Review Article

Neuropathic Pain
Address correspondence to
Dr Lindsay A. Zilliox,
110 S Paca St, 3rd floor,
Baltimore, MD 21201,
lzilliox@som.umaryland.edu. Lindsay A. Zilliox, MD, MS
Relationship Disclosure:
Dr Zilliox has received salary
support from the US
Department of Veterans Affairs ABSTRACT
Career Development Grant. Purpose of Review: Neuropathic pain is a frequently encountered condition that
Unlabeled Use of
Products/Investigational
is often resistant to treatment and is associated with poor patient satisfaction of
Use Disclosure: their treatment. Several medications have been shown to be effective in treating
Dr Zilliox discusses the neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia, and
unlabeled/investigational
use of duloxetine, gabapentin,
these medications are often used to treat neuropathic pain associated with other
lamotrigine, pregabalin, conditions as well. This article summarizes the diagnosis and assessment of patients
tricyclic antidepressants, with neuropathic pain as well as available pharmacologic and interventional treat-
valproic acid, and venlafaxine
for the management of
ment options.
patients with neuropathic pain. Recent Findings: Evidence-based recommendations for the treatment of neuropathic
* 2017 American Academy pain have been published, and first-line medications include antidepressants,
of Neurology. anticonvulsants, topical agents, as well as opioid analgesics. Interventional options
include anesthetic and steroid injections, nerve blocks, and spinal cord stimulation.
Essential to the treatment algorithm of neuropathic pain is the assessment and
treatment of psychosocial comorbidities and the utilization of a multidisciplinary team
approach, including cognitive-behavioral and rehabilitative therapies. Questions remain
about the comparative effectiveness of various medications and combination therapies.
Increasing interest also exists in the optimization and personalization of pharmacother-
apy based upon the underlying mechanism(s) of neuropathic pain according to the
quality of the patient’s symptoms.
Summary: The management of chronic neuropathic pain is challenging and is best
achieved with the use of a multidisciplinary team. Pain is a subjective experience, and it
is important to validate a patient’s pain, address psychosocial comorbidities, and set
realistic treatment goals. Evidence-based guidelines are available to guide treatment,
but frequently, high-quality evidence-based recommendations are lacking.

Continuum (Minneap Minn) 2017;23(2):512–532.

INTRODUCTION vention (CDC) estimated that 30 mil-

Neuropathic pain is a common prob- lion people in the United States had
lem in clinical practice. Exactly how diabetes mellitus, and this number
common neuropathic pain is can be is rising.
difficult to quantify because of prob- In addition to painful diabetic pe-
lems with how to define and assess ripheral neuropathy, other neuro-
neuropathic pain, but the prevalence pathic pain conditions that are often
in the general population is estimated seen by neurologists include painful
to be between 7% and 10%.1 In the nondiabetic neuropathy, postherpetic
United States, painful diabetic pe- neuralgia, trigeminal neuralgia, ra-
ripheral neuropathy alone affects ap- diculopathy and failed back surgery
proximately 10 million people. An syndrome, central poststroke pain,
Supplemental digital content: estimated one-third of patients with spinal cord injury, and multiple sclero-
Direct URL citations appear in diabetes mellitus have painful dia- sis (Table 8-1).
the printed text and are in-
cluded in the HTML, PDF, and betic neuropathy,2 and in 2014 the Although neuropathic pain is a
app versions of this article. Centers for Disease Control and Pre- common symptom, most patients are

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 KEY POINTS
sion. In fact, measures of quality of life h Chronic neuropathic
TABLE 8-1 Conditions in people with chronic neuropathic
Associated With pain is associated with
Neuropathic Pain pain were rated as low as for patients low measures of
with clinical depression, coronary artery quality of life.
b Peripheral Neuropathic Pain disease, recent myocardial infarction, or h A thorough history and
poorly controlled diabetes mellitus.3 neurologic examination
Painful diabetic neuropathy
The American Academy of Neurol- are especially important
Human immunodeficiency ogy (AAN) has published practice when evaluating
virusYassociated neuropathy
guidelines on the treatment of painful patients with suspected
Chemotherapy-induced diabetic neuropathy (Supplemental neuropathic pain.
peripheral neuropathy Digital Content 8-1, links.lww.com/ h It is important to
Postherpetic neuralgia CONT/A216),4 postherpetic neural- include assessments
Trigeminal neuralgia
gia,5 and trigeminal neuralgia.6 Several of psychological
other clinical practice guidelines for comorbidities, sleep
Complex regional pain the treatment of neuropathic pain also disturbances,
syndrome
have been published.7Y9 work-related issues,
Compressive treatment expectations,
mononeuropathies DIAGNOSIS and availability of social
support in patients with
Radiculopathies No single diagnostic test or pathogno-
neuropathic pain.
Inflammatory neuropathies monic symptom exists to identify neu-
(acute and chronic ropathic pain. In fact, most patients
inflammatory demyelinating with neuropathic pain typically have
polyneuropathy) multiple different types of coexistent
Posttraumatic neuropathy pain. This makes a careful history and
physical examination of utmost im-
Phantom limb pain
portance in patients who are being
b Central Neuropathic Pain evaluated for neuropathic pain. The
Spinal cord injury International Association for the Study
Central poststroke pain
of Pain defines neuropathic pain as pain
caused by a lesion or disease of the
Compressive myelopathy somatosensory nervous system.9 This
Multiple sclerosisYrelated definition means that the presence of
pain signs or symptoms alone is not suffi-
Syringomyelia cient for the diagnosis of neuropathic
pain, but clinical judgment is often
required. There are screening tools,
often unsatisfied with their treatment. such as the Neuropathic Pain Scale
This may be because neuropathic pain and the Neuropathic Pain Question-
is often refractory to available treat- naire, that are available specifically for
ments, the treatments often have patients with neuropathic pain. How-
adverse effects, insufficient evidence- ever, a careful clinical assessment is still
based guidelines exist for treatment, needed because these screening tools
and patients may have unrealistic fail to identify 10% to 20% of patients
goals for their treatment. It is impor- with neuropathic pain.10
tant to recognize that neuropathic In cases of chronic neuropathic
pain affects many aspects of daily life pain, it is important to include assess-
and is associated with poor general ments of psychological comorbidities,
health, reduction in quality of life, poor sleep disturbances, work-related issues,
sleep, and higher anxiety and depres- treatment expectations, and availability
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 Neuropathic Pain

KEY POINT
h Ancillary studies are of social support. Occasionally, condi- unique aspects of neuropathic pain
used in conjunction with tions such as anxiety or depression can include hyperalgesia (increased re-
the physical cause exaggerated responses to pain, sponse to a stimulation that is normally
examination to confirm but it is important to communicate painful) and allodynia (pain due to a
or exclude underlying clearly with patients, validate their stimulus that typically does not pro-
etiologies for experience with pain, and set realistic voke pain). Other terms frequently
neuropathic pain, treatment goals. used in neuropathic pain are defined
but no diagnostic When interviewing a patient, it is in Table 8-3. These positive symptoms
test for neuropathic important to remember that pain is a are thought to represent excessive
pain exists. subjective experience and may be activity in a sensory pathway due to
described differently by different peo- a lowered threshold or heightened
ple. In general, the clinician should excitability. Negative signs and symp-
establish the intensity, quality, dura- toms are experienced as diminished
tion, and location of the symptoms. or absent feeling and are due to a loss
The presence of stimulus-evoked pain of sensory function.
or stimulus-independent pain should A complete neurologic examination
also be noted, as this can affect the can often assess non-neuropathic
choice of treatment. Typically, neuro- causes of pain and localize the lesion
pathic pain has both positive and that is causing neuropathic pain. In
negative sensory symptoms and signs general, during sensory testing, the
(Table 8-2). Positive symptoms are examiner should first apply sensory
generally painful or altered sensations stimuli to an unaffected area and then
and are often described as burning, to the area affected by pain. Patients
stinging, prickling, tingling, pins and should be instructed to state whether
needles, stabbing, or aching. Some the second stimulus felt the same as
the first and, if not, whether it felt more
or less intense. They can then go on to
TABLE 8-2 Positive and
Negative Symptoms describe the quality of the stimulus.
of Neuropathic Pain The different sensory modalities that
should be tested include pinprick, light
b Positive Symptoms touch, temperature, vibration, and pro-
Tingling (pins and needles)
prioception. Pinprick, light touch, and
temperature sensation are carried by
Prickling small unmyelinated fibers and ascend
Lightninglike or lancinating in the spinothalamic pathway. Vibra-
Aching tion and proprioception are carried
by large myelinated fibers and ascend
Knifelike
in the dorsal columns.
Pulling or tightening Several ancillary studies are used in
Burning or searing conjunction with the physical exami-
nation to confirm or exclude underly-
Electrical
ing etiologies for neuropathic pain.
b Negative Symptoms Nerve conduction studies and needle
Numbness EMG examine peripheral nerve func-
tion, but importantly do not assess
Deadness
small unmyelinated pain fibers. Skin
Feeling of wearing socks all biopsy is a reliable technique to
the time
diagnose small fiber neuropathy and
assess the nociceptive skin nerve fiber

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 KEY POINT

TABLE 8-3 Terminology Associated With Neuropathic Pain h Multiple mechanisms

underlie neuropathic
b Hyperesthesia: Increased sensitivity to stimulation pain and represent
many potential targets
b Hyperalgesia: Increased response to a stimulation that is normally painful for therapies.
b Allodynia: Pain due to a stimulus that typically does not provoke pain
b Paresthesia: An abnormal sensation (may be provoked or spontaneous)
b Dysesthesia: An unpleasant abnormal sensation
b Hypoesthesia: Decreased sensitivity to stimulation
b Hypoalgesia: Diminished pain in response to a normally painful stimulus
b Analgesia: Loss of pain sensation
b Anesthesia: Loss of sensation

density. However, the relationship the problem remains to identify the

between skin biopsy results and pain predominant mechanism in a particu-
is unclear. Quantitative sensory testing lar individual and to target it appropri-
determines a perception threshold ately. In practice, several different
for mechanical, thermal, and painful mechanisms can coexist and change
stimuli that is delivered at a con- over time, and an individual’s response
trolled intensity. Quantitative sensory to a medication remains unpredictable.
testing has been used for the early In the peripheral nervous system,
diagnosis of small fiber neuropathy new growth from an injured nerve will
and early diabetic neuropathy and can spontaneously fire (ectopic discharges),
be used to quantify mechanical and and eventually, connections may de-
thermal allodynia and hyperalgesia. velop between these new areas of
However, quantitative sensory testing growth and nearby afferent neurons.11
also shows changes in non-neuropathic This way neuropathic pain may be
pain states and relies upon patient generated from either injured or intact
participation, which can be influenced sensory neurons. Neuronal damage also
by psychological factors, response bias, leads to an increase in the num-
or malingering. ber of sodium and calcium channels
that are present. Other causes of pe-
PATHOPHYSIOLOGY ripheral sensitization include height-
Neuropathic pain is frequently classi- ened responsiveness to inflammatory
fied as central or peripheral, depen- mediators released by damaged cells
ding on the site of the lesion that is and sprouting of sympathetic neurons
causing the pain (Table 8-1). How- in the dorsal root ganglion.
ever, neuropathic pain can be thought Central sensitization refers to in-
of as a manifestation of multiple creased excitation and reduced inhibi-
peripheral and central nervous system tion of central nervous system pathways
processes that result in sensitization of that are associated with neuropathic
both the peripheral and central ner- pain. Repeated input from peripheral C
vous systems. As knowledge about the fibers results in enhanced spinal cord
underlying pathophysiology of neuro- excitability. In addition, injury to central
pathic pain grows, several different nervous system structures may alter
targets exist for treatment. However, sensory processing.
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 Neuropathic Pain

KEY POINTS
TREATMENT illustrated in Case 8-1. The exception
h Prior to beginning
pharmacotherapy, it is
Establishing realistic goals is an impor- to this is trigeminal neuralgia. For
important to validate tant first step in treatment. The vast more information on management of
the patient’s pain and majority of patients will not achieve trigeminal neuralgia, refer to the article
jointly set realistic complete pain relief but can expect the ‘‘Trigeminal Neuralgia’’ by Giorgio
treatment goals. pain to be made tolerable. In general, a Cruccu, MD,13 in this issue of Contin-
h Tricyclic antidepressants 30% reduction of pain on an 11-point uum. Recommendations for first-line
are effective in treating numerical rating scale is considered to pharmacotherapy of neuropathic pain
several different types be clinically important and constitutes are summarized in Table 8-5.
of neuropathic pain. ‘‘moderate relief’’ or ‘‘much improved.’’12
It is also important to recognize and Tricyclic Antidepressants
h The analgesic effect of
tricyclic antidepressants treat comorbidities such as anxiety and The analgesic effect of tricyclic antide-
is independent of their depression, and secondary treatment pressants is due to inhibition of norepi-
antidepressant effect, goals may include improving sleep, nephrine reuptake at the spinal dorsal
and the analgesic effect advancing function, and enhancing synapses, with secondary activity at so-
is achieved by much overall quality of life. These goals are dium channels.14 Amitriptyline is rela-
lower doses in best achieved when pharmacologic ther- tively balanced in its ability to inhibit
comparison to the apy is just one component of a multi- norepinephrine and serotonin reuptake
antidepressant effect. disciplinary approach to treatment. while nortriptyline, which has similar
Most randomized controlled drug efficacy but fewer side effects, demon-
trials in neuropathic pain have been in strates greater inhibition of norepineph-
painful diabetic neuropathy and post- rine reuptake. Tricyclic antidepressants
herpetic neuralgia, and the US Food are effective for several different types
and Drug Administration (FDA) has of neuropathic pain, mainly painful
approved six medications for three diabetic neuropathy and postherpetic
neuropathic pain syndromes: trigemi- neuralgia. Tricyclic antidepressants are
nal neuralgia (carbamazepine), posther- considered effective in treating central
petic neuralgia (gabapentin, pregabalin, pain, but there are limited data in spe-
5% lidocaine patch, capsaicin cream, and cific central pain etiologies. Tricyclic
capsaicin 8% patch), and painful diabetic antidepressants are also efficacious in
neuropathy (pregabalin, duloxetine, and treating depression, but their analgesic
capsaicin cream) (Table 8-4). Although effect is independent of their antide-
the results from one neuropathic pain pressant effect, and the analgesic effect
syndrome cannot directly be applied to is achieved by much lower doses in com-
another, most first-line therapies have parison to the antidepressant effect.
been found to be effective in multiple Tricyclic antidepressants should be
types of neuropathic pain,9 which is initiated at low dosages (10 mg/d to

TABLE 8-4 Neuropathic Pain Medications Approved by the US Food

and Drug Administration

Indication Medication
Trigeminal neuralgia Carbamazepine
Painful diabetic neuropathy Duloxetine, pregabalin, capsaicin cream
Postherpetic neuralgia Gabapentin, pregabalin, topical lidocaine,
capsaicin 8% patch, capsaicin cream

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 KEY POINT

Case 8-1 h The use of tricyclic

antidepressants is
A 56-year-old man presented with numbness, burning, and tingling of his
limited by their side
right anterolateral thigh. The pain was present throughout the day and
effects. Nortriptyline is
was distracting while he was at work. His past medical history was
generally better tolerated
significant for obesity, benign prostatic hypertrophy, glaucoma, coronary
than amitriptyline.
artery disease, hypertension, and hyperlipidemia.
Neurologic examination was notable only for hyperesthesia in the
distribution of the right anterolateral thigh in the distribution of the
lateral femoral cutaneous nerve.
He was diagnosed with meralgia paresthetica and was advised to wear
loose-fitting clothing and to lose weight. Additionally, because of the impact
of the constant pain on his daily life, he was started on topical capsaicin.
After 2 weeks, the patient returned and stated that he often missed doses of
the capsaicin because of the burning sensation he experienced, and he had
only received minimal improvement in his pain. After discussion about
potential weight gain and sedation due to pregabalin and gabapentin and
the potential risks of tricyclic antidepressants in patients with heart disease
as well as the risk of urinary retention, he decided upon a trial of venlafaxine.
The topical capsaicin was discontinued, and he was started on extended
release venlafaxine 75 mg/d, which was titrated to 150 mg/d. Upon his return
visit 1 month later, he stated that his pain was tolerable, and that he had
recently lost 4.5 kg (10 lb).
Comment. Many common neuropathic pain conditions do not have
high-quality evidence to recommend specific treatments. However, in
general, outcomes from the treatment of other peripheral neuropathic
pain conditions can frequently be applied with good results. It is important
to personalize treatment based on patient preferences and medication
side effects. If neuropathic pain does not respond to the first prescribed
medication, it is not necessarily an indication that it is resistant to all
first-line therapies, and another medication should be tried.

25 mg/d at bedtime), and the dose urinary retention, and postural hypo-
can be increased every 3 to 7 days by tension). They must be used with
10 mg/d to 25 mg/d as tolerated. The caution in patients with a history of
goal dose is 75 mg/d to 150 mg/d; heart disease (a screening ECG for
before prescribing higher doses, an conduction abnormalities is recom-
ECG should be performed if not mended before beginning treatment),
already performed, and blood levels glaucoma, urinary retention, or auto-
should be monitored. In patients with nomic neuropathy. Caution is advised
a history of heart disease, the dose when a risk exists for suicide or
should be limited to less than 100 mg/d. overdose because of the risk of fatal
An adequate trial of a tricyclic antide- cardiac dysrhythmias and serotonin
pressant should last 6 to 8 weeks with syndrome. Nortriptyline is generally
1 to 2 weeks at the maximum toler- recommended rather than amitripty-
ated dose. line in elderly patients because it is
Adverse effects are the main problem usually better tolerated.
with use of tricyclic antidepressants.
Common side effects include sedation Calcium Channel !2% Ligands
and anticholinergic effects (eg, dry Gabapentin and pregabalin are effective
mouth, blurred vision, constipation, in treating several neuropathic pain

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 Neuropathic Pain

TABLE 8-5 First-Line Pharmacotherapy of Neuropathic Pain

Medication Dose Adequate Trial Side Effects Comments

Tricyclic antidepressants
Amitriptyline, 10Y25 mg at 6Y8 weeks Sedation, Use with caution in
nortriptyline bedtime, titrate up (2 weeks at anticholinergic patients with cardiac
to a maximum maximum dose) effects (eg, dry disease, risk of
of 150 mg/d mouth, blurred serotonin syndrome
vision, urinary
retention), cardiac
conduction
abnormalities
Serotonin norepinephrine reuptake inhibitors (SNRIs)
Duloxetine 30 mg once a 4 weeks Nausea, increased Risk of serotonin
day, titrate up to sweating, increased syndrome, risk of
60 mg twice a day blood pressure hepatic dysfunction;
venlafaxine immediate
Venlafaxine Venlafaxine 4Y6 weeks release in particular is
immediate release: associated with a
75 mg/d in 2 or withdrawal syndrome
3 divided doses, if the patient forgets
titrate up to total to take a dose on time
daily dose of
225 mg/d
Venlafaxine
extended release:
37.5 mg or 75 mg
once daily, titrate
up to 225 mg
once daily
Calcium channel !2% ligands
Gabapentin 100Y300 mg once or 5Y10 weeks Sedation, Reduce dose in
3 times a day, titrate (2 weeks at dizziness, patients with renal
up to total daily maximum dose) weight gain, impairment
dose of 3600 mg/d edema
Pregabalin 50 mg 3 times a 4 weeks Sedation, Reduce dose in
day or 75 mg dizziness, patients with renal
2 times a day, weight gain, impairment; risk of
titrate up to edema dependence and
300Y600 mg/d tolerance (schedule V
controlled substance)
Topical lidocaine 1Y3 patches for a 3 weeks Local erythema Not effective in
maximum or rash central neuropathic
of 12 hours pain

conditions. They are generally well tol- it has no proven effect on GABA re-
erated with few medication interactions ceptors. It is thought to work by
but can cause sedation and dizziness. modulation of voltage-gated calcium
Gabapentin. Gabapentin is a ,- channels to inhibit neurotransmitter
aminobutyric acid (GABA) analog, but release. Gabapentin is FDA approved

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 KEY POINTS
for the treatment of postherpetic neu- The starting dose is 600 mg/d for h Starting with a single
ralgia. Gabapentin and pregabalin have 3 days and then is increased to 600 mg bedtime dose of
the most evidence-based data for the twice a day. Dosage adjustment is gabapentin can help to
treatment of painful diabetic neuro- necessary in patients with renal impair- reduce side effects.
pathy. Gabapentin has also been ment. Side effects include sedation, h Pregabalin has linear
shown to be effective in phantom limb dizziness, headache, and, less com- pharmacokinetics and an
pain, pain in Guillain-Barré syndrome, monly, edema and nausea. easier dosing schedule
and pain from spinal cord injury. Pregabalin. Pregabalin is also calcium than gabapentin.
The typical starting dose is 100 mg channel "2& ligand and is closely h Pregabalin has
to 300 mg 3 times a day, and it is ti- related to gabapentin. However, it has dose-dependent effects
trated up every 1 to 7 days by 100 mg/d linear pharmacokinetics, a higher af- with several negative
to 300 mg/d as tolerated up to a target finity for the presynaptic calcium studies for 150 mg/d and
dose of 1800 mg/d to 3600 mg/d. To channel than gabapentin, and an positive results for total
reduce side effects, practitioners may easier dosing schedule than gaba- daily doses of 300 mg/d
start with a single bedtime dose, in- pentin. Pregabalin is FDA approved to 600 mg/d. However,
crease to twice a day, and then in- for the treatment of painful diabetic total daily doses of more
crease to 3 times daily. Although 3 times neuropathy and is also effective in than 300 mg/d may not
a day dosing is ideal, occasionally a postherpetic neuralgia and spinal cord be more effective and
are often associated with
higher dose is given at bedtime to limit injury and other causes of central neuro-
increased side effects.
daytime sedation. An adequate trial of pathic pain. Pregabalin has dose-
gabapentin would include 3 to 8 weeks dependent effects and is typically
for titration and development of toler- not effective at the starting dose of
ance to adverse effects, plus 1 to 2 weeks 150 mg/d. The initial dose is either
at the maximum tolerated dose. Dosage 50 mg 3 times daily or 75 mg 2 times
adjustment is necessary in patients with a day, which can be increased to a
renal impairment. total dose of up to 300 mg/d after
In general, gabapentin is well toler- 1 to 2 weeks. If a patient tolerates
ated with few drug interactions. Com- 300 mg/d, but has persistent pain,
mon side effects of dizziness and the dose can be increased to a total
sedation are dose dependent and can dose of 600 mg/d. However, total
be reduced by starting with lower daily doses of more than 300 mg/d
doses and using a slow titration sched- are not necessarily more effective and
ule. Other side effects include gait and are associated with a higher rate of side
balance problems, gastrointestinal symp- effects. The dose should be adjusted
toms, and peripheral edema. Gaba- in patients with renal impairment.
pentin has been found to have a similar Pregabalin has a similar side effect
efficacy to nortriptyline, but difficulty profile to gabapentin, but patients tend
concentrating was reported more often to tolerate a more rapid dose titration.
with gabapentin, and dry mouth was The most common side effects include
seen more often with nortriptyline.15 dizziness, somnolence, weight gain,
Gabapentin enacarbil. Gabapentin peripheral edema, and diplopia. Pre-
enacarbil is an extended release form gabalin is a schedule V controlled sub-
of gabapentin. It has been found to be stance that can cause feelings of euphoria
effective and well tolerated in treating and has the potential for abuse. In addi-
postherpetic neuralgia. However, it tion, all antiepileptics, including pregab-
was not found to be effective in alin, have been shown to be associated
treating painful diabetic neuropathy.16 with an increased risk of suicidal thoughts
Gabapentin enacarbil is given once or or actions, and patients should be mon-
twice a day with a larger dose at night. itored for changes in behavior.
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 Neuropathic Pain

KEY POINTS
h Serotonin norepinephrine Serotonin Norepinephrine various etiologies. Venlafaxine is avail-
reuptake inhibitors treat Reuptake Inhibitors able in short- and long-acting formu-
major depressive disorder Serotonin norepinephrine reuptake in- lations. The starting dose for venlafaxine
and generalized anxiety hibitors (SNRIs) inhibit the reuptake immediate release is 75 mg/d in 2 or
disorder in addition to of serotonin and norepinephrine. Dulo- 3 divided doses, and it can be in-
neuropathic pain. xetine is a balanced inhibitor of seroto- creased as tolerated up to 225 mg/d.
h The most frequent side nin and norepinephrine reuptake, Venlafaxine extended release is started
effect of duloxetine and while venlafaxine inhibits serotonin at 37.5 mg or 75 mg once a day and
venlafaxine is nausea. reuptake at lower dosages and inhibits is increased over 2 to 4 weeks to
The extended release the reuptake of both neurotransmitters 150 mg/d to 225 mg/d. Increased
formulation of at higher dosages of 150 mg/d or more. sweating is a frequent side effect.
venlafaxine may be Duloxetine. Duloxetine is FDA ap- Cardiac conduction abnormalities and
better tolerated than proved for the treatment of painful blood pressure increases have been
the immediate release reported, so caution is advised when
diabetic neuropathy and has also been
formulation. No
found to be effective in chemotherapy- prescribing this medication to patients
additional benefit has
induced painful neuropathy. Based on with cardiac disease. Patients taking
been found from taking
more than 60 mg/d of a meta-analysis, its efficacy is similar venlafaxine immediate release should
duloxetine, and higher to that of gabapentin and pregabalin.17 be cautioned not to abruptly stop this
total daily dosages are It has not been found to be effective medication because of the risk of a
associated with more in central neuropathic pain. However, withdrawal syndrome, which can occur
side effects. it is also effective in the treatment upon abrupt discontinuation of any
h First-line medications for of major depression and generalized selective serotonin reuptake inhibitor
the treatment of anxiety disorder. The typical starting (SSRI) or SNRI but is of concern with
neuropathic pain include dose is 60 mg/d, but starting at 30 mg/d venlafaxine immediate release because
tricyclic antidepressants may reduce the incidence of nausea. of its short half-life.
(amitriptyline or The usual total daily dose is 60 mg/d
nortriptyline), to 120 mg/d, but no additional benefit Topical Lidocaine
anticonvulsants has been found from taking dosages Topical lidocaine acts locally by antag-
(gabapentin or of more than 60 mg/d. onizing sodium channels and reducing
pregabalin), serotonin Nausea is the most common adverse spontaneous ectopic nerve discharges.
norepinephrine reuptake
effect. Additional side effects include The 5% lidocaine patch is FDA ap-
inhibitors (duloxetine
increased sweating, somnolence, dry proved for the treatment of posther-
or venlafaxine), and
topical lidocaine.
mouth, constipation, diarrhea, and diz- petic neuralgia, but the treatment
ziness. Cardiac conduction abnormali- effect is moderate. It also has been
ties and blood pressure increases have shown to be efficacious in allodynia
been reported, so caution is advised due to different types of peripheral
when prescribing this medication to neuropathic pain. Lidocaine gel (5%) is
patients with cardiac disease. Cases of less expensive and is effective in
hepatotoxicity have also been reported, treating postherpetic neuralgia and
so its use is not recommended in allodynia. Patches should be applied
patients with hepatic insufficiency, but directly to painful sites and can be cut
routine liver function monitoring is not as needed. No more than 3 patches
recommended. should be worn concurrently for a
Venlafaxine. Venlafaxine is FDA ap- maximum of 12 hours. In patients
proved for the treatment of major with normal hepatic function, blood
depression, but it has been studied levels are minimal; however, systemic
and found to be effective in the treat- absorption must be considered in
ment of painful diabetic neuropathy as patients taking Class I antiarrhythmic
well as in painful polyneuropathies of medications. No titration is needed,
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 KEY POINTS
and an adequate trial would be for they are typically recommended for h A single application of
2 to 4 weeks. Side effects are minimal patients who do not respond to first- capsaicin 8% patch
and include skin reactions at the line medications. However, they are can be effective for
application site. recommended as first-line treatments in up to 12 weeks, but
acute neuropathic pain, neuropathic the effects from
Topical Capsaicin pain due to cancer, and episodic repeat applications
Capsaicin is a hot chili pepper ex- exacerbations of severe neuropathic are unknown.
tract, and its mechanism of action in pain. They are also used while a first- h Because of concerns
treating neuropathic pain is not well line medication is being titrated when about long-term safety,
understood, but it is thought to result immediate pain relief is needed. opioid narcotics are
in desensitization of sensory axons Tramadol. Tramadol has a dual generally recommended
and epidermal denervation.18 mechanism of action: as a central only for patients who
High-concentration capsaicin patches. opioid agonist at the mu receptor and do not respond to
The high-concentration capsaicin 8% as an inhibitor of norepinephrine and first-line medications.
patch has been shown to be effective serotonin reuptake. Tramadol has been h Tramadol should be
in postherpetic neuralgia and painful shown to be effective in several neuro- avoided in patients with
human immunodeficiency virus (HIV)- pathic pain conditions, including painful a history of substance
associated neuropathy. A single treat- diabetic neuropathy and mixed neuro- abuse, and it is
increasingly being
ment, which must be applied by a health pathic pain syndromes. Although it has
misused or abused.
care provider, can provide a sustained generally been considered to be a safer
Tramadol can also
reduction in pain for up to 12 weeks. It alternative to other narcotic analgesics, lower the seizure
is generally safe and well tolerated, but it is a schedule IV controlled substance threshold and should
it often requires the preapplication of a and is increasingly being misused or be avoided in individuals
local anesthetic because of an intense abused. Tramadol should be avoided with a history of
burning sensation. Long-term repeat in patients with a history of substance seizure disorders.
applications have unclear effects, and a abuse. Tramadol should be started at
possible risk exists of transient epider- a low dose, 50 mg once or twice a
mal denervation and resultant loss of day, and titrated every 3 to 7 days
heat pain sensation. by 50 mg/d to 100 mg/d in divided
Capsaicin cream. Capsaicin creams doses as tolerated. The maximum dose
(0.075%) are moderately effective in is 100 mg 4 times a day (maximum
postherpetic neuralgia, but inconsistent total daily dose 300 mg/d in patients
results have been seen in the treatment older than 75 years). An adequate trial
of neuropathic pain due to peripheral is 4 weeks. The dosage should be re-
neuropathy. The creams are available in duced in patients with renal or hepatic
a range of potencies, can be difficult to impairment.
apply, must be applied multiple times a Adverse effects of tramadol include
day to the entirety of the painful area, dizziness, nausea, constipation, som-
and often cause painful sensations nolence, and orthostatic hypotension.
during the first few weeks of use. The tramadol/acetaminophen combi-
Adverse effects at the application site nation may be better tolerated. Impor-
include pain and erythema. tantly, tramadol can lower the seizure
threshold, and seizures can occur if
Tramadol and Opioid Analgesics high doses are used. A risk exists of
Tramadol and opioid analgesics are the serotonin syndrome if tramadol is
effective in different types of neuropathic used simultaneously with other sero-
pain but are generally not recommended tonergic medications.
as first-line treatments because of con- Opioid analgesics. Strong opioids
cerns about long-term safety. Instead, that are used in chronic pain include
Continuum (Minneap Minn) 2017;23(2):512–532 ContinuumJournal.com 521
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Neuropathic Pain

KEY POINT
h The American Academy codeine, morphine, oxycodone, and every visit, (5) using a state prescrip-
of Neurology position fentanyl. Their use in treating a variety tion drug monitoring program to mon-
paper and Centers for of neuropathic pain conditions is itor prescriptions, and (6) consulting
Disease Control and controversial, and the use of opioids with a pain management specialist if the
Prevention guidelines to treat chronic noncancer pain is a daily morphine equivalent dose reaches
both stress that public health concern given the rising 80 mg/d to 120 mg/d.21,22
nonpharmacologic and number of deaths related to prescrip-
nonopioid pharmacologic tion opioids in the United States. Opi- Additional Medications
therapy are preferred for oids have been shown to be efficacious This category includes medications that
chronic pain, and if in patients with painful diabetic neu- have been shown to be effective in a
opioids are used, they
ropathy with at least moderate pain for single randomized controlled trial or
should be part of a
a minimum of 3 months as well as inconsistently in multiple randomized
multidisciplinary approach
to pain management.
in patients with postherpetic neural- controlled trials. Carbamazepine is FDA
gia.19,20 However, as discussed in the approved for the treatment of trigeminal
AAN position paper on opioids for neuralgia and is the first-line medication
chronic noncancer pain, evidence for for treatment in this neuropathic pain
long-term pain relief or improved condition. However, small studies in pain-
function is lacking, and serious risks ful neuropathy have not demonstrated
of overdose, dependence, or addiction clear efficacy. In addition, carbamaze-
exist.21 It is difficult to assess which pine has poor tolerability and multiple
patients will benefit from chronic treat- pharmacokinetic interactions. Side ef-
ment with opioids, and for some fects include skin rash, hyponatremia,
patients the risks of chronic opioid decreased bone density, and hemato-
therapy outweigh any potential bene- poietic issues. Similar to carbamaze-
fits. The AAN position paper and CDC pine, conflicting results exist regarding
guidelines both stress that nonphar- the efficacy of oxcarbazepine in treating
macologic and nonopioid pharmaco- painful diabetic neuropathy. However,
logic therapy are preferred for chronic it is significantly better tolerated than
pain, and if opioids are used, they carbamazepine and has fewer drug in-
should be part of a multidisciplinary ap- teractions than carbamazepine. Patients
proach to pain management.21Y23 should be monitored for hyponatremia.
Opioid prescribing guidelines have Divalproex sodium has been found
been published.23 In general, immediate- to have a beneficial effect in treating
release opioids should be started at painful diabetic neuropathy and trigem-
the lowest effective dosage. The ben- inal neuralgia but lacks efficacy in
efits and harms of opioid therapy reducing overall pain or improving
should be reexamined with the pa- quality of life.24,25 Lamotrigine is the
tient every 3 months or within 1 to only drug that has been found to be
4 weeks after starting opioids or chang- moderately effective in patients with
ing the dose. Additional best practices HIV-associated neuropathy who were
when using opioids for chronic pain receiving antiretroviral treatment. How-
include: (1) using a patient treatment ever, overall, no convincing evidence
agreement, (2) screening for sub- exists that lamotrigine is effective in
stance abuse or misuse as well as treating other forms of neuropathic
depression, (3) random urine drug pain.26 A slow titration schedule is
screening prior to starting opioid required because of risk of a severe
therapy and periodically thereafter, rash and Stevens-Johnson syndrome.
(4) tracking pain and function as well Lacosamide, topiramate, zonisamide,
as daily morphine equivalent dose at and phenytoin have also been studied
522 ContinuumJournal.com April 2017

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 KEY POINT
in painful diabetic neuropathy, but only for negative effects on cognition and h A combination of two
inconclusive evidence exists for their mood as well as the risk of tolerance first-line medications
use in the treatment of neuropathic pain. and dependency. may be more
SSRIs have been shown to have efficacious than either
efficacy in the treatment of neuro- Combination Therapy medication alone.
pathic pain in small studies, but Although multiple drugs are often used
pooled data failed to show a signifi- in combination to treat neuropathic
cant difference in pain relief com- pain in patients who have a partial re-
pared to placebo.27 A weak analgesic sponse to monotherapy, only a few
effect has been found for citalopram, studies have examined the efficacy of
paroxetine, and escitalopram, but not this strategy. In theory, combination
fluoxetine. SSRIs must be used with pharmacotherapy may improve the
caution alongside tricyclic antidepres- analgesic efficacy and reduce side
sants because of an increased risk for effects of individual drugs, but not
serotonin syndrome. enough evidence exists to recommend
Mexiletine is an oral analog of a specific drug combination. This is a
lidocaine that has shown efficacy in frequent strategy in clinical practice
only small studies of neuropathic pain. and is illustrated by Case 8-2. Com-
It is generally not recommended for pared to monotherapy, the combina-
use in neuropathic pain because of its tion of gabapentin and morphine or
side effects, which include agranulocy- gabapentin and nortriptyline was found
tosis, hepatotoxicity, and toxic epider- to provide better pain relief at lower
mal necrosis. Its use is contraindicated dosages in patients with painful dia-
in patients with second- and third- betic neuropathy and postherpetic
degree atrioventricular block, and pa- neuralgia.15,29,30 However, there have
tients should be monitored with been conflicting results from similar
complete blood cell count, ECG, and trials of pregabalin and oxycodone.31,32
liver function tests. In addition, a large study in painful
Cannabinoids have been found to diabetic neuropathy did not find a
be effective in treating neuropathic significant difference in efficacy be-
pain associated with multiple sclerosis tween high-dose monotherapy with
and in neuropathic pain with allodynia, pregabalin or duloxetine compared to
but overall the results of clinical trials combination therapy.33
have been inconsistent, and legal and
regulatory issues surround its use. SPECIFIC CONDITIONS
They are recommended as third-line Different types of neuropathic pain
analgesics for the treatment of neuro- may respond well to a particular
pathic pain by the Canadian Pain medication or class of medications.
Society.8 The use of cannabinoids is This section will provide specific treat-
limited by many negative effects that ment recommendations for select
include dizziness, nausea, dry mouth, neuropathic pain conditions.
sedation, gastrointestinal effects, and
oral discomfort. Cannabinoids should Painful Peripheral Neuropathy
be used with caution in patients with a As stated previously, the efficacy of most
history of heart disease or seizures and of the medications discussed in the
are not recommended for patients with treatment of neuropathic pain has
psychiatric disorders because of a risk been established in studies of painful
of psychosis.28 Controversy exists about diabetic neuropathy. The 2011 AAN
their long-term use and the potential evidence-based guideline on the
Continuum (Minneap Minn) 2017;23(2):512–532 ContinuumJournal.com 523
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Neuropathic Pain

KEY POINT
h Human
immunodeficiency
Case 8-2
A 65-year-old man with a history of preYdiabetes mellitus presented with
virusYassociated
numbness and tingling in his feet that had been slowly progressive for the
neuropathy and
past 5 years. He noted that he experienced an unpleasant sensation when
chemotherapy-associated
the bedsheets touched his skin or when wearing socks. His pain interfered
neuropathy tend to be
with physical activity and exercise, and thus, he had gained weight, had been
relatively refractory to
feeling down, and lacked interest in activities that he used to enjoy.
first-line treatments.
Neurologic examination revealed full strength throughout and normal
deep tendon reflexes. Sensation to pinprick was decreased in the lower
extremities to the midcalves bilaterally and decreased to vibration and
proprioception at the great toes bilaterally.
He was started on duloxetine with an improvement in his pain, but he
was still frequently up at night because of painful sensations. Gabapentin
was then added at night before bedtime.
Comment. Due to coexisting depression, duloxetine was initially chosen
for neuropathic pain control. After a partial response, low-dose gabapentin
was added to help with neuropathic pain and sleep. The combination of
two first-line medications is often effective in controlling neuropathic pain.
In addition, the use of lower doses than typically used in monotherapy
can often alleviate side effects.

treatment of painful diabetic neurop- caine. Some benefit has been seen
athy found that pregabalin was effec- in studies of lamotrigine, gabapentin,
tive in the treatment of painful diabetic cannabinoids, and high-concentration
neuropathy, and venlafaxine, duloxetine, (8%) capsaicin patches.
amitriptyline, gabapentin, valproate,
opioids, and capsaicin were probably Neuropathic Pain in Patients
effective.4 Limited evidence exists on With Cancer
the efficacy of oral "-lipoic acid, an Patients with cancer often experi-
antioxidant, but it is often prescribed in ence more than one type of pain,
painful diabetic neuropathy because of and the World Health Organization
its potential benefits and low side has published guidelines for the
effect profile. It is typically dosed at treatment of non-neuropathic can-
600 mg once or twice daily and should cer pain. 34 However, neuropathic
be used with caution in patients who are cancer pain may respond poorly to
at risk of hypoglycemia. opioids, and very few clinical trials
In general, the treatment options have been performed to help guide
for diabetic and nondiabetic painful clinical management in this scenario.
peripheral neuropathy are similar, and Gabapentin and tricyclic antidepres-
recommendations for common condi- sants may be effective in treating neuro-
tions are outlined in Table 8-6. The pathic pain from cancer, and pregabalin
exception is for HIV-associated neu- is often used because of its rapid
ropathy and chemotherapy-induced titration schedule and tolerability.35
neuropathy, which tend to be relatively
refractory to first-line neuropathic Postherpetic Neuralgia
pain treatments. In HIV-associated In general, tricyclic antidepressants,
neuropathy, no evidence exists to gabapentin, and pregabalin are the
recommend treatment with amitrip- drugs of first choice in the treat-
tyline, pregabalin, or topical lido- ment of postherpetic neuralgia. Other

524 ContinuumJournal.com April 2017

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 KEY POINT

TABLE 8-6 Therapies for Common Neuropathic Pain Conditions h In general, central
neuropathic pain tends
b Painful Diabetic Neuropathy to be more refractory to
treatment than peripheral
First line: pregabalin, duloxetine, gabapentin, tricyclic antidepressant, neuropathic pain.
venlafaxine
Second line: capsaicin, opioids, valproic acid, venlafaxine
Other: spinal cord stimulation
b Postherpetic Neuralgia
First line: gabapentin, pregabalin, tricyclic antidepressants, topical lidocaine
Second line: opioids and topical capsaicin
Other: valproic acid, botulinum toxin
b Central Pain
First line: gabapentin, pregabalin (spinal cord injury), tricyclic antidepressants
Second line: duloxetine, lamotrigine, opioids, tramadol, cannabinoids
(multiple sclerosis)
b Human Immunodeficiency VirusYAssociated Neuropathya
Capsaicin 8% patch, lamotrigine, cannabinoids
b Cancer Neuropathic Paina
Gabapentin, tricyclic antidepressants, pregabalin, opioids
b Phantom Paina
Opioids, gabapentin
b Posttraumatic Neuropathic Paina
Pregabalin, tricyclic antidepressants, venlafaxine, topical capsaicin
b Complex Regional Pain Syndromea
Physical and occupational therapy, corticosteroids, tricyclic
antidepressants, gabapentin, pregabalin, duloxetine, bisphosphonates,
calcitonin, opioids, sympathetic nerve blocks, spinal cord stimulation
b Radiculopathy and Failed Back Surgery Syndromea
Physical therapy, pregabalin, duloxetine, gabapentin, tricyclic antidepressants,
venlafaxine, spinal cord stimulation (failed back surgery syndrome)
a
Neuropathic pain conditions that lack high-quality evidence for treatment recommendations.

medications that have been shown to Neuralgia’’ by Giorgio Cruccu, MD,13

be beneficial include opioids, topical in this issue of Continuum.
capsaicin, and topical lidocaine. A ben-
efit may exist from valproic acid and Central Neuropathic Pain
botulinum toxin. In general, central neuropathic pain
tends to be more refractory to treatment
Trigeminal Neuralgia than peripheral neuropathic pain, and
The treatment of trigeminal neuralgia relatively few randomized controlled tri-
is addressed in the article ‘‘Trigeminal als in patients with central neuropathic

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 Neuropathic Pain

KEY POINTS
pain have been carried out. Despite this, no reduction in neuropathic pain was
h A recent systematic
review did not find any central neuropathic pain is generally found from amitriptyline.
effective treatments for responsive to the same medications as
central poststroke pain. peripheral neuropathic pain. One ex- Complex Regional Pain
ception to this is the use of topical lido- Syndrome
h Pregabalin is often the
drug of choice in caine and capsaicin, which are thought Complex regional pain syndrome
neuropathic pain to be only effective in peripheral neu- (CRPS) is characterized by intense neu-
associated with spinal ropathic pain. In central poststroke ropathic pain that includes allodynia or
cord injury. pain, amitriptyline and lamotrigine are hyperalgesia. CRPS can be difficult to
h The treatment of typically recommended as first-line diagnose, which has led to a lack of
complex regional pain medical therapies. However, a recent evidence-based recommendations for
syndrome requires systematic review of therapies for cen- treatment. Multidisciplinary care with a
multidisciplinary care tral poststroke pain found that all focus on functional therapies is often
with a focus on therapies examined (anticonvulsants, recommended, and pharmacotherapy
functional therapies, an antidepressant [amitriptyline], an is often required to enable patients to
and pharmacotherapy opioid antagonist [naloxone], repetitive participate in these therapies. Cortico-
is often required to transmagnetic stimulation, and acu- steroids can be used within the first
enable patients to puncture) had little or no effect on 3 months of CRPS to treat inflammation
participate in
pain.36 In spinal cord injury, pregabalin and have been found to have a benefi-
these therapies.
has been shown to be effective in treat- cial effect in the prevention and treat-
ing neuropathic pain. Other medication ment of CRPS.38,49 Other medications
options for treating central neuropathic used to treat neuropathic pain in CRPS
pain associated with spinal cord injury include tricyclic antidepressants, gaba-
include gabapentin, tricyclic antidepres- pentin, pregabalin, duloxetine, bisphos-
sants, SNRIs, and opioids. phonates, calcitonin, topical lidocaine
or capsaicin, and opioids. Bisphospho-
Posttraumatic Neuropathy and nates, which are used to treat osteopo-
Phantom Limb Pain rosis, may be effective in treating
Gabapentin and pregabalin have been neuropathic pain in patients with early
shown to affect neuropathic pain asso- CRPS who have abnormal uptake on a
ciated with posttraumatic neuropathy, bone scan.40,41 Calcitonin, a hormone
and some evidence supports the use of secreted in the thyroid that inhibits
tricyclic antidepressants and SNRIs. bone resorption, has also been found
However, results for topical capsaicin to possibly provide pain relief in pa-
have been inconsistent. In the treatment tients with CRPS.41 Opioids are occa-
of post-thoracotomy pain, there have sionally used in patients with CRPS
been varying results from the use of whose neuropathic pain is refractory to
tricyclic antidepressants or gabapentin, other therapies or who require opioids
but caution must be used when pre- for pain relief in order to participate
scribing tricyclic antidepressants in pa- in therapy.
tients with a history of cardiac disease.
In the treatment of postmastectomy Low Back Pain and Lumbar
pain, amitriptyline and venlafaxine pro-
Radiculopathy and Failed Back
vided moderate pain relief, although
Surgery Syndrome
venlafaxine did not have an effect on
the primary end point of the study.37 In Low back pain and lumbar radiculo-
the treatment of phantom limb pain, pathy are addressed in the article ‘‘Low
opioids and tramadol have been found Back Pain’’ by Jinny O. Tavee, MD, and
to be effective. In addition, gabapentin Kerry H. Levin, MD, FAAN,42 in this
has been shown to be beneficial, but issue of Continuum.

526 ContinuumJournal.com April 2017

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 KEY POINT
INTERVENTIONAL TECHNIQUES Pain Special Interest Group from the h Epidural or paravertebral
In the treatment of chronic neuro- International Association for the Study local anesthetic and
pathic pain, interventional techniques of Pain recommends that sympathetic steroid injections are
are typically used if medical manage- nerve blocks be generally avoided in used for the treatment
ment fails to provide adequate pain postherpetic neuralgia.45 Similarly, in- of acute pain associated
control (Table 8-6). However, for many trathecal medication delivery, spinal with herpes zoster, but
interventional treatments, a lack of evi- cord stimulation, deep brain stimula- a lack of high-quality
dence exists to recommend their use tion, and radiofrequency ablation have evidence exists to
because of a lack of high-quality trials. all been reported as treatments for recommend this
postherpetic neuralgia, but these thera- treatment. Intrathecal
pies lack randomized trials. steroid administration is
Herpes Zoster and Postherpetic
not recommended.
Neuralgia Trigeminal Neuralgia
The use of steroid injections in the For a discussion of interventional pro-
treatment of herpes zoster and post- cedures in trigeminal neuralgia, refer
herpetic neuralgia is based on their to the article ‘‘Trigeminal Neuralgia’’
ability to reduce inflammation at the by Giorgio Cruccu, MD,13 in this issue
dorsal root ganglion. Only weak evi- of Continuum.
dence recommends their use, and
not all studies use the same technique Painful Peripheral Neuropathies
for the injections, so the ideal number There are several small, prospective
and frequency of procedures remains studies on the effect of spinal cord
unknown. Epidural injections of local stimulation on refractory painful dia-
anesthetic and steroids have been betic neuropathy that have demon-
found to reduce acute pain in herpes strated a beneficial effect on pain and
zoster,43 but conflicting results exist on quality of life.48,49 Weak evidence sup-
whether they can reduce the progres- ports a beneficial effect of deep brain
sion of acute herpes zoster to post- stimulation in peripheral neuropathic
herpetic neuralgia. 43,44 Therefore, pain.50 Surgical decompression, other
epidural or paravertebral local anes- than for compressive mononeuro-
thetic and steroid injections are an pathies, in patients with painful dia-
option for the treatment of acute pain betic neuropathy remains unproven and
associated with herpes zoster, but there cannot be recommended until further
high-quality studies are completed.51,52
is a lack of high-quality evidence.45 A
single study exists, which could not be Central Neuropathic Pain
reproduced, which found that intrathe- Only case series have examined the
cal injections of methylprednisolone use of spinal cord stimulation in the
acetate and lidocaine reduced pain treatment of neuropathic pain associ-
intensity in postherpetic neuralgia.46,47 ated with spinal cord injury. Likewise,
However, because of the potential risks intrathecal medication delivery, deep
associated with intrathecal methyl- brain stimulation, and dorsal root entry
prednisolone administration and the zone lesioning have not been well
inconsistencies in the literature, this studied in patients with spinal cord
treatment has not been recommended.45 injury with chronic neuropathic pain.
Sympathetic blockade has also been Evidence from case series has sug-
performed for short-term pain relief in gested a benefit from motor cortex
herpes zoster and postherpetic neural- stimulation and deep brain stimulation
gia, but very few data demonstrate a for the treatment of central poststroke
beneficial effect, and the Neuropathic pain. Spinal cord stimulation has also

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Neuropathic Pain

only been examined by case series, but syndrome. In comparison to conven-

the results were unfavorable.53 tional medical management, spinal cord
stimulation was found to be superior at
Radiculopathy 6 and 12 months, but almost one-third
Epidural injections of a local anesthetic of the patients required surgical revi-
and steroid are among the most com- sion of the generator.54 One study
mon procedures to treat radicular pain. found that, compared to reoperation,
Their widespread use is based on the spinal cord stimulation was more effec-
fact that an inflammatory response to tive in terms of pain relief and was a
foreign proteins that are released from cost-effective treatment option.55
the nucleus pulposus into the spinal
canal causes nociceptors to be more Complex Regional Pain
sensitive to mechanical stimulation. Syndrome
However, the efficacy of epidural ste- In patients with CRPS who have failed
roid injections is controversial, and the medical therapy, interventional proce-
evidence to support their use is lim- dures may include regional sympathetic
ited. Likewise, much of the evidence nerve block, spinal cord stimulation, or
for other procedures such as facet chemical or mechanical sympathectomy.
injections, radiofrequency ablation, The published literature for these
intradiscal electrothermal therapy, and methods is limited, but often practi-
adhesiolysis are limited by small num- tioners will begin with sympathetic
bers or lack of a placebo. nerve blocks and try spinal cord stim-
ulation in patients who do not re-
Failed Back Surgery Syndrome spond. No randomized controlled trials
Failed back surgery syndrome is a hete- have examined the long-term effect of
rogeneous condition that is character- sympathetic blockade in CRPS, and the
ized by the presence of persistent back quality of evidence for their efficacy is
or leg pain despite the patient having low, but because of the lack of treat-
undergone spinal surgery. In patients ment options in this condition and the
with prominent radicular symptoms, relative safety of the procedure, it is
epidural steroid injections may be at- generally considered a reasonable
tempted, despite the lack of evidence, treatment option in patients who are
prior to recommending more invasive early in the disease course and
procedures. Adhesiolysis has been stud- have pain that is refractory to medical
ied in failed back surgery syndrome and management. Spinal cord stimulation
has proven to be effective, but its effect is a more invasive treatment option,
on neuropathic versus musculoskeletal but it has been shown to be beneficial
pain is unclear.45 in CRPS type 1. The benefit may de-
Spinal cord stimulation is thought to crease over time, and patients may re-
work by stimulating large-diameter, quire reoperation, but the majority of
non-nociceptive sensory fibers in the patients were happy with their initial
dorsal column to cause the release of decision to undergo the procedure.56,57
GABA, which leads to decreased activa- Because of the benefits that are often
tion of the small diameter nociceptive seen with sympathetic blockade,
fibers. It has been studied in patients chemical and surgical ablative pro-
with failed back surgery syndrome with cedures of autonomic structures have
prominent radicular symptoms and is been performed (sympathectomy).
FDA approved for use in chronic pain However, weak evidence supports
associated with failed back surgery these procedures, and the risk of
528 ContinuumJournal.com April 2017

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 KEY POINTS
adverse events is relatively high. studying the effect of acupuncture in the h Spinal cord stimulation
These risks include the potential to treatment of neuropathic pain include has been shown to be
develop postablation pain that is the fact that many different acupuncture beneficial in failed back
worse than the original pain. Repeated techniques are used and a strong surgery syndrome and
ketamine infusions have been shown placebo effect from both acupuncture complex regional pain
to be of benefit in CRPS, but because and sham acupuncture seems to exist. syndrome. Spinal cord
of the risks associated with the treat- However, both acupuncture and sham stimulation may be
ment, it is not recommended outside acupuncture appear to be superior to helpful in painful
of clinical trials.45 Not enough evidence no treatment. Overall, there seems to peripheral neuropathy
exists to recommend intrathecal baclo- be a small positive effect in the treat- and spinal cord injury.
fen for the treatment of dystonia ment of chronic pain, but the results h Individuals will
associated with CRPS, and a large risk of studies have been inconsistent.58 experience pain and
for potential complications exists. Questions remain about whether on- respond to treatment
going benefits from acupuncture exist in very different ways.
NONPHARMACOLOGIC An individualized
and if habituation and tolerance de-
TREATMENT treatment approach and
velop over time. In general, acupunc-
use of a multidisciplinary
The multidisciplinary care of patients ture is considered to be very safe, and team can help to
with chronic neuropathic pain ideally practitioners are required to use dis- improve outcomes.
includes physical and occupational posable sterile needles.
therapy as well as psychotherapy. Ran- Pain, and especially chronic pain, is
domized controlled trial evidence is a biopsychosocial experience, and pain
lacking for therapy-based treatment ap- psychology and the use of cognitive-
proaches, but, in general, they are safe behavioral therapy is an integral part
and may decrease pain and the use of of its treatment. Psychosocial disorders
medications, increase function, and im- affect not only how a person perceives
prove overall quality of life. As a general pain but how they respond to treat-
rule, physical therapy is appropriate ment, so identifying and addressing
once the primary impairments to activ- depression and anxiety, which are very
ity restriction have been determined. In common in patients with chronic pain,
patients with neuropathic pain, the is essential to a successful treatment
primary impairment is typically pain, plan. In cognitive-behavioral therapy,
and the goal of physical therapy is to patients are taught to conceptualize
maximize function while minimizing their thoughts about the meaning
pain. Therapists often accomplish this of their pain with the goal of managing
by addressing fear of movement and their pain better, improving their mood,
sensory impairments. Aquatic therapy increasing their level of activity, and
may be particularly useful because of reducing their overall disability.
the pain-relieving effects of the warm
water and the ease of movement while CONCLUSION
in water. Occupational therapy can help Neuropathic pain is a common but
to maximize function by addressing often difficult to treat condition that is
limitations in performing activities of affected by multiple patient comor-
daily living and activities at work or bidities. It is important to set realistic
leisure. Occupational therapists teach treatment expectations together with
patients how to adapt a task or their the patient and to approach manage-
environment to optimize productivity ment with a multidisciplinary team.
and minimize pain. Acupuncture is also Treatment algorithms for neuropathic
often used in the management of pain typically start with pharmacotherapy
chronic neuropathic pain. Challenges in and recommend tricyclic antidepressants,
Continuum (Minneap Minn) 2017;23(2):512–532 ContinuumJournal.com 529
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Neuropathic Pain

gabapentin, pregabalin, duloxetine, report on the Quality Standards

Subcommittee of the American Academy of
venlafaxine, or topical lidocaine as first- Neurology. Neurology 2004;63(6):959Y965.
line therapies and reserve opioid anal- doi:10.1212/01.WNL.0000140708.62856.72.
gesics for second-line therapy. Aside 6. Gronseth G, Cruccu G, Alksne J, et al. Practice
from painful diabetic neuropathy and parameter: the diagnostic evaluation and
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