Clinical Review & Education

Clinical Crossroads

Fibromyalgia
A Clinical Review
Daniel J. Clauw, MD

Author Video Interview at

IMPORTANCE Fibromyalgia is present in as much as 2% to 8% of the population, is jama.com
characterized by widespread pain, and is often accompanied by fatigue, memory problems, Related article page 1570 and
and sleep disturbances. JAMA Patient Page page 1577

Supplemental content at
OBJECTIVE To review the epidemiology, pathophysiology, diagnosis, and treatment of jama.com
fibromyalgia.
CME Quiz at
jamanetworkcme.com and
EVIDENCE REVIEW The medical literature on fibromyalgia was reviewed from 1955 to March
CME Questions page 1560
2014 via MEDLINE and the Cochrane Central Registry of Controlled Trials, with an emphasis
on meta-analyses and contemporary evidence-based treatment guidelines. Treatment
recommendations are based on the most recent evidence-based guidelines from the
Canadian Pain Society and graded from 1 to 5 based on the level of available evidence.

FINDINGS Numerous treatments are available for managing fibromyalgia that are supported
by high-quality evidence. These include nonpharmacological therapies (education, exercise,
cognitive behavioral therapy) and pharmacological therapies (tricyclics, serotonin Author Affiliation: Professor of
norepinephrine reuptake inhibitors, and gabapentinoids). Anesthesiology, Medicine
(Rheumatology), and Psychiatry and
Director, Chronic Pain and Fatigue
CONCLUSIONS AND RELEVANCE Fibromyalgia and other “centralized” pain states are much Research Center, University of
better understood now than ever before. Fibromyalgia may be considered as a discrete Michigan, Ann Arbor.
diagnosis or as a constellation of symptoms characterized by central nervous system pain Corresponding Author: Daniel J.
amplification with concomitant fatigue, memory problems, and sleep and mood Clauw, MD, University of Michigan, 24
Frank Lloyd Wright Dr, PO Box 385,
disturbances. Effective treatment for fibromyalgia is now possible.
Ann Arbor, MI 48106 (dclauw@med
.umich.edu).
JAMA. 2014;311(15):1547-1555. doi:10.1001/jama.2014.3266 Section Editor: Edward H.
Livingston, MD, Deputy Editor, JAMA.

This article is based on a conference that took place at the Medicine Grand Ms P has hypertension, Graves disease with hypothyroidism, de-
Rounds at Beth Israel Deaconess Medical Center, Boston, Massachu- generative disk disease, migraines, hyperlipidemia, fibroadenoma-
setts, on October 4, 2012. tous breast disease, eczema, gastroesophageal reflux disease, and
carpal tunnel syndrome. She takes amlodipine, cyclobenzaprine, hy-
drochlorothiazide, hydrocodone-acetaminophen, levothyroxine,
Dr Tess Ms P is a 64-year-old woman who has ongoing diffuse moexipril, pantoprazole, pravastatin, pregabalin, aspirin, and mul-
muscle pain and fatigue. She developed chronic back pain in 1991, tivitamins. She is a former nurse who no longer works because of
followed by chronic ankle pain after a motor vehicle collision. In her physical limitations.
2009, she developed a deep ache in her lower extremities and During the physical examination, Ms P was found to be afebrile
back that worsened over several months. Her pain is aggravated and had normal vital signs. She did not have alopecia, oral ulcers, or
by touch or pressure and relieved by rest and topical heat. The exudates. There were no skin lesions or rashes and her nails were nor-
pain has limited her ability to exercise. She was diagnosed as hav- mal. There were many areas of tenderness with palpation, including
ing fibromyalgia and given numerous medications (gabapentin, her upper and lower back, near lateral epicondyle, upper chest, and
venlafaxine, pregabalin, and hydrocodone/acetaminophen), most trochanteric prominences. Her joint examination results were nor-
of which resulted in significant adverse effects. She currently mal, as was the remainder of her physical examination.
undergoes treatment with acupuncture therapy along with Her complete blood count, chemistries, and liver function tests
pregabalin, hydrocodone/acetaminophen, and cyclobenzaprine. yielded normal results. Antinuclear antibody, anticytoplasmic anti-
Over the past several years, she has experienced loss of body, serum protein electrophoresis, urine protein electrophore-
energy, weight gain, occasional headaches, insomnia, and occa- sis, and Lyme serology test results were all unremarkable. Her eryth-
sional depressed mood. Pain and fatigue limit her physical activity rocyte sedimentation rate was 33 mm/h.
to not more than a few contiguous hours. She does not have Ms P now asks if there is a treatment regimen that will allow her
paresthesias. to be more functional while avoiding adverse effects.

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 Clinical Review & Education Clinical Crossroads Fibromyalgia

Patients developing fibromyalgia commonly have lifelong his-

Ms P: Her View tories of chronic pain throughout their body. Any regional or wide-
spread chronic musculoskeletal pain occurs in about 30% of the
Most people do not understand fibromyalgia. They don’t really get population.4 Ms P’s “pain-prone phenotype,” manifested by having
it; they see you, they look at you, and you look fine. So they do not many discrete episodes of chronic pain in her lifetime, is an impor-
understand. The fibromyalgia pain feels like a deep muscle strain or tant part of her medical history. Patients with fibromyalgia are likely
pain. For me, it has been mostly a dull, deep pain and ache through- to have a history of headaches, dysmenorrhea, temporomandibu-
out my body. I never know what my day is going to be like. I have to lar joint disorder, chronic fatigue, irritable bowel syndrome and other
wake up in the morning and see what hurts and how I can medicate functional gastrointestinal disorders, interstitial cystitis/painful blad-
it and how I can function for the day. During the day, I feel I have an der syndrome, endometriosis, and other regional pain syndromes
expiration date on me. It’s like I have a weight around my neck, back, (especially back and neck pain).8,9 What might appear to one health
or waist and I start to go down after a while. I still can feel okay men- care practitioner as a new episode of acute or subacute pain can in
tally but my body just quits on me and I have to lie down. fact be simply another region of the body associated with pain.10
The medication is affecting my activities of daily living. I usu- Fibromyalgia can be thought of as a centralized pain state. Cen-
ally take it at night so that I can function in the morning but I can never tralized pain is a lifelong disorder beginning in adolescence or young
just jump up to go and do anything the way I used to. I have to have adulthood manifested by pain experienced in different body re-
a grace period for getting up, seeing what hurts … see if I need to gions at different times.11-13 “Centralized” refers to central nervous
take additional medication. It’s kind of like I’m walking through a fog. system origins of or amplification of pain. This term does not imply
The acupuncture has helped alleviate the pain. I did not expect it to that peripheral nociceptive input (ie, damage or inflammation of body
be as helpful as other medications, but with it I can take less medi- regions) is not contributing to these individuals’ pain but rather that
cation overall. they feel more pain than would normally be expected based on the
At first, the hardest part was getting a diagnosis. It had to be degree of nociceptive input. Understanding centralized pain is im-
either A, B, C, D, or E, and it was not. Since my doctor diagnosed me, portant for surgeons and proceduralists because patients with these
the frustrating part has been finding medications or treatments that disorders may request interventions to eliminate pain (eg, hyster-
will help me to get back to as much of a normal life as I can. Is there ectomy, back surgery).14 Not surprisingly, this pain-prone pheno-
a better plan for me? type, best exemplified by a patient with fibromyalgia, predicts fail-
ure to respond to opioids or operations performed to reduce pain.15
Family members of patients with fibromyalgia may also have a
history of chronic pain. Compared with relatives of individuals with-
Fibromyalgia
out fibromyalgia, first-degree relatives of patients with fibromyal-
Search Methods gia are more likely (odds ratio, 8.5; 95% CI, 2.8-26; P<.001) to have
Dr Clauw The medical literature on fibromyalgia was searched from fibromyalgia and other chronic pain states.16 Genetic factors may ex-
1955 to March 2014 using MEDLINE and the Cochrane Central Reg- plain the strong familial predisposition to fibromyalgia and many
istry of Controlled Trials. The search terms used were fibrositis and chronic pain conditions.13,17 Genes associated with increased or de-
fibromyalgia. The limits used were “clinical trial” or “review.” creased frequency of chronic pain states or pain sensitivity regu-
The best-quality evidence (eg, meta-analyses, systematic re- late the breakdown or binding of pain sensitivity–modulating neu-
views) received the greatest emphasis. Treatments recommenda- rotransmitters and others of inflammatory pathways. Pain sensitivity
tions in this review are generally derived from the Canadian Pain So- is polygenic, and differential pain sensitivity between individuals may
ciety guidelines,1 which are the most recent guidelines to have result from imbalances or altered activity of various neurotransmit-
considered North American randomized clinical trials of drugs for ters, explaining why centrally acting analgesics either help many co-
this condition. Recommendations were graded from 1 to 5 based on occurring symptoms (pain, sleep, mood, fatigue) or do not help at
the evidence quality.2 all in a given individual. Twin studies suggest that approximately 50%
of the risk of developing fibromyalgia and related conditions such
Epidemiology and Pathophysiology of Fibromyalgia as irritable bowel syndrome and headache is genetic and 50% is
After osteoarthritis, fibromyalgia is the second most common “rheu- environmental.18
matic” disorder. Depending on the diagnostic criteria used, the preva- Environmental factors most likely to trigger fibromyalgia in-
lence is from 2% to 8% of the population.3-5 The diagnostic criteria clude stressors involving acute pain that would normally last for a
for fibromyalgia were originally published in 1990 and emphasized few weeks. Fibromyalgia or similar illnesses, such as chronic fa-
chronic widespread pain with a number of tender points.6 Using this tigue syndrome, can be triggered by certain types of infections19 (eg,
definition, almost all patients with fibromyalgia were women be- Epstein-Barr virus, Lyme disease, Q fever, viral hepatitis), trauma20
cause they have many more tender points than do men. Newer diag- (motor vehicle collisions), or deployment to war.21 Psychological
nostic criteria are entirely symptom based and do not require counts stress may also trigger fibromyalgia.
of the number of tender points.7 With the newer diagnostic criteria, Fibromyalgia may also occur with other chronic pain condi-
the disease has a female:male ratio of 2:1, similar to other chronic pain tions like osteoarthritis, rheumatoid arthritis, and lupus. Approxi-
conditions.5 Fibromyalgia can develop at any age, including in child- mately 10% to 30% of patients with these rheumatic disorders also
hood. The prevalence is similar in different countries, cultures, and eth- meet criteria for fibromyalgia.22 Previously termed secondary fibro-
nic groups; there is no evidence that fibromyalgia has a higher preva- myalgia, this phenomenon is better viewed as centralized pain be-
lence in industrialized countries and cultures.4 cause this presentation is common and might occur in a subset of

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 Fibromyalgia Clinical Crossroads Clinical Review & Education

any chronic pain cohort. The term centralization implies that periph- tient self-report survey that is administered on a single piece of paper
eral nociceptive input might be responsible for some of a patient’s pain (Figure). Patients fill out a symptom survey asking about the loca-
but central nervous system factors likely amplify the pain. An individu- tions of pain as well as the presence and severity of fatigue, sleep
al’s “set point” or “volume control” for pain is set by a variety of fac- disturbances, memory difficulties, headaches, irritable bowel, and
tors, including the levels of neurotransmitters that facilitate pain trans- mood problems. Practitioners may prefer this approach of assess-
mission(turnupthegainorvolumecontrol)andthosethatreducepain ment for fibromyalgia because it does not require performing a ten-
transmission. These central factors may also result in fatigue, memory der-point examination. These criteria identify most of the same in-
problems, and sleep and mood disturbances, probably because the dividuals who meet the 1990 criteria but identifies many more male
same neurotransmitters that control pain and sensory sensitivity also patients (who rarely meet the 1990 criteria because of inadequate
control sleep, mood, memory, and alertness.22 numbers of tender points).7,28 The new criteria have the advan-
The observation that fibromyalgia patients had diffuse tender- tage of conceptualizing the core symptoms of fibromyalgia as a con-
ness led to functional, chemical, and structural brain neuroimaging tinuum of pain centralization or “fibromyalgia-ness.”29
studies. These studies showed a biological basis for fibromyalgia pain In clinical practice, fibromyalgia should be suspected in pa-
and related pain amplification syndromes.23 Fibromyalgia patients tients having multifocal pain not fully explained by injury or inflam-
experience pain for what patients without fibromyalgia perceive as mation. In most cases, musculoskeletal pain is the most prominent
touch. Functional magnetic resonance imaging studies of the brain feature. Because pain pathways throughout the body are ampli-
response to these stimuli show brain activation patterns in pain pro- fied, pain can occur anywhere. Consequently, chronic headaches,
cessing areas in fibromyalgia patients when given a mild pressure sore throats, visceral pain, and sensory hyperresponsiveness are very
or heat stimulus.24,25 common in individuals with fibromyalgia and were seen in Ms P.
Psychological, behavioral, and social issues contribute to the Pain is a defining feature of fibromyalgia. Features of the pain
pathogenesis of fibromyalgia and complicate its treatment. Indi- distinguishing fibromyalgia from other disorders are important to
viduals with fibromyalgia more likely have psychiatric disorders, in- consider when evaluating patients (Box 1). These same features are
cluding depression, anxiety, obsessive-compulsive disorder, and also useful when considering other centralized pain syndromes.
posttraumatic stress disorder. This may result from common trig- Ms P had nearly all of the characteristics summarized in Box 1.
gers for these psychiatric conditions and fibromyalgia like early-life Usually, the physical examination is unremarkable in patients
stress or trauma. Neurotransmitters mediating pain transmission may with fibromyalgia. Nevertheless, most patients have diffuse tender-
also affect mood, memory, fatigue, and sleep. Potentially modifi- ness. This can be ascertained by performing a tender-point count
able risk factors for developing fibromyalgia include poor sleep, obe- as was done for Ms P. Patients with fibromyalgia are more sensitive
sity, physical inactivity, and poor job or life satisfaction. Cognitive fac- to the inflation of a blood pressure cuff.31 The overall pain thresh-
tors such as catastrophizing (a way of thinking about pain such that old also can be assessed by performing a rapid examination of the
it will have very negative consequences) or fearing that movement hands and arms by applying firm pressure over several interphalan-
will worsen pain are poor prognostic factors for fibromyalgia and geal joints of each hand and over the adjacent phalanges, then cau-
other chronic pain states. The psychological components of fibro- dally to include firm palpation of the muscles of the forearm. Dif-
myalgia or other pain conditions are treatable by cognitive behav- fuse tenderness from a low central pain threshold is present if the
ioral therapy, which can be very effective but, unfortunately, is rarely patient has tenderness in many of these areas or only in the fore-
used in clinical practice. Many patients seen in routine clinical prac- arm muscles. When tenderness is present only over the interpha-
tice who have fibromyalgia or fibromyalgia-like syndromes may re- langeal joints and not the other regions (especially if there is any
spond well to simple interventions such as stress reduction, im- swelling over these joints), a diagnosis of a systemic autoimmune
proved sleep patterns, and increased activity and exercise. These disorder should be considered.
interventions should always be emphasized and may suffice, pre- Apart from sorting through the differential diagnosis, labora-
cluding the need for drug therapy. tory testing is not useful for establishing a diagnosis of fibromyal-
gia. Basic laboratory evaluation may include complete blood count,
Diagnosis of Fibromyalgia routine serum chemistries, thyrotropin, vitamin D, erythrocyte sedi-
The 1990 American College of Rheumatology criteria for fibromy- mentation rate, and C-reactive protein. Serologic studies such as an-
algia were research classification criteria and were never intended tinuclear antibody and rheumatoid factor assays are generally
to be used as strict diagnostic criteria for use in clinical practice.6 avoided unless symptoms or signs (eg, swollen joints) suggest an au-
These criteria require that individuals have widespread pain (pain toimmune disorder.
in the axial skeleton, above and below the waist, and on both sides Once other pain disorders are excluded and any peripheral
of the body) as well as tenderness in 11 or more of 18 possible “ten- sources of pain are treated, an important and perhaps controver-
der points.” Many individuals who clearly have fibromyalgia do not sial step is asserting the diagnosis of fibromyalgia. Some believe that
have pain throughout their entire body or may not have at least 11 a label of fibromyalgia may harm patients. However, studies sug-
tender points. Moreover, the symptoms of pain and tenderness are gest that the opposite is true: establishing a diagnosis of fibromy-
common and it is impossible to know where to draw the line be- algia can provide substantial relief for patients.32 In fact, once the
tween an individual with isolated symptoms and someone with a diagnosis is established, there may be decreased health care utili-
pain-inducing illness.26 zation, with fewer referrals and reduced diagnostic testing seeking
The alternative 2011 fibromyalgia survey criteria were in- causes of pain.33 Ms P was relieved once her diagnosis of fibromy-
tended for use in epidemiological studies and represent an alterna- algia was established. Once she knew the cause of her pain, she could
tive method to assess fibromyalgia.7,27,28 These criteria include a pa- concentrate on treatment.

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 Clinical Review & Education Clinical Crossroads Fibromyalgia

Figure. Example of a Patient Self-report Survey for the Assessment of Fibromyalgia Based on Criteria in the 2011 Modification of the ACR Preliminary
Diagnostic Criteria for Fibromyalgia7

Widespread Pain Index Symptom Severity

(1 point per check box; score range: 0-19 points) (score range: 0-12 points)
1 Please indicate if you have had pain or tenderness during the 2 For each symptom listed below, use the following scale to indicate the severity of
past 7 days in the areas shown below. the symptom during the past 7 days.
Check the boxes in the diagram for each area in which you have • No problem
had pain or tenderness. • Slight or mild problem: generally mild or intermittent
• Moderate problem: considerable problems; often present and/or at a moderate level
• Severe problem: continuous, life-disturbing problems

No problem Slight or mild Moderate Severe

Right jaw Left jaw problem problem problem

Neck Points 0 1 2 3
Right shoulder Left shoulder A. Fatigue
Chest or Upper
back B. Trouble thinking or remembering
Right breast Left
upper arm upper arm C. Waking up tired (unrefreshed)
Right
lower arm Abdomen Left Lower 3 During the past 6 months have you had any of the following symptoms?
lower arm back
Points 0 1
Right hip or Left hip or A. Pain or cramps in lower abdomen No Yes
buttocks buttocks B. Depression No Yes
C. Headache No Yes
Right upper leg Left upper leg

Additional criteria (no score)

4 Have the symptoms in questions 2 and 3 and widespread pain been present at a
Right lower leg Left lower leg similar level for at least 3 months?
No Yes

5 Do you have a disorder that would otherwise explain the pain?

No Yes

ACR indicates American College of Rheumatology. Scoring information is shown printer-ready version of this survey that patients can complete are available
in blue. The possible score ranges from 0 to 31 points; a score ⱖ13 points is online (eFigure 1 and eFigure 2 in the Supplement).
consistent with a diagnosis of fibromyalgia. Additional scoring information and a

Treatment of Fibromyalgia be continually reinforced. Pharmacological therapies can be help-

Fibromyalgia is best approached by integrating pharmacological and ful in alleviating some symptoms, but patients rarely achieve mean-
nonpharmacological treatments while engaging patients as active ingful improvements without adopting these core self-
participants in the process. Fibromyalgia can be diagnosed and management strategies.
treated in the primary care setting. Referral to specialists should be
necessary only for patients in whom the diagnosis is uncertain (eg, Pharmacological Therapies
to a rheumatologist or neurologist, depending on symptoms) or for The general approach to pharmacological therapy is summarized in
patients refractory to therapy (eg, to multidisciplinary pain clinics) Box 2. Effective pharmacological therapies generally work in part by
or with significant comorbid psychiatric issues (eg, to a psychiatrist reducing the activity of facilatory neurotransmitters (eg, gabapen-
or psychologist). Developing treatment teams is useful, even if they tinoids reduce glutamate46,47) or by increasing the activity of inhibi-
are only virtual teams. The team should include clinicians with ex- tory neurotransmitters such as norepinephrine and serotonin (eg,
pertise in patient education (eg, midlevel practitioners or nurse edu- tricyclics, serotonin norepinephrine reuptake inhibitors48,49) or
cators), exercise therapy (eg, physical or occupational therapists), γ-aminobutyric acid (eg, γ-hydroxyglutamate43,50). The hyperac-
and cognitive behavioral therapy. tive endogenous opioid system51 in fibromyalgia may explain why
The Table summarizes the recommendations of the Canadian opioids appear to be ineffective15,52 and low-dose naltrexone44 is a
National Fibromyalgia Guideline Advisory Panel.34 These and other promising new treatment. Several drugs or classes of drugs have
guidelines generally recommend that all patients should receive edu- strong evidence (level 1A evidence) for efficacy in treating
cation about the nature of this condition (ie, that the pain is not due fibromyalgia,53 including tricyclic compounds40 (amitriptyline, cy-
to damage of painful regions and is not progressive) as well as about clobenzaprine), gabapentinoids54 (pregabalin, gabapentin), sero-
the importance of playing an active role in their own care. In par- tonin norepinephrine reuptake inhibitors (duloxetine, 5 5
ticular, the importance of stress reduction, sleep, and exercise should milnacipran56), and γ-hydroxybutyrate.43 Drugs with more limited

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 Fibromyalgia Clinical Crossroads Clinical Review & Education

evidence of efficacy include older selective serotonin reuptake in-

hibitors with greater noradrenergic activity when used at higher Box 1. Characteristics of Fibromyalgia and Other Centralized Pain
Syndromes
doses (eg, fluoxetine, 57 paroxetine, sertraline), low-dose
naltrexone,58 esreboxetine59 (a serotonin norepinephrine reup- Character and quality of pain
take inhibitor not available in the United States), and Diffuse or multifocal, often waxes and wanes, and is frequently
cannabanoids.60 When treating polygenic chronic illnesses, it is of- migratory in nature
ten necessary to use combinations of several drugs having differ- Often accompanied by dysesthesia or paresthesias and described
ing mechanisms of action. as more “neuropathic” (eg, with terms such as numbness, tingling,
Drugs frequently used to treat peripheral pain such as nonste- burning)
roidal anti-inflammatory drugs, opioids, and corticosteroids do not Patients may note discomfort when they are touched or when
effectively treat fibromyalgia pain. In fact, all oral analgesics (eg, non- wearing tight clothing
steroidal anti-inflammatory drugs and opioids) are only modestly ef- History of pain in other body regions earlier in life
fective for treating chronic pain (ie, work well in only a third of Accompanying comorbid symptoms also of central nervous
patients).61 There is evidence that opioids might worsen fibromy- system origin
algia-related hyperalgesia and other centralized pain states, lead- Often fatigue, sleep disturbances, memory, and mood difficulties
ing to opioid-induced hyperalgesia.15 accompany centralized pain states such as fibromyalgia
Several of these symptoms will typically improve along with pain
Nonpharmacological Therapies when individuals are successfully treated with appropriate
The 3 best-studied nonpharmacological therapies are education, cog- pharmacological or nonpharmacological therapies
nitive behavioral therapy, and exercise. All have strong (level 1A evi- Symptoms suggesting more global sensory hyperresponsiveness
dence) evidence for efficacy in fibromyalgia. The magnitude of the Sensitivity to bright lights, loud noises, and odors and even many
treatment response for these therapies often exceeds that for phar- visceral symptoms may be in part due to a global sensory
maceuticals. The greatest benefit is observed for improved func- hyperresponsiveness seen in conditions such as fibromyalgia
tion, which should be the main treatment goal for treating chronic Often leads to a “pan-positive review of symptoms” that has often
pain.62,63 These treatments can result in sustained (eg, >1 year) im- mischaracterized these individuals as “somatizers” as the biology
provements. Access, adherence, and compliance to treatment are of somatization is increasingly recognized as that of sensory
the most important limitations when trying to implement them in hyperresponsiveness30
clinical practice.
Complementary and alternative therapies can be useful as treat-
ment adjuncts for fibromyalgia. As with other disorders, relatively
few controlled trials support their use. Trigger-point injections, chi-
ropractic manipulation, tai chi, yoga, acupuncture, and myofascial Recommendations for Ms P
release therapy all have some evidence of efficacy and are among
the more commonly used treatments.64 Some evidence suggests Ms P has a fairly typical history for fibromyalgia. In addition to her
that these treatments give patients a greater sense of control over pain symptoms, she has a sense of helplessness and hopelessness
their illness. Giving patients a choice of therapies may improve the and she is frustrated. Of note was Ms P’s frustration while she
likelihood for a placebo response by activating the body’s internal struggled to obtain a diagnosis. Rarely, providing a diagnosis might
analgesic mechanisms. Despite the absence of high-quality evi- be ill advised. This may the case for a child or adolescent who might
dence regarding their efficacy, alternative therapies may be useful use a fibromyalgia diagnosis as a reason to restrict activities. More
as long as they do not cause harm since options for treating chronic commonly, patients are relieved to have a diagnosis established.
pain are limited. Once the diagnosis is established, health care utilization may de-
Although fibromyalgia is generally not thought to be caused crease as fruitless searches for the cause of pain are no longer
by peripheral damage or inflammation, some evidence exists sup- needed.
porting treatment of peripheral pain generators. Conceivably, Referral to a specialist was not necessary because Ms P’s symp-
peripheral nociceptive input drives central sensitization. 13,65 toms were long-standing and typical of fibromyalgia and there were
Patients with fibromyalgia and concomitant osteoarthritis or many treatment options yet to be tried. Once a diagnosis of fibro-
myofascial pain had improvement in their overall fibromyalgia myalgia is given, providing patient education is helpful (level 1A
pain and tenderness when treated with local therapies.66 Some evidence1). Patient education may be provided by a physician or
patients with fibromyalgia also have been shown to have small other health care practitioner. Education delivered in 1 long or sev-
fiber neuropathy on biopsy.67 The treatment implications of this eral shorter sessions emphasizes that fibromyalgia symptoms are
observation remain unclear. not due to damage or inflammation of tissues, that pharmacologi-
Various neurostimulatory therapies can effectively treat mus- cal therapies have limited efficacy, and that it is important for pa-
culoskeletal pain. Transcutaneous electrical nerve stimulation has tients to use self-management therapies (for example, https:
been used to treat peripheral musculoskeletal pain with some suc- //fibroguide.med.umich.edu). The importance of behavioral
cess. Newer central neurostimulatory therapies are in develop- therapies should be emphasized, as should be normalization of sleep
ment that presumably stimulate brain structures involved in pain pro- patterns and institution of exercise therapy. Patients should under-
cessing and are showing promise in treating centralized pain states stand that these treatments often will be more effective than phar-
such as fibromyalgia.39,68 macological treatments.1

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 Clinical Review & Education Clinical Crossroads Fibromyalgia

Table. Summary of Treatment Guidelines34

Evidence
Treatment Cost Details Level Adverse Effects Clinical Pearls
General
recommendations
Patient education35 Low Incorporate principles of 1A Following initial diagnosis, spend several
self-management including a visits (or use separate educational
multimodal approach sessions) to explain the condition and set
treatment expectations
Nonpharmacological
therapies
Graded exercise36 Low Aerobic exercise has been best 1A Worsening of symptoms Counsel patients to “start low,
studied but strengthening and when program is begun too go slow”
stretching have also been shown rapidly For many patients, focusing first on
to be of value increasing daily “activity” is helpful
before actually starting exercise
Cognitive behavioral Low Pain-based CBT programs have 1A No significant adverse Internet-based programs are gaining
therapy (CBT)37 been shown to be effective in effects of CBT per se but acceptance and are more convenient for
one-on-one settings, small patient acceptance is often working patients
groups, and via the Internet poor when viewed as a
“psychological” intervention
Complementary and Variable Most CAM therapies have not 1A Generally safe Evidence emerging that CAM treatments
alternative medicine been rigorously studied such as tai chi, yoga, balneotherapy, and
(CAM) therapies38 acupuncture may be effective
Allowing patients to choose which CAM
therapies to incorporate into an active
treatment program can
increase self-efficacy
Central nervous Several types of CNS neu- Headache These treatments continue to be
system (CNS) rostimulatory therapies have refined as optimal stimulation targets,
neurostimulatory been effective in fibromyalgia “dosing,” etc, become understood
therapies39 and other chronic pain states
Pharmacological Therapies best chosen based 5, Consensus Prescribing patients a drug regimen that
therapies on predominant symptoms and helps improve symptoms prior to
initiated in low doses with slow initiating nonpharmacological therapies
dose escalation can help improve adherence
Tricyclic Amitriptyline, 10-70 mg once 1A Dry mouth, weight gain, When effective, can improve a wide
compounds40,41 daily before bedtime constipation, “groggy” range of symptoms including pain, sleep,
Cyclobenzaprine, 5-20 mg once or drugged feeling bowel, and bladder symptoms
daily before bedtime Taking several hours prior to bedtime
improves adverse effect profile
Serotonin norepi- Duloxetine Duloxetine, 30-120 mg/d 1A Nausea, palpitations, Warning patients about transient
nephrine reuptake is generic; Milnacipran, 100-200 mg/d headache, fatigue, nausea, taking with food, and slowly
inhibitors40 milnacipran tachycardia, hypertension increasing dose can increase tolerability
is not Milnacipran might be slightly more
noradrenergic than duloxetine and thus
potentially more helpful for fatigue and
memory problems but also more likely
to cause hypertension
Gabapentinoids42 Gabapentin is Gabapentin, 800-2400 mg/d 1A Sedation, weight gain, Giving most or all of the dose at bedtime
generic, in divided doses dizziness can increase tolerability
pregabalin not Pregabalin, up to 600 mg/d
in divided doses
γ-Hydroxybutyrate43 For treating 4.5-6.0 g per night in divided 1A Sedation, respiratory Shown as efficacious but not approved
narcolepsy/ doses depression, and death by Food and Drug Administration
cataplexy because of safety concerns
Low-dose naltrexone44 Low 4.5 mg/d 2 small
single-center
randomized
trialsa
Cannabanoids45 NA Nabilone, 0.5 mg orally at 1Aa Sedation, dizziness, dry No synthetic cannabinoid has US
bedtime to 1.0 mg twice daily mouth approval for treatment of pain
Selective serotonin SSRIs that Fluoxetine, sertraline, 1A Nausea, sexual dysfunction, Older, less selective SSRIs may have
reuptake inhibitors should be paroxetine weight gain, sleep some efficacy in improving pain,
(SSRIs)40 used in disturbance especially at higher doses that have more
fibromyalgia prominent noradrenergic effects
are all generic Newer SSRIs (citalopram, escitalopram,
desvenlafaxine) are less effective or
ineffective as analgesics
Nonsteroidal anti- No evidence of efficacy; can be 5D Gastrointestinal, renal, and Use the lowest dose for the shortest
inflammatory drugs helpful for comorbid “peripheral cardiac adverse effects period of time to reduce adverse
pain generators” effects
Opioids Tramadol with or without 5D Sedation, addiction, Increasing evidence suggests that
acetaminophen, 50-100 mg tolerance, opioid-induced opioids are less effective for treating
every 6 h hyperalgesia chronic pain than previously thought and
No evidence of efficacy for their risk-benefit profile is worse than
stronger opioids other classes of analgesics

a
Evidence rated by author; not rated by Canadian National Fibromyalgia Guideline Advisory Panel.

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 Fibromyalgia Clinical Crossroads Clinical Review & Education

There are many pharmacological treatment options for Ms P, in-

cluding limiting the use of cyclobenzaprine to a low dose (5-10 mg) Box 2. General Approach to Pharmacological Therapy

at bedtime, optimizing the dose of pregabalin by giving most or all All patients should receive
of the dose at bedtime to decrease her grogginess, and adding a sero-
Education about nature of disorder
tonin norepinephrine reuptake inhibitor (all level 1 evidence1). More
Counseling regarding role of exercise, cognitive behavioral
importantly, it appears that she has not been informed about the
techniques
nonpharmacological therapies that should be the mainstay of treat-
Pharmacological therapy should be guided by predominant symp-
ing chronic pain, including education, exercise, and cognitive be-
toms that accompany pain
havioral therapy. If these are not readily available locally, web-
All patients should have a good therapeutic trial of a low-dose tri-
based programs are available that have been tested and shown to
cyclic compound (eg, cyclobenzaprine, amitriptyline, nortriptyline)
be effective.69
Patients with comorbid depression or fatigue should next try a
serotonin norepinephrine reuptake inhibitor
Patients with comorbid anxiety or sleep issues should next try a
Questions and Discussion gabapentinoid
It is often necessary to use several of these classes of drugs together
QUESTION Is progress being made in developing animal models
that may result in new treatment modes? Use of opioids is discouraged
DR CLAUW Many animal models of hyperalgesia/allodynia exist, but Nonsteroidal anti-inflammatory drugs and acetaminophen can be
these lack the other features of the human fibromyalgia “pheno- used to treat comorbid “peripheral pain generators”
type.” Moreover, animal studies are usually performed on inbred Therapies that have been less well studied but show promise
strains of animals that do not exhibit the genetic heterogeneity hu- Complementary and alternative therapies
mans have. Classic animal models also measure “pain behaviors” me- Drugs including low-dose naltrexone, cannabinoids
diated by spinal reflexes and generally do not probe the central ner- Cortical electrostimulatory therapies
vous system response to peripheral stimuli. So, phenotypically
relevant animal models using operant paradigms as outcomes will
likely be very useful for bidirectional translation.
ity, all of which are counterproductive to rehabilitation approaches
QUESTION Will injury occur if fibromyalgia patients push them- that benefit chronic pain patients. Clinicians should be aware that
selves to continue exercising even while in pain? there are few, if any, diseases where “objective” factors correlate well
DR CLAUW In general, and not just for fibromyalgia but for almost with disability. They should not expect this to be the case in
every chronic pain condition, activity and exercise are beneficial and fibromyalgia.71
not harmful. Nearly any type of exercise is good for fibromyalgia or
any form of chronic pain. Patients should be advised to start with QUESTION How should physicians manage a clinic visit with a pa-
modest exercise and build up their activity level slowly. Many pa- tient like this to avoid feeling like they are manipulated by their pa-
tients tend to try to do too much too soon, leading to worsened pain. tient?
DR CLAUW If clinicians treat fibromyalgia or other chronic pain con-
QUESTION How much of a problem is secondary gain resulting from ditions with drugs alone, they will fail. This is akin to treating diabe-
disability financial support as an alternative to work in fibromyalgia tes with insulin or drugs alone, without any corresponding attempt
patients? to modify diet or weight. In contrast to diseases like diabetes or hy-
DR CLAUW There will always be individuals who fake or magnify pertension that lack physical symptoms, patients with chronic pain
symptoms to benefit financially, but this is seen in a minority of pa- hurt, motivating them to be more adherent to nondrug therapies.
tients. More problematic is the nonvolitional worsening occurring Be on the offensive. Be persistent in encouraging your patients about
when patients with pain enter the disability and compensations sys- doing exercise and trying web-based nondrug therapies. Do not be
tems. As eloquently noted by Hadler, “If you have to prove that you’re defensive and think that every time these patients come in, chang-
sick, you can’t get well.”70 I think that chronic pain patients are very ing to a different drug is the only available approach. If practition-
deserving of disability but find that they almost always clinically ers use nondrug therapies more aggressively and use fewer opi-
worsen when they get involved in disability or litigation. The dis- oids, nonsteroidal anti-inflammatory drugs, and procedures and
ability system results in frustration, anxiety, isolation, and inactiv- more centrally acting analgesics, fibromyalgia is easier to manage.

ARTICLE INFORMATION The conference on which this article is based Libman, MD, Eileen E. Reynolds, MD, Amy N. Ship,
Conflict of Interest Disclosures: The author has took place at the Medicine Grand Rounds at Beth MD, Gerald Smetana, MD, and Anjala V. Tess, MD.
completed and submitted the ICMJE Form for Israel Deaconess Medical Center, Boston,
Disclosure of Potential Conflicts of Interest. Dr Massachusetts, on October 4, 2012. REFERENCES
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