol-
this has not been directly studied. Outcomes tend lis, infantile colic, and alternating hemiplegia of
to be worse for older patients, female gender, and childhood [17].
those with comorbid depression and anxiety.
More severe headaches develop with penetrating
TBI and pre-injury headaches [158]. Epidemiology
Chronic daily headache affects 1.5–3.5% of chil-

hronic Daily Headache in Children
C dren and adolescents [180–182]. There is a higher
and Adolescents prevalence of chronic daily headache in girls
compared to boys, even prior to adolescence
Chronic daily headaches may also affect children (approximately 2:1) [181, 182].
and adolescents, with frequent headaches affect-
ing children as young as 2 years old [177].
Identification of primary headache in children Chronic Daily Headache in Elderly
can be difficult for parents and healthcare provid-
ers due to the common belief that migraine only Although primary headache disorders generally
affects adults. As a result, a definite diagnosis for begin at a younger age, they may become chronic
recurrent headache is often delayed by at older ages, and 5.4% of all de novo headaches
occur in patients 65 years and older [183]. ictal headache, and obstructive sleep apnea with
Secondary headache is more common in the headache. Because hypnic headache arises dur-
elderly, and new headaches arising in this popula- ing sleep at night, it can often be differentiated
tion should prompt a thorough work-up. From from cluster headache by the low degree of cra-
population-based studies, around 4% of the total nial autonomic features. The clinical prevalence
elderly population experiences chronic daily of hypnic headache is 0.07–0.4%. A majority of
headache [184, 185]. There may be some pheno- patients with hypnic headache experience head-
typic differences in elderly patients with primary aches upon wakening more than four times per
headache disorders. For example, patients with week [188], with the length of headaches averag-
migraines between 60 and 70 years of age were ing between 15 and 180 min.
less likely to have unilateral headaches, nausea, Because it is so rare and often misdiagnosed,
vomiting, photophobia, and phonophobia com- the prognosis of hypnic headache is not well
pared to younger migraine patients. Instead, studied. A systematic analysis of published case
elderly patients with migraine were more likely reports on hypnic headache demonstrated sponta-
to describe paleness, dry mouth, and anorexia as neous remission in about 5% of reported cases
symptoms of migraine [186]. Furthermore, case and 43% remission in patients treated with pro-
reports have documented late-life migrainous phylactic agents [189].
accompaniments in the elderly, such as visual Overall, treatment of headache in the elderly
aura, sensory symptoms, motor weakness, ver- should take into account the higher frequency of
tigo, and other brainstem symptoms [187]. These coexisting medical conditions and polypharmacy.
symptoms can pose a diagnostic challenge in dif- Elderly patients have decreased medication toler-
ferentiating between migraine versus stroke or ance due to reduced hepatic and renal clearance,
so lower doses of acute and preventive medica-
tions should be used and slowly titrated to effect.
Hypnic Headache Criteria
A. Recurrent headache attacks fulfilling

criteria B through E Refractory Headaches
B. Developing only during sleep and caus-
ing wakening In general, refractory headaches have failed
C. Occurring on ≥10 days per month for multiple classes of acute and preventive treat-
more than 3 months ments at adequate doses for an adequate time
D. Lasting ≥15 min and for up to 4 h after period due to lack of efficacy. Surprisingly, a
waking consensus on the definition of refractory head-
E. No cranial autonomic symptoms or ache has not been reached nor defined in the
restlessness ICHD classifications. Schulman et al. have pro-
F. Not better accounted for by another posed criteria for refractory migraine based on
ICHD-III diagnosis surveying members of the American Headache
Society: proposed criteria for refractory
migraine include (1) the fulfillment of criteria
for migraine or chronic migraine and (2) signifi-
transient ischemic attacks. cant interference with function and quality of
Hypnic headache is a primary headache disor- life despite adequate trials of abortive and pre-
der described exclusively in the elderly with a ventive medications. Adequate trials of preven-
mean age of onset of 60 years old. Pain in hypnic tives include adequate doses of at least 2 months
headache is described as diffuse, non-throbbing, at maximally tolerated doses alone or in combi-
and moderate in severity. nation, from at least two different drug classes.
Important secondary causes to rule out include For abortive medications, intranasal and inject-
temporal arteritis, nocturnal seizures with post- able formulations of triptans and/or dihydroer-
gotamine (DHE) should be trialed in addition to 3. Stovner L, Hagen K, Jensen R, et al. The global
burden of headache: a documentation of headache
either NSAIDs or combination analgesics [190]. prevalence and disability worldwide. Cephalalgia.
This definition may be included into the ICHD 2007;27(3):193–210.
as a separate chapter, a refractory subset for 4. Lipton RB, Stewart WF, Merikangas KR. Reliability
each headache type, an “R” modifier for refrac- in headache diagnosis. Cephalalgia. 1993;13(Suppl
12):29–33.
toriness, or as a new axis [191]. 5. Ramadan NM, Olesen J. Classification of headache
One reason that no formal definition exists disorders. Semin Neurol. 2006;26(2):157–62.
may be that refractory headaches reflect difficult 6. Mathew NT, Stubits E, Nigam MP. Transformation
to treat headaches of existing categories. of episodic migraine into daily headache: analysis of
factors. Headache. 1982;22(2):66–8.
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Index
A Antiepileptics, 218
Aberrant autonomic dysfunction, 328 cluster headache treatment, 88
Acceptance and commitment therapy (ACT), 234 gabapentin, 219
Acetaminophen, 211 levetiracetam, 220
Acupuncture, 53, 72 pregabalin, 220
and chronic daily headache, 254, 281 topiramate, 218–219
and cluster headache, 256 valproate sodium, 219
cost analysis, 256 zonisamide, 220
and migraine, 255 Antihistaminics, cluster headache treatment, 89
and pediatric headache, 256 Antinuclear antibodies (ANA), 172
side effects, 254 Antiphospholipid antibody syndrome, 172
and tension headache, 255 Antiphospholipid protein syndrome (APS), 171, 172
Acupuncture point injection (API), 254, 256 Anxiety disorders, 199
Acute headache, 195, 196 and CDH, 322
treatment, 208 Aromatherapy, 265
Acute herpes zoster, 127 Arteriovenous malformations (AVMs), 117
Acute migraine Arthritis Self-Efficacy Scale, 14
management, 214 Atenolol, 220
nonspecific therapies, 211 ATP1A2 gene, 179
opiate/opioid treatment, 211 Atypical facial pain, 34
patients, 165 Aura (CSD), 170, 295
rational pharmacologic management, 209, 210 Autoimmune disorders, 172
specific therapies, 212 Autoimmune hepatitis, 172
Acute retroviral syndrome, 174
Acute symptomatic HIV infection, 174
Acute therapies, 210 B
Acute-onset neurological symptoms, 178 Baclofen, 129
Advanced kinetic modeling, 165 Beck anxiety inventory (BAI), 188
Allodynia/hyperalgesia, 43, 225, 295, 296 Beck depression inventory for primary care
Alpha-blockers, tizanidine, 223 (BDI-PC), 188
American Academy of Neurology, 84 Beck depression inventory-II (BDI-II), 188
American Headache Society, 45 Behavioral approaches, 231–234
American Migraine Prevalence and Prevention (AMPP) CBT
study, 39, 315–316, 360 acceptance-based interventions, 234
American Physical Therapy Association (APTA), 257 behavioral strategies, 232
Amitriptyline, 143 cognitive strategies, 232
tricyclic antidepressants, 222 psychological education, 232
Anaesthetic blocks relaxation techniques, 232–233
anaesthetic occipital nerve blockade, 224 non-pharmacological treatments, 231
sphenopalatine ganglion blockade, 223 psychological interventions
Anaesthetic occipital nerve blockade, 224 CAM, 231
Angiotensin II receptor blockers, candesartan, 223 CBT, 231
Angiotensin-converting enzyme (ACE), 175–178 relaxation training, 231
I/D polymorphism, 197 Behavioral variant of frontotemporal dementia
Animal CM model, 289, 290 (bvFTD), 353

M. W. Green et al. (eds.), Chronic Headache, https://doi.org/10.1007/978-3-319-91491-6
384 Index
Benzodiazepines, 211 clinical signs of, 68

β-blockers Cephalic allodynia, 296
atenolol, 220 Cerebral aneurysm, 117
propranolol, 220 Cerebral autosomal dominant arteriopathy with
Blood oxygen level-dependent (BOLD), 158 subcortical infarcts and leukoencephalopathy
Blood-volume-pulse feedback (BVP), 233 (CADASIL), 177
Body mass index (BMI), 189 Cerebral hyperperfusion syndrome (CHS), 355
Borrelia burgdorferi, 190 Cerebral venous thrombosis (CVT), 102, 117, 171
Botox, 4 Cerebrospinal fluid (CSF) pressure, 30
Botulinum neurotoxin type A (BoNT-A), 297 glutamate, 314
Botulinum toxin, 47, 225 hypotension syndrome, 351–352
injections, 130 Cervical spinal cord, 82
toxin A, 71 Cervical vascular disorder
Brain abnormalities, in headache syndromes, 157 cerebral aneurysm, 117
Brain gray matter (GM), 157 cerebral venous thrombosis, 117
Brain tumor, 120 cervicocephalic artery dissection, 118
Brain-derived neurotrophic factor Val66Met giant cell arteritis, 118
polymorphism, 197 hemorrhagic stroke, 117
Brainstem auditory-evoked potential (BAEP) vascular malformations, 117
measurements, 297 Cervicalgia, 323
Bridging therapies, 198, 200 Cervicocephalic artery dissection, 118
Brief symptom inventory (BSI), 187 Cervicogenic headache, 32
Burning mouth syndrome, 140 Cervicoscapular musculature, 190
clinical presentation and diagnostic criteria, 140 CGRP, see Calcitonin gene-related peptide
epidemiology, 140 CHD, see Chronic daily headache
etiology, 140 Chiari I malformations, 31, 120–121
management, 141 Childhood maltreatment, 322
Burning mouth syndrome (BMS), 34 Chiropractic manipulation
adverse events, 261
cervicogenic headache, 258
C and chronic daily headache, 258
CACNA1A gene, 179 cost analysis, 261
CADASIL, see Cerebral autosomal dominant and migraine, 260
arteriopathy with subcortical infarcts and and pediatrics, 260
leukoencephalopathy and tension headache, 259
Calcitonin gene-related peptide (CGRP), 50–53, 88, 227, Chronic central poststroke pain (CPSP), 35
292, 294, 314 Chronic daily headache (CDH), 15–19, 148–154, 157,
in FHM-1, 300 158, 160–162, 164, 165, 316–319, 321–329,
upregulation of, 300 335–341, 357–359, 373–374
using monoclonal antibodies, 298 case study, 20–21
Calcium channel blockers, 3, 223 characteristics, 313
Canadian Occupational Performance Measure (COPM), children and adolescents, 147, 373
186 in elderly, 373–374
Carbamazepine, 128, 143 epidemiology, 148, 373
Carcinomatous meningitis, 176 impacts, 149–150
Cardiovascular injury, 189 prognosis, 154
Carotid endarterectomy-related headaches, 354–355 risk factors for, 148–149
Catecholamine-secreting tumors, 171 treatment, 150–154
CBT, see Cognitive-behavioral therapy chronobiology, (see also Cluster headaches), 79
Celiac disease, 328 classification
Center for Disease Control (CDC), 151 components of, 359
Central executive network (CEN), 164 goals of, 357–358
Central neuropathic pain history of, 358–359
classification, 142 multiaxial, 358
definition, 142 comorbid disorders, 321
management, 143 definition, 1, 6, 147
multiple sclerosis, 142 diagnosis and classification, 2
pathogenesis, 142 diagnostic criteria, 6
Central post stroke pain, 142 differential diagnoses, 359–360
Central sensitization, 43 epidemiology, 1
Index 385
episodic migraine patients, 361 short duration, 28

future aspects, 166 Silberstein and Lipton (S-L) criteria, 358
genetics, 314–315 subtypes, 25
ICHD-IIR diagnostic criteria definition, 358 treatment, 6–7
medical disorders Chronic headache, 171
allergic rhinitis and asthma, 327–328 Chronic meningitis, 191
cardiovascular diseases, 328–329 Chronic migraine (CM), 1, 2, 44–55, 158, 185, 196,
irritable bowel syndrome, 328 209–212, 217, 290–300, 302
obesity, 326–327 acute headache treatment, 208
sleep disorders, 326 acute migraine treatments, 210
thyroid disorders, 325–326 nonspecific therapies, 211
mood disorders rational pharmacologic management, 209, 210
anxiety disorders, 322 specific therapies, 212
childhood maltreatment, 322–323 acute treatment, 289
depression, 321–322 in adults, 373
post-traumatic stress disorder, 323 allodynia/hyperalgesia, genetic manipulations, 290
MRI, 157, 158 animal models, 289–291
brain structure, 158, 160–162 anatomical networks, repeated nociceptive
functional brain abnormalities, 162, 164, 165 stimulations, 290–295
musculoskeletal disorders, 323–324 blood–brain barrier permeability, 295
cervicalgia, 323 clinical human phase trials, 292
connective tissue disorders and pain disorders, electrophysiological mechanisms and non-
324 pharmacological treatment, 296–298
temporal mandibular dysfunction, 323 by isosorbide dinitrate, 292
neuroimaging modalities, 165 limitations, 302
neurological disorders mechanical trigeminal (periorbital) aversive
epilepsy, 325 nociception, 302
head injury, 324 mechanism, 299
ischemic stroke, 325 pharmacological triggers, migraine, 292
neurostimulation preclinical behavioral features, 295–296
characterisation, 335 preclinical drug screenings, 292
implantable occipital nerve stimulation, 336–337 repeated dural application of IS, 294
repetitive-pulse transcranial magnetic stimulation, sensory nociception, 300
338 tetracycline-derived antibiotics, 295
single-pulse transcranial magnetic stimulation, therapeutic significance, 299
338 trigeminal nociception, 300
sphenopalatine nerve stimulation, 340–341 in children, 373
transcranial direct current stimulation, 339 clinical practice, 37
transcranial stimulation methods, 337–338 clinical trials, 55–56
transcutaneous supraorbital nerve stimulation, comorbidities, 361
336–337 cost and economic burden, 309–311
transcutaneous vagus nerve stimulation, 339–340 definition, 147–148
non-pharmacologic treatment, 8 diagnosis and classification, 37–39
pathophysiology, 2, 314 diagnostic criteria for, 2–3, 38
prevalence, 321, 357 epidemiology, 39–40, 360
primary and secondary causes, 26, 359 features of, 290
psychoeducation, 20 ICHD-IIR definition, 358
psychosocial interventions, 15 long duration, 26
cognitive-behavioral therapy, 15–17 management and treatment
motivational interview, 17–19 calcitonin gene-related peptide, 50–53
quality of life in, 315–316 comorbidity, 44
risk transformation, factors for dihydroergotamine, 45
acute stress, 317–318 nonpharmacological, 53–55
depression, 318–319 peripheral neurostimulation, 54–55
medication overuse, 316–319 pharmaceutical preventive, 46
menstrual-related migraines, 319 pharmacological, 45–49
obesity, 316 preventive, 44
sleep, 317 medication overuse headache, 208, 209
secondary, 26 medications, 290
self-efficacy, 19 molecular mechanisms, 298, 300
386 Index
Chronic migraine (CM) (cont.) characteristics, (see also Chronic cluster

neurobiological mechanisms of migraine headache), 364
transformation, 289 classification, 364
neurological condition and treatment, 290 clinical features, 78–79
neurostimulation, 297 comorbidities, 365
neurotransmitter pathways, 298 description, 77
noninvasive vagus nerve stimulation, 298 differential diagnoses, 79–80
pain-modulating system, serotonin depletion/chronic hemicrania continua, 81
hyperleptinemia, 290 paroxysmal hemicrania, 80
pain-sensing pathways, 298 SUNA, 81
pathophysiology, 40–44, 289, 361–362 SUNCT, 81
pharmacological treatment, 297 epidemiology, 77–78, 365
practical management, 226 functional neuroimaging, 83–84
prevalence, 321 forms, 78
primary CNS, 298 management, 84
receptor-mediated signaling, 298 ergotamine derivatives, 85
repeated trigeminal nociceptive stimulation greater occipital nerve injection, 86
inflammatory soup/mediator, 290 indomethacin, 86
nitroglycerin, 290 interventional and surgical, 89–91
risk factors, 360–361 lidocaine, 85
selected therapy, 210 long-term preventive therapy, 86–89
status migrainosus, 212, 213, 215 octreotide, 85
suppression, 207 oxygen, 84–85
synaptic function, 298 triptans, 85
therapeutic approaches, 289 nerve stimulation, 335
therapeutic paradox, 207 pathophysiology, 83, 365–366
transcranial direct current stimulation, 297 physicians taking care, 91
transcranial magnetic stimulation, 297 prognosis, 366
transcutaneous nerve stimulation, 298 risk factors, 365
transmembrane remodeling enzymes, 298 signs and symptoms, 365
treatment, 3–4 synonyms, 77
with and without aura, 360 CMP, see Complete metabolic profile
Chronic Migraine Epidemiology and Outcomes Codeine-based analgesia, 348
(CaMEO) study, 39, 360 Coenzyme Q10 (ubiquinone), 277, 278
Chronic migraine OnabotulinumtoxinA Prolonged anti-inflammatory properties, 278
Efficacy open-label (COMPEL), 225 cardiovascular benefits, 278
Chronic occipital neuralgia, 34 efficacy, 278
Chronic pain electron transport chain, 277
brain networks, 163 episodic/chronic migraine, 278
disorders, 166 in mitochondrial function, 278
Chronic paroxysmal hemicranias, 28 Cognitive-behavioral minimal contact program, 197
Chronic posttraumatic headache, 371, 372 Cognitive behavioral therapy (CBT), 8, 231, 233,
Chronic primary headache disorder, 189 235–236
Chronic refractory headache, 175 acceptance-based interventions, 234
Chronic tension-type headache (CTTH), 4, 65, 158, 185, assessment, 16
196, 313, 314, 316 autogenic training, 16
diagnostic criteria, 4 behavioral strategies, 232
ETTH vs., 66 biofeedback, 16
long duration, 26 in children, 152
vs. migraine, 202 for chronic pain, 15
prevalence, 321 cognitive strategies, 232
treatment, 4–5 goals, 15
See also Tension-type headache healthy habits
Chronification of headache, 196 exercise, 236
Classical nervus intermedius neuralgia, 132 hydration, 235–236
Classical trigeminal neuralgia, 34, 126 nutrition, 235
Clinical Evaluation Guide (CEG), 188 sleep, 236
Clomiphene citrate, 89 HMSE scale, 17
Clonazepam, 130 HSLC scale, 17
Cluster headache, 80, 81, 84–91 interventions, 54
Index 387
medication overuse, with chronic migraine, 54 Drug-induced liver injury, 170

pain catastrophizing scale, 17 Duloxetine, 223
progressive muscle relaxation, 16 Dystonia, 33
psychological education, 232
relaxation techniques
biofeedback and neurofeedback, 233 E
PMR, 233 Economic burden, CDH, 309–311
relaxation training, 16 E-diaries, 191
review and outcomes, 233–234 Electroencephalogram (EEG), 191
TTH, 72 Electromyographic (EMG), 233, 242
Comorbid psychiatric disorders, 187 Emergency practitioner, 169
Complementary and alternative approaches, 240, 241 Emergency rooms (ERs), 210
Complementary and alternative medicine (CAM), 231, Endarterectomy-related headaches, 354–355
239, 253, 281–283 Endocrine testing, thyroid function studies, 172, 173
Complete blood count, 169, 170 Enzyme immunoassay (EIA), 173
Complete metabolic profile (CMP), 170 Epilepsy, and CDH, 325
Computed tomography (CT), 190 Episodic headache disorders, 157
Contact point headache, 103 Episodic migraine (EM), 159, 160, 208, 209, 218, 222
Cortical excitability, 42 Episodic tension-type headache (ETTH), 64
Cortical spreading depression (CSD), 295 Erenumab, 51
migraine progression, 297 Erythrocyte sediment rate (ESR), 171, 172
Cortical thickness, 161 European Federation of Neurological Sciences, 70
Cortical thickness analysis (CTA), 157 European Headache Alliance, 91
Corticosteroids, 105–106 European Headache Federation Expert Group, 56
cluster headache treatment, 87 European vs. North American health systems, 186
Corticosteroids vs. placebo, 200 Evoked potentials (EPs), 297
Cranial vascular disorders, 29–30 Extracephalic cutaneous allodynia, 296
Craniectomy, 347, 349, 351, 354
Craniosacral manipulation, 265
Craniotomy, 116, 347 F
C-reactive protein (CRP), 171, 172, 190 Facial nerve, 132
CTTH, see Chronic tension-type headache False-positive enzyme immunoassays, 173
Cutaneous allodynia, 295, 296 Familial hemiplegic migraine (FHM), 179, 300
dysfunction of channels and pumps, 290
FHM-1, 300
D FHM-2, 301
Daily headache disorders, 197 FHM-3, 301
Daith piercing, 266 FHM-4, 301
D-dimer study, 171 Fast-onset oral triptans, 212
Deep breathing, 247–248 Fernald Medical Monitoring Program (FMMP), 325
Default mode network (DMN), 164 Feverfew
Dehydration, 170 adverse events, 275
Delayed preventative therapy, 198 during pregnancy, 275
Depression, 44, 188, 199, 202 efficacy of, 275
and CDH, 322 headache prevention, 274
Dermatomyositis, 172 histamine release, 274
Detox studies, 316 mechanism of action, 274
Detoxification, 198–200, 202 medical conditions, 274
Developmental venous anomalies (DVAs), 117 parthenolide, 274
Dietary Supplement Health and Education Act platelet secretion, 274
(DSHEA), 273 preparation/dosage, 274
Dietary supplements, 273 prophylactic migraine treatment, 275
children, 274 vascular contraction and relaxation, 274
Diffusion tensor imaging (DTI), 157 Fibromyalgia (FMS), 68
Diffusion-weighted imaging (DWI), 158 Flunarizine, 223
Dihydroergotamine (DHE), 45, 85, 106, 200, 212 Fluoxetine, 222
Divalproex sodium, 88 Food and Drug Administration (FDA), 91
Dopamine antagonists, 212 Fremanezumab, 52, 53
Dorsolateral prefrontal cortex (DLPFC), 159, 163 Frequent episodic tension-type headache, 64
Droperidol, 213 Frequent Headache Epidemiology Study, 324
388 Index
Frontotemporal brain sagging syndrome, 353–354 prevalence, 321

Frovatriptan, 87 prognosis, 368
Functional brain abnormalities, 166 short duration, 28
Functional MRI (fMRI) methods, 158, 162, 164, 165 treatment, 5
Hemiplegic migraine, 179
Hemorrhagic stroke, 117
G Herbal medicine, 280
Gabapentin, 88, 130, 219 Herbal remedies, 273, 274
Gamma knife surgery, 130 Herbs, natural and safe profiles, 281
General pain VAS (GnVAS) levels, 219 Histamine, 89
Generalized Anxiety Disorder 7-item scale (GAD-7), 188 Homeopathic remedies, 281
Genetic effect, in rats, 302 Homeopathy, 274
Genetics and headache, 314–315 Homeostasis disorder, 121
Geniculate neuralgia, 132 Horner’s syndrome, 189
Giant cell arteritis (GCA), 29, 103, 118, 171 Hydrotherapy, 265
Ginkgo biloba, 280 Hyperalgesia, 295, 296
Ginkgolide B (Ginkgo biloba), 280 Hyperbaric oxygen therapy, 266
Glossopharyngeal neuralgia Hypercoagulability, migraine, 180
clinical presentation and diagnostic criteria, 131–132 Hypercoagulable disorders, 170
epidemiology, 131 Hypersensitivity to NTG, 296
etiology, 131 Hypertension, 171
medical management, 132 Hypnic headache (HH), 374
surgical management, 132 short duration, 29
Greater occipital nerve (GON) injections, 86 Hypoglycemia, 170
Hypothalamic or pituitary tumors, 173
Hypothalamic-targeted therapy, 91
H Hypothyroidism, 32, 172, 173
Head injury, and CDH, 324
Headache chronification, 198
Headache diaries, 191, 192 I
Headache disability index (HDI), 260, 263 ICHD-diagnosed cyclic vomiting syndrome, 276
Headache disorders, 169, 170, 172 Identify Chronic Migraine (ID-CM), 38
hypercoagulable state, 181 Idiopathic intracranial hypertension (IIH), 30, 102, 118,
opening pressure measurements, 175 172, 191
pathophysiology, 189 IgG index, 177
thyroid function, 172 Immediate preventative therapy, 198
Headache management self-efficacy (HMSE) scale, Immunocompromised, daily headaches, 179, 180
14, 17 Immunofluorescence assays, 173
Headache rescue rooms, 213 Immunoglobulin G (IgG), 173
Headache specialist, 186 Immunoglobulin M (IgM), 173
Headache transformation Implantable occipital nerve stimulation, 336–337
drug overuse, 315 Indomethacin, 5
obesity and, 317 Infrequent episodic tension-type headache, 63
pathophysiology of, 314 Intercellular adhesion molecule (ICAM), 247
reversible cause of, 316 International Association for Study of Pain, 125
risk in, 316 International Burden of Migraine Study, 39
role in, 318 International Classification of Headache Disorders
Headache-specific locus of control (HSLC) scale, (ICHD), 125, 147, 358
12–14, 17 International Classification of Headache Disorders 3rd
Healthcare providers, 187 edition (ICHD-3), 37, 185
Helicobacter pylori, 173 International Classification of Headache Disorders 3rd
Hemicrania continua (HC), 81, 148, 158, 196, 313 edition beta version (ICHD-3 beta), 113
characteristics, 366–368 International Headache Society (IHS) guidelines, 355
classification, 366 International Headache Society Classification of
definition, 5 Headache Disorders (ICHD), 25
epidemiology, 367 Intracranial hypotension, 119–120
long duration, 27 Intracranial neoplasia, 31
pain, 367 Intracranial sectioning, 132
pathophysiology, 367–368 Intracranial thrombosis, 190
post-surgical headaches, 350 Intracranial vasculature and meninges, 292
Index 389
Intranasal agents, cluster headache treatment, 89 Long-lasting headaches, 196

Ischemic ocular motor nerve palsy, 136 Low cerebrospinal fluid (CSF) pressure/volume, 30
clinical presentation and diagnostics criteria, 136 Lumbar puncture (LP), 175, 191
etioloy, 136 opening pressure, 175
treatment, 137 Lyme disease, 173, 174, 190
Ischemic stroke and CDH, 325 Lyme neuroborreliosis, 174
Isolated migraine aura, 177 Lymphocytic hypophysitis, 173
L M
Laboratory investigation, in CDH, 169–179 Magnesium, 276, 277
endocrine testing blood level testing, 276
prolactin, GH and ACTH, 173 in children with migraine, 277
thyroid function studies, 172, 173 Magnesium deficiency, 276
genetic testing Magnetic resonance imaging (MRI), 157, 191
CADASIL, 177 brain GM, 157
familial hemiplegic migraine, 179 multiple structural approaches, 157
MELAS, 178, 179 white matter, 157, 158
MTHFR and ACE polymorphisms, 178 Magnetic resonance spectroscopy (MRS), 157
hypercoagulability states, 180 Magnetoencephalography (MEG), 157
IGG index, 177 Manipulation-based therapies, 253–256, 258–264
immunocompromised, 179 acupressure, 257
infectious acupuncture
HIV, 174 and chronic daily headache, 253–255
Lyme, 173, 174 and cluster headache, 256
lumbar puncture, 175 cost analysis, 256
angiotensin-converting enzyme, 175, 176 and migraine, 255
cell count and differential, protein and glucose, and pediatric headache, 256
175 and tension headache, 255–256
cytology, 176 chiropractic manipulation, 261–262
infectious workup, 176 adverse events, 261
tumor necrosis factor alpha, 176, 177 cervicogenic headache, 258
lumbar puncture, 175 and chronic daily headache, 258
oligoclonal bands, 177 cost analysis, 261
opening pressure, 175 and migraine, 260
pregnancy, 179 and pediatrics, 260
serological testing spinal manipulation, 258
coagulation studies, 170, 171 spinal mobilization, 258
complete blood profile, 169 and tension headache, 259–260
complete metabolic profile, 170 dry needling, 257–258
inflammation markers, 171, 172 massage
plasma metanephrines, 171 and adverse events, 264
traumatic brain injury, 180 and cervicogenic headache, 263–264
Lamotrigine, 129 and chronic headache, 262
Leiden University Cluster headache neuro-Analysis and cost analysis, 264
(LUCA) study, 79 and migraine, 263
Levetiracetam, 220 and pediatric headaches, 264
Lidocaine injections, 257 and tension headache, 262–263
Lidocaine plus corticosteroid injections, 257 reflexology, 265
Lipton-Silberstein classification system, 38 Manufacturing process, 273
Lithium Massage
carbonate, 6 and adverse events, 264
cluster headache treatment, 87 and cervicogenic headache, 263
Liver function, 170 and cost analysis, 264
Locus of control (LOC) and migraine, 263
definition, 11 and pediatric headaches, 264
patient-provider frustration, 19 and tension headache, 262
psychological construct, 11 Maximum pain VAS levels (MaxVAS), 219
Long-duration CDHs, 185 Mechanism-based CM therapy, 298, 300
Long-duration headaches, 185 Medial prefrontal cortex (mPFC), 163
390 Index
Medical costs, CDH, 310 meditation, 242–246

Medical preventive therapy, 198 Tai chi, 247
Medication, 152 yoga, 246–247
Medication overuse (MO), 148, 161 Mindfulness-based cognitive therapy (MBCT), 234
Medication- overuse headache (MOH), 31, 82, 148, 158, Mindfulness-based stress reduction (MBSR), 234, 242
160, 161, 208, 209, 300 Minnesota Multiphasic Personality Inventory-II
characteristics, 369 (MMPI-II), 187
classification, 370 Mirtazapine, 71
comorbidities, 370 Mitochondrial encephalomyelitis with lactic acidosis and
definition of, 195, 369 stroke-like episodes (MELAS), 170, 178, 179
diagnosis and clinical features, 196 Mitochondrial energy deficiency, 278
diagnostic criteria, 196 Mixed connective tissue disease, 172
drug withdrawal or detoxification, 199, 200, 202 MOH, see Medication overuse headache
epidemiology, 196, 370 Monitoring of chronic daily headaches, 185
existence of, 369 headache diaries, 191, 192
individual with chronic migraine, 209 laboratory assessments, 190
limitation of, 370 mental health monitoring, 187, 188
outpatient vs. inpatient treatment, 201 office visit, 186, 187
pathophysiological mechanisms, 197 physical monitoring, 189, 190
pathophysiology, 371 radiological monitoring, 190
post-surgical headaches, 351–353 specialized testing, 191
preventive therapy, 199 vital signs monitoring, 188
prognosis, 371 Motivational interview (MI)
relapse, 202 client-centered, 18
risk factors, 197, 370 clinical principles, 18, 19
treatment, 198, 199, 202 directive method, 18
withdrawal-associated symptoms, 200 identify change strategy, 18
Meditation meta-analysis, 17
for headache, 243, 245 motivation for change, 19
MBSR, 242 philosophy, 18
mindfulness meditation, 242 stages of change model, 18
neuroscientific underpinnings, 245 Motor trephine syndrome, 354
physiological benefits, 242 Multidimensional psychiatric screening, 188
potential mechanism, 244–245 Multidisciplinary headache programs, 186
RCT, 242 Multidisciplinary therapy (MDT), 186, 187
secular meditation, 244 Multiple sclerosis (MS), 127, 142, 175, 177
spiritual meditation, 244 Musculoskeletal pathology, 189
Medullary dorsal horn (MDH), 345
Melatonin, 278, 279
cluster headache treatment, 87 N
Meningitis, 175 Naltrexone, 8, 107
Menstrual-related migraines, 318–319 Naratriptan, 88, 107
Mental health monitoring, 187, 188 National Association of State Controlled Substances
Methylenetetrahydrofolate reductase (MTHFR), Authorities, 2
177, 178 National Health Interview Survey (NHIS), 239
Methysergide, 89 Natural medicines, 273
Microvascular decompression, 130, 132 NDPH, see New daily persistent headache
Microvascular ischemia, 170 Near-daily headache, 207
Midcingulate cortices (MCC), 159 Neck injury, 116
Migraine, 157, 170, 172, 177 Neck pain, 44
chronification, 40, 43, 164 Nefazodone, 223
and obstructive sleep apnea, 326 Nerve blocks, 154
phenotypic traits, 296 Nervus intermedius neuralgia, 132
progression, 218 classification, 132
Migraine Treatment Optimization Questionnaire diagnosis, 132
(mTOQ-4), 39 medical management, 133
Migraine-related stroke, 180 surgical management, 133–134
Mild traumatic brain injury, 149 Neural circuitry, CM, 290, 292, 294, 295
Mind/body therapies Neurofibromatosis type 1 (NF1), 302
vs. behavioral therapies, 241 Neurogenic theory of migraine, 290
deep breathing, 247 Neuroimaging, 157, 158, 166, 190
Index 391
biomarkers, 166 treatment, 7–8

brain abnormalities, 157 triggering event, 108
Neuro-inflammatory disorder, 211 Next-generation sequencing (NGS) technologies, 177
Neurologists, 186, 189 Nociceptive stimuli, 158
Neuromodulation techniques, 223 Non-cephalic pain, 44
Neuronal hypersensitivity, 297 Noninvasive VNS (nVNS), 91
Neuropathy, 125 Nonmedical preventive therapy, 198
Neurosarcoidosis, headache, 175 Non-medication therapy, 152
Neurostimulation, CDH Non-pharmacological research, 282
characterisation, 335 Nonspecific migraine therapies, 211, 212
implantable occipital nerve stimulation, 336–337 Nonsteroidal anti-inflammatory drugs (NSAIDs), 170,
repetitive-pulse transcranial magnetic stimulation, 172, 196, 211
337–338 gastrointestinal (GI) intolerance and bleeding, 211
single-pulse transcranial magnetic stimulation, Nonvascular intracranial disorders
338–339 brain tumor, 120
sphenopalatine nerve stimulation, 339–341 Chiari I malformations, 120–121
transcranial direct current stimulation, 339 idiopathic intracranial hypertension, 118–119
transcranial stimulation methods, 337–338 intracranial hypotension, 119–120
transcutaneous supraorbital nerve stimulation, 337 intracranial infection, 121
transcutaneous vagus nerve stimulation, 339–340 substances, 121
Neurotransmitter metabolism, 197 Normobaric oxygen therapy, 266
New daily persistent headache (NDPH), 101–103, 105, NOTCH3 gene, 177
107, 108, 158, 176, 196, 313 NTG-induced CM model, 300
botulinum toxin, 106 NTG-induced hyperalgesia, 294, 296
characteristics, 368 NTG-triggered hyperalgesia in rodents, 293
classification, 368 NTG-triggered migraine model, 294
comorbidities, 369 Nummular headache (NH), 27
definition, 7 Nutraceuticals, 273
description, 97 benefits, 274, 281
diagnostic criteria, 7, 98 coenzyme Q10, 277, 278
differential diagnosis, 100 feverfew, 274, 275
primary headache disorders, 101 Ginkgo biloba, 280
secondary headache disorders, 101–103 magnesium, 276, 277
emerging therapy melatonin, 278, 279
diet and lifestyle, 108 riboflavin, 275, 276
naltrexone, 107 vitamin D, 280
naratriptan, 107
prazosin, 107
epidemiology, 97–98, 368 O
etiology and pathophysiology, 99–100 Obesity, 44, 189
evaluation, 104 Obstructive sleep apnea (OSA), 189
features of, 368 Occipital nerve stimulation (ONS), 296, 336–337
flu-like illness, 100 Occipital nerve-targeted therapy, 90–91
ICHD-II classification, 368 Occipital neuralgia
long duration, 27 clinical presentation, 134–135
nerve blocks, 106 definition, 134
pathophysiology, 369 etiology, 134
pharmacologic treatment, 105 incidence and prevalence, 134
antidepressants, 105 management, 135
antiepileptics, 105 Occupational therapists (OTs), 186
corticosteroids, 105 Oligoclonal bands, 177
leukotriene antagonists, 105 OnabotulinumtoxinA, 153, 199, 200, 207, 218, 222
Na channel blockers, 105 antinociceptive central effects, 47
tetracycline derivatives, 105 injection sites, 47
prevalence, 321 injection therapy, 44
prognosis, 108–109, 369 markers of, 48
risk factors, 369 mode of action, 47
stressful event, 100 in PREEMPT, 47
subdivision, 98–99 safety profile, 48
subforms, 27 SNARE proteins, 47
surgery, 100 treatment of chronic migraine, 48
392 Index
OnabotulinumtoxinA A, 4 pathophysiology, 372–373

Ophthalmoplegic migraine, see Recurrent painful prognosis, 373
ophthalmoplegic neuropathy risk factors, 372
Optic neuritis, 135 Pharmacologic approaches, 218–220, 224–226
clinical presentation and diagnostic criteria, 136 amitriptyline, tricyclic antidepressants, 222
epidemiology, 135 drugs, 221
etiology, 135 neuromodulation techniques, 223
management, 136 onabotulinumtoxinA
Optic Neuritis Treatment Trial (ONTT), 136 adequate dose, 224
Oral corticosteroids, 6 clinical trials and practices, 225
Oral mucosal diseases, 140 PREEMPT, 224, 226
Otolaryngologic assessment, 189 oral drug treatment
Oxycarbamazepine, 128 antiepileptics, 218–220
Oxygen administration β-blockers, 220
hyperbaric oxygen therapy, 266 preventive treatment, 217–218
normobaric oxygen therapy, 266 Pharmacologic prophylactic therapy, 207
risk, 266 Pharmacological detoxification programs, 198
Oxygen responsiveness, 84–85 Phase III Research Evaluating Migraine Prophylaxis
Therapy (PREEMPT), 224
Phenytoin, 130
P Physical medicine and rehabilitation (PMR), 233
Pain catastrophizing scale (PCS), 17 Physical therapists (PTs), 186
Pain disorders, 160, 197 Pimozide, 129
Pain frequency (PF), 219 Pituitary apoplexy, 173
Pain modulatory pathways, 290 Pituitary function tests, 173
Pain Patient Profile (P-3), 188 Pituitary hormonal function, chronic headache, 173
Pain processing, central neural activation, 292 Pizotifen, 89
Painful post-traumatic trigeminal neuropathy, 127 Plasma metanephrines, 171
Painful trigeminal neuropathy, 127 Polycystic ovary syndrome (POS), 172
Papilledema, 189 Polymyositis, 172
Paratrigeminal oculosympathetic syndrome, 138, 139 Positron emission tomography (PET), 157
clinical presentation and diagnostic criteria, 139 Post feverfew syndrome, 275
epidemiology, 139 Post-concussion syndrome, 115
etiology, 139 Postherpetic trigeminal neuralgia, 127
treatment, 140 Postherpetic trigeminal neuropathy, 34
Parenteral ketorolac, 211 Post-surgical headaches, 347–350
Paresthesias, 45 acute
Patient questionnaire (PQ), 188 acetaminophen with codeine, 348
Patients, drug withdrawal, 199 characteristics, 347–349
Pediatric Migraine Disability Assessment dexmedetomidine, 349
(PedMIDAS), 149 local anesthetics, 349
PedMIDAS, 54 morphine PCA, 348
Periaqueductal gray (PAG), 159, 160 nonsteroidal anti-inflammatory drug (NSAID)
Pericranial muscle tenderness, 67 medications, 349
Peripheral denervation techniques, 130 opioid medications, 348
Peripheral nerve blockade, 55 postcraniotomy headache, 348
Peripheral neurostimulation, 54–55 tramadol, 348
Persistent headache, to traumatic injury, 29 treatment, 348
Persistent idiopathic facial pain (PIFP), 34, 82 carotid endarterectomies, 354
clinical presentation and diagnostic criteria, 141 chronic
epidemiology, 141 characteristics, 349
etiology, 141 incidence in, 350
management, 142 treatment, 350
Persistent secondary headaches CSF hypotension syndrome, 351–352
attributed to traumatic injury to head, 371 frontotemporal brain sagging syndrome, 353–354
characteristics, 371 hemicrania continua, 350–351
classification, 372–371 medication overuse headache (MOH), 352
clinical features, 372 pathophysiology of, 345
comorbidities, 372 scalp neuralgias, 351
epidemiology, 372 syndrome of the trephine (SoT), 354
Index 393
Post-traumatic headache (PTH), 115, 324 Refractory headache, 19, 186, 374–375
Post-traumatic stress disorder (PTSD), and CDH, 323 coagulation studies, 170
Prazosin, 107 Refractory migraine, 212
Preeclampsia, 179 Region of interest (ROI) approach, 161
Pregabalin, 220 vs. whole-brain approach, 162
Preventive migraine therapy, 199 Renal function, 170
Primary angiitis of central nervous system (PACNS), 172 Repeated dura nociceptive stimulation caused
Primary Care Evaluation of Mental Disorders maladaptive neuroplasticity, allodynia, 296
(PRIME-MD), 188 Repetitive transcranial magnetic stimulation therapy, 166
Primary chronic daily headache, 26–29, 196 Repetitive-pulse transcranial magnetic stimulation, 338
of long duration Resting-state FMRI, 43
chronic migraine, 26 Retropharyngeal tendonitis, 33
chronic tension-type headache, 26 Reversible cephalic allodynia, 296
hemicrania continua, 27 Reversible cerebral vasoconstriction syndrome (RCVS),
new daily persistent headache, 27 30, 102
nummular headache, 27 Rhizotomy, 130
of short duration Riboflavin, 275, 276
chronic cluster headache, 28
chronic paroxysmal hemicranias, 28
hemicrania continua, 28 S
hypnic headache, 29 Salience network (SN), 164
primary stabbing headache, 29 Scalp neuralgias, post-surgical post-surgical
SUNCT, 28 headaches, 351
trigeminal autonomic cephalalgias, 27 Scleroderma, 172
Primary headache disorder, 169, 189, 190, 196, 197 SCN1A gene, 179
Primary health questionnaire (PHQ), 188 Secondary chronic daily headaches, 26, 32–35
Primary hypothyroidism diagnosis, 173 Chiari malformation type I, 31
Primary somatosensory cortices, 159 cranial vascular disorders, 29–30
Primary Stabbing Headache (PSH), 29 disorder of cranial bone, 32
Prophylactic medication, migraine, 218 cervicogenic headache, 32
Prophylaxis, 3 dystonia, 33
Propranolol, 153, 220 recurring rhinosinusitis, 33
Protriptyline, 4 retropharyngeal tendonitis, 33
Provider-administered rescue therapy, 213 temporomandibular disorder, 33
Pseudotumor cerebri, 30 disorders of homeostasis
Psilocybin, 88 hypothyroidism, 32
Psychiatric comorbidity, 199 sleep apnea, 32
Psychiatric Diagnostic Screening Questionnaire (PDSQ), evidence of causation, 29
187–188 intracranial infections, 32
Psychiatric disorders, 33, 187, 188 intracranial neoplasia, 31
Psychiatric monitoring, 187 intracranial nonvascular disorders, 30–31
Psychologists, 186 low cerebrospinal fluid pressure/volume, 30
medication-overuse headache, 31–32
non-headache medications, 31
R noninfectious inflammatory disease, 31
Raeder’s syndrome, 138. See also Paratrigeminal painful cranial neuropathy
oculosympathetic syndrome burning mouth syndrome, 34
Ramsay Hunt syndrome, 133 chronic central poststroke pain, 35
Randomized clinical trials (RCTs), 233, 242, 255 chronic occipital neuralgia, 34
RCVS, see Reversible cerebral vasoconstriction classical trigeminal neuralgia, 34
syndrome persistent idiopathic facial pain, 34
Rebound headache, 208 postherpetic trigeminal neuropathy, 34
Recurrent painful ophthalmoplegic neuropathy, 137 psychiatric disorders, 33
clinical presentation and diagnostic criteria, 137 systemic infections, 32
epidemiology, 137 to trauma, 29
etiology, 137 Secondary headache disorders, 113, 169, 190
management, 138 head and neck, 114
Recurring rhinosinusitis, 33 red flags, 114
Reflexology, 265 Secondary nervus intermedius neuropathy, 133
Refractory chronic migraine, 56 Secondary somatosensory cortices, 159
394 Index
Secular meditation, 244 Supplementary motor area (SMA), 159

Selective serotonin reuptake inhibitors, 222 Symptomatic medication overuse, 208
Self-efficacy (SE) Syndrome of the trephine (SoT), 354
definition, 14 Systemic illness, 103
in fibromyalgia patients, 14 Systemic lupus erythematosus (SLE), 171, 172
HMSE scale, 14
HSLC, 15
influenced health, 14 T
Serological testing T1-weighted MRI, 157
complete blood profile, 169 T2-weighted MRI, 160
complete metabolic profile, 170 Tai chi, 247
Serotonergic hypofunction, 314 Tanacetum parthenium (feverfew), 274, 275
Serotonin-norepinephrine reuptake inhibitors, 222 Temperature feedback (TEMP), 233
Severe CoQ10 deficiencies, 278 Temporal mandibular dysfunction, 323
Short-duration headaches, 185 Temporomandibular disorder (TMD), 33, 70
Short-lasting unilateral neuralgiform headache with Temporomandibular joint (TMJ), 70, 190
conjunctival injection and tearing (SUNCT), classification of, 362
28, 82 clinical features of, 362
Short-lasting unilateral neuralgiform headache with comorbidities, 363
cranial autonomic symptoms (SUNA), 28, 82 epidemiology, 363
Shotgun approach, 190 pathophysiology, 363–364
Silberstein and Lipton (S-L) criteria, 358 prognosis, 364
Single-pulse transcranial magnetic stimulation, 338 risk factors, 363
Sinking skin flap syndrome, 354 secondary causes, 363
Sjögren’s syndrome, 172 Tension-type headache (TTH), 66–72, 185, 276,
Sleep apnea, 32 279–281, 283, 309–311
Slow-onset oral triptans, 212 in adults, 373
S-lysergic acid diethylamide (LSD), 88 in children, 373
Soluble N-ethylmaleimide-sensitive factor attachment classification of, 362
protein receptor (SNARE) proteins, 47 clinical and physical features, 64, 69, 362
Somatization disorder, 33 cervicogenic, 69
Space-occupying lesion, 127 comorbidity, 69
Specific migraine therapies, 212 mood/behavioral, 70
Sphenoid sinusitis, 103 secondary headache, 69
Sphenopalatine ganglion (SPG), 55, 89–90, 223 comorbidities, 363
Sphenopalatine nerve stimulation, 340–341 definition, 63
Spinal and supraspinal mechanisms, 253 epidemiology, 147, 363
Spinal manipulative therapy, 258, 260 heterogeneous characteristics, 63
Spinal mobilization, 258 incidence, 64
Spiritual meditation, 244 infrequent episodes of headache, 63
Spontaneous intracranial hypotension (SIH), 30, motivational pathway, 66
101–102, 120 pain model, 65
Status migrainosus, 212, 213, 215 pathophysiology, 363–364
Steroids, 172, 211 algogenic chemical mediators, 67
Stomatodynia, see Burning mouth syndrome central sensitization, 66
Stress headaches, 317–318 ETTH vs. CTTH, 66
Stroke, 170, 180, 189 myofascial trigger points, 67
Structural brain abnormalities, 166 neuroplastic changes, 68
Subclinical hypothyroidism, 172, 173 nociceptive input, 66
Subdural hematomas (SDH), 115 pain pressure point, 67
Suboccipital musculature, 347 pericranial muscle tenderness, 67
Suicide headache, 77 stress and genetics, 68–69
Sumatriptan, 85, 212 population-based study, 69
SUNA, see Short-lasting unilateral neuralgiform prevention, 71
headache with cranial autonomic symptoms treatment, 70
SUNCT, see Short-lasting unilateral neuralgiform botulinum toxin A, 71–72
headache with conjunctival injection and cognitive behavioral therapy, 72
tearing prophylactic, 70–71
Sunken brain and scalp flap syndrome, 354 triptans, 70
Superficial dry needling, 257 See also Chronic tension-type headache
Index 395
Thrombin-activatable fibrinolysis inhibitor (TAFI), 171 Trigeminovascular system, 292

Thrombosis, 170 rodent cephalic pain pathways, 293
Tizanidine, 129 Triptans, cluster headache treatment, 87
Tocainide, 129 Tuberculosis, 175
Tolosa-Hunt syndrome, 138 Tumor necrosis factor alpha (TNF-α), 176, 177
clinical presentation and diagnostic criteria, 139
epidemiology, 138
etiology, 138 U
management, 139 Ubiquinone, 278
Topical ophthalmic anesthesia, 129 Urgent care centers, 210
Topiramate, 71, 88, 153, 199, 218, 226
efficacy and safety, 45
INTREPID study, 45 V
mechanism of action, 45 Vagoglossopharyngeal neuralgia, see Glossopharyngeal
Tract-based spatial statistics (TBSS), 161 neuralgia
Transcranial direct current stimulation, 338–339 Vagus nerve-targeted therapy, 91
Transcranial stimulation methods, 337–338 Valproate, 130
Transcutaneous supraorbital nerve stimulation, 337 Valproate sodium, 219
Transcutaneous vagus nerve stimulation, 339–340 Vascular cell adhesion molecule (VCAM), 247
Transdiagnostic symptoms (TDS), 187 Vascular malformations, 117
Transformed migraine (TM), 313–316, 318, 358 Venlafaxine, 71
Traumatic brain injury (TBI), 115, 173, 180 duloxetine, 223
Trephine, 354 nefazodone, 223
Tricyclic antidepressants (TCAs), 4, 70 treatment, for depression, 223
Trigeminal autonomic cephalalgias (TACs), 27, 366 Venous angiomas, 117
clinical characteristics, 28 Ventro-postero-medial nucleus of the thalamus
Trigeminal autonomic cephalalgias, characteristics (VPM), 345
of, 129 Verapamil, 6
Trigeminal brainstem nuclear complex (TBNC), cluster headache treatment, 86
345, 346 Viral meningitis, 102
Trigeminal ganglion-targeted therapy, 90 Visual analog scale (VAS), 219
Trigeminal neuralgia, 128–130 Vitamin B2, 275, 276
classification and clinical presentation, 126 Vitamin D deficiency, 279, 280
epidemiology, 125 Voxel-based morphometry (VBM), 157, 197
etiology, 125–126
medical management, 128
baclofen, 129 W
botulinum toxin injections, 130 Whiplash, 116
carbamazepine, 128 White matter (WM), 157
lamotrigine, 129 Whole-brain approach, 162
oxycarbamazepine, 128
pimozide, 129
tizanidine, 129 Y
tocainide, 129 Yoga, 246
topical ophthalmic anesthesia, 129 for headache, 246, 247
pathogenesis, 126 physical exercise, of postures
surgical management, 130 asanas, 246
gamma knife surgery, 130 pranayama, 246
microvascular decompression, 130 shavasana, 246
peripheral denervation techniques, 130
rhizotomy, 130
Trigeminal nociceptive activation, 290 Z
Trigeminal nucleus caudalis (TNC), 323 Zolmitriptan, 85
Trigeminal pain matrix, 296 Zonisamide, 88, 220

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What is the book about?

What is the book about?

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What conditions are discussed in the book?

Chronic

ISBN 978-3-319-91490-9 ISBN 978-3-319-91491-6 (eBook)

© Springer International Publishing AG, part of Springer Nature 2019

Printed on acid-free paper

Chronic daily headache occurs in 3 and 5% of the population worldwide.

New York, NY Mark W. Green

1 Chronic Daily Headache: Do We Know

14 Medication Overuse in Chronic Daily Headache������������������������ 195

Iryna S. Aberkorn, MD Dartmouth-Hitchcock Medical Center, Lebanon,

Salman Farooq, MD Neurology, Medical College of Wisconsin,

Teshamae S. Monteith, MD Department of Neurology, Miller School of

Shweta Teckchandani, DO Department of Neurology, Stanford Headache

Definition stand to be embraced within that shorthand

© Springer International Publishing AG, part of Springer Nature 2019 1

A. Headache (tension-type-like and/or migraine-­

Table 1.1 Medications for the Treatment of Chronic Migraine

and treated for an adequate period of time. Once Diagnostic Criteria

Chronic Cluster Headache

second-­line therapy in cases where verapamil is Diagnostic Criteria

Conclusion 12. Garza I, Schwedt TJ. Diagnosis and manage-

Introduction between patient and provider and to help each

S. E. Trost (*) · R. C. Anderson Locus of Control

© Springer International Publishing AG, part of Springer Nature 2019 11

HSLC an important consideration in and poten- Unlike LOC, standardized measures of

 eadache-Specific Locus of Control (HSLC)

Acknowledgments The authors wish to thank Annette

© Springer International Publishing AG, part of Springer Nature 2019 25

 lassification of Chronic Daily

headache, gradually developing daily or almost  ummular Headache (NH)

 hronic Cluster Headache (CCH)

Table 3.1 Chronic trigeminal autonomic cephalalgias: clinical characteristics

 ypnic Headache (HH)

Secondary Chronic Daily Headaches  DH Attributed to Giant-Cell Arteritis

 hronic Headache Attributed

reduced cervical range of motion, and head-  hronic Headache Attributed

 ainful Cranial Neuropathies

 hronic Migraine: Diagnosis

© Springer International Publishing AG, part of Springer Nature 2019 37

Insufficient acute pain relief

Intake of acute medication

Cortex Release of CGRP and PACAP

Hypothalamus Pain transmission or sensitisation

Upper cervical nerves

was performed in 18 episodic migraineurs, 17 migraineurs, 18 episodic migraineurs, and 19

Table 4.2 Pharmaceutical preventive treatment for chronic migraine

(Mean Change from Baseline) OnabotulinumtoxinA(n=688)

a Trigeminal nerve (CN V)

Anterior view Lateral view

Midpupilary Limbus Orbital

Upper 1/3 Hairline

Monoclonal Antibodies CGRP is a 37-amino acid neuropeptide formed

Eptinezumab Yeast lgG1 CGRP ligand

(a) Antibody Erenumab Murine lgG2 CGRP receptor

(c) Fully human

on pain-free rates of moderate to severe attacks randomized in a double-blind and placebo-con-

New York, NY Mark W. Green

1 Chronic Daily Headache: Do We Know

14 Medication Overuse in Chronic Daily Headache�� 195

Definition stand to be embraced within that shorthand

A. Headache (tension-type-like and/or migraine-

and treated for an adequate period of time. Once Diagnostic Criteria

Chronic Cluster Headache

second-line therapy in cases where verapamil is Diagnostic Criteria

Conclusion 12. Garza I, Schwedt TJ. Diagnosis and manage-

Introduction between patient and provider and to help each

S. E. Trost (*) · R. C. Anderson Locus of Control

eadache-Specific Locus of Control (HSLC)

lassification of Chronic Daily

headache, gradually developing daily or almost ummular Headache (NH)

hronic Cluster Headache (CCH)

ypnic Headache (HH)

Secondary Chronic Daily Headaches DH Attributed to Giant-Cell Arteritis

hronic Headache Attributed

reduced cervical range of motion, and head- hronic Headache Attributed

ainful Cranial Neuropathies

hronic Migraine: Diagnosis

Monoclonal Antibodies CGRP is a 37-amino acid neuropeptide formed

eripheral Nerve Blockade

from trigger points in the craniocervical muscles Fundamentals

Tension-Type Headache In ETTH, the pericranial myofascial mechanisms

Chemical pressure stimulus that is perceived as painful)

europlastic Changes and Central

have a 3.1-fold increase in the odds of having Secondary Headache

Indomethacin Busch has demonstrated functional connectivity

Other Drugs Long-Term Prophylactic Treatments

Methysergide was one of the few drugs avail- Intranasal Agents

nerve stimulator [156]. Stimulator placement is The Cluster Patient Perspective

Introduction migraine and/or tension-type headache [2]. Most

NDPH was ruled out by imaging and history. Stressful Event

Secondary Headaches (NDPH Mimics)

Evaluation treatment. The lumbar puncture can rule out indo-

Pharmacologic Treatment Antidepressants

Emerging Therapies to have episodic headache [66]. These findings

Overview and Clinical Assessment

Headaches Following Head Injury disruption of blood-brain barrier, and release of

eadache Attributed to Cranial or

Cerebral Venous Thrombosis Vascular Malformation

iant Cell Arteritis

are other common complaints. Neurological Brain Tumor

Glossopharyngeal Neuralgia ryngeal neuralgia occurs in the distribution of the

all the patients (100%), followed by temporary Etiology

Clinical Presentation Management

The ICHD-3 has defined the following criteria Epidemiology

A. Unilateral headache fulfilling criterion C. Etiology

Management It was previously known as ophthalmoplegic

Introduction A. At least two attacks fulfilling criterion B.

It is characterized by episodic, unilateral orbital Paratrigeminal Oculosympathetic

Tolosa-Hunt syndrome is a benign syndrome. Clinical Presentation

term “painful Horner’s syndrome” as a diagnosti- Clinical Presentation

Epidemiology ICHD Criteria for Burning Mouth Syndrome

Etiology 1. Burning quality.

Management maxillae, teeth, or gums from minor procedures

Management craniocervical pain with variable presentation,

Introduction of the International Classification of Headache