Review Article

Neuropathic Pain
Address correspondence to
Dr Lindsay A. Zilliox,
110 S Paca St, 3rd floor,
Baltimore, MD 21201,
lzilliox@som.umaryland.edu.
Relationship Disclosure:
Dr Zilliox has received salary
support from the US
Department of Veterans Affairs
Career Development Grant.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Zilliox discusses the
unlabeled/investigational
use of duloxetine, gabapentin,
lamotrigine, pregabalin,
tricyclic antidepressants,
valproic acid, and venlafaxine
for the management of
patients with neuropathic pain.
* 2017 American Academy
of Neurology.
Lindsay A. Zilliox, MD, MS
ABSTRACT
Purpose of Review: Neuropathic pain is a frequently encountered condition that
is often resistant to treatment and is associated with poor patient satisfaction of
their treatment. Several medications have been shown to be effective in treating
neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia, and
these medications are often used to treat neuropathic pain associated with other
conditions as well. This article summarizes the diagnosis and assessment of patients
with neuropathic pain as well as available pharmacologic and interventional treat-
ment options.
Recent Findings: Evidence-based recommendations for the treatment of neuropathic
pain have been published, and first-line medications include antidepressants,
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-

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

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TABLE 8-1 Conditions
Associated With
Neuropathic Pain
b Peripheral Neuropathic Pain
Painful diabetic neuropathy
Human immunodeficiency
virusYassociated neuropathy
Chemotherapy-induced
peripheral neuropathy
Postherpetic neuralgia
Trigeminal neuralgia
Complex regional pain
syndrome
Compressive
mononeuropathies
Radiculopathies
Inflammatory neuropathies
(acute and chronic
inflammatory demyelinating
polyneuropathy)
Posttraumatic neuropathy
Phantom limb pain
b Central Neuropathic Pain
Spinal cord injury
Central poststroke pain
Compressive myelopathy
Multiple sclerosisYrelated
pain
Syringomyelia
often unsatisfied with their treatment.
This may be because neuropathic pain
is often refractory to available treat-
ments, the treatments often have
adverse effects, insufficient evidence-
based guidelines exist for treatment,
and patients may have unrealistic
goals for their treatment. It is impor-
tant to recognize that neuropathic
pain affects many aspects of daily life
and is associated with poor general
health, reduction in quality of life, poor
sleep, and higher anxiety and depres-
Continuum (Minneap Minn) 2017;23(2):512–532
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KEY POINTS
sion. In fact, measures of quality of life h Chronic neuropathic
in people with chronic neuropathic
pain is associated with
pain were rated as low as for patients low measures of
with clinical depression, coronary artery quality of life.
disease, recent myocardial infarction, or h A thorough history and
poorly controlled diabetes mellitus.3 neurologic examination
The American Academy of Neurol- are especially important
ogy (AAN) has published practice when evaluating
guidelines on the treatment of painful patients with suspected
diabetic neuropathy (Supplemental neuropathic pain.
Digital Content 8-1, links.lww.com/ h It is important to
CONT/A216),4 postherpetic neural- include assessments
gia,5 and trigeminal neuralgia.6 Several of psychological
other clinical practice guidelines for comorbidities, sleep
the treatment of neuropathic pain also disturbances,
have been published.7Y9 work-related issues,
treatment expectations,
DIAGNOSIS and availability of social
support in patients with
No single diagnostic test or pathogno-
neuropathic pain.
monic symptom exists to identify neu-
ropathic pain. In fact, most patients
with neuropathic pain typically have
multiple different types of coexistent
pain. This makes a careful history and
physical examination of utmost im-
portance in patients who are being
evaluated for neuropathic pain. The
International Association for the Study
of Pain defines neuropathic pain as pain
caused by a lesion or disease of the
somatosensory nervous system.9 This
definition means that the presence of
signs or symptoms alone is not suffi-
cient for the diagnosis of neuropathic
pain, but clinical judgment is often
required. There are screening tools,
such as the Neuropathic Pain Scale
and the Neuropathic Pain Question-
naire, that are available specifically for
patients with neuropathic pain. How-
ever, a careful clinical assessment is still
needed because these screening tools
fail to identify 10% to 20% of patients
with neuropathic pain.10
In cases of chronic neuropathic
pain, it is important to include assess-
ments of psychological comorbidities,
sleep disturbances, work-related issues,
treatment expectations, and availability
ContinuumJournal.com 513
 Neuropathic Pain
KEY POINT
h Ancillary studies are
used in conjunction with
the physical
examination to confirm
or exclude underlying
etiologies for
neuropathic pain,
but no diagnostic
test for neuropathic
pain exists.
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of social support. Occasionally, condi-
tions such as anxiety or depression can
cause exaggerated responses to pain,
but it is important to communicate
clearly with patients, validate their
experience with pain, and set realistic
treatment goals.
When interviewing a patient, it is
important to remember that pain is a
subjective experience and may be
described differently by different peo-
ple. In general, the clinician should
establish the intensity, quality, dura-
tion, and location of the symptoms.
The presence of stimulus-evoked pain
or stimulus-independent pain should
also be noted, as this can affect the
choice of treatment. Typically, neuro-
pathic pain has both positive and
negative sensory symptoms and signs
(Table 8-2). Positive symptoms are
generally painful or altered sensations
and are often described as burning,
stinging, prickling, tingling, pins and
needles, stabbing, or aching. Some
TABLE 8-2 Positive and
Negative Symptoms
of Neuropathic Pain
b Positive Symptoms
Tingling (pins and needles)
Prickling
Lightninglike or lancinating
Aching
Knifelike
Pulling or tightening
Burning or searing
Electrical
b Negative Symptoms
Numbness
Deadness
Feeling of wearing socks all
the time
unique aspects of neuropathic pain
include hyperalgesia (increased re-
sponse to a stimulation that is normally
painful) and allodynia (pain due to a
stimulus that typically does not pro-
voke pain). Other terms frequently
used in neuropathic pain are defined
in Table 8-3. These positive symptoms
are thought to represent excessive
activity in a sensory pathway due to
a lowered threshold or heightened
excitability. Negative signs and symp-
toms are experienced as diminished
or absent feeling and are due to a loss
of sensory function.
A complete neurologic examination
can often assess non-neuropathic
causes of pain and localize the lesion
that is causing neuropathic pain. In
general, during sensory testing, the
examiner should first apply sensory
stimuli to an unaffected area and then
to the area affected by pain. Patients
should be instructed to state whether
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
describe the quality of the stimulus.
The different sensory modalities that
should be tested include pinprick, light
touch, temperature, vibration, and pro-
prioception. Pinprick, light touch, and
temperature sensation are carried by
small unmyelinated fibers and ascend
in the spinothalamic pathway. Vibra-
tion and proprioception are carried
by large myelinated fibers and ascend
in the dorsal columns.
Several ancillary studies are used in
conjunction with the physical exami-
nation to confirm or exclude underly-
ing etiologies for neuropathic pain.
Nerve conduction studies and needle
EMG examine peripheral nerve func-
tion, but importantly do not assess
small unmyelinated pain fibers. Skin
biopsy is a reliable technique to
diagnose small fiber neuropathy and
assess the nociceptive skin nerve fiber
April 2017
 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
is unclear. Quantitative sensory testing
determines a perception threshold
for mechanical, thermal, and painful
stimuli that is delivered at a con-
trolled intensity. Quantitative sensory
testing has been used for the early
diagnosis of small fiber neuropathy
and early diabetic neuropathy and can
be used to quantify mechanical and
thermal allodynia and hyperalgesia.
However, quantitative sensory testing
also shows changes in non-neuropathic
pain states and relies upon patient
participation, which can be influenced
by psychological factors, response bias,
or malingering.
PATHOPHYSIOLOGY
Neuropathic pain is frequently classi-
fied as central or peripheral, depen-
ding on the site of the lesion that is
causing the pain (Table 8-1). How-
ever, neuropathic pain can be thought
of as a manifestation of multiple
peripheral and central nervous system
processes that result in sensitization of
both the peripheral and central ner-
vous systems. As knowledge about the
underlying pathophysiology of neuro-
pathic pain grows, several different
targets exist for treatment. However,
Continuum (Minneap Minn) 2017;23(2):512–532
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predominant mechanism in a particu-
lar individual and to target it appropri-
ately. In practice, several different
mechanisms can coexist and change
over time, and an individual’s response
to a medication remains unpredictable.
In the peripheral nervous system,
new growth from an injured nerve will
spontaneously fire (ectopic discharges),
and eventually, connections may de-
velop between these new areas of
growth and nearby afferent neurons.11
This way neuropathic pain may be
generated from either injured or intact
sensory neurons. Neuronal damage also
leads to an increase in the num-
ber of sodium and calcium channels
that are present. Other causes of pe-
ripheral sensitization include height-
ened responsiveness to inflammatory
mediators released by damaged cells
and sprouting of sympathetic neurons
in the dorsal root ganglion.
Central sensitization refers to in-
creased excitation and reduced inhibi-
tion of central nervous system pathways
that are associated with neuropathic
pain. Repeated input from peripheral C
fibers results in enhanced spinal cord
excitability. In addition, injury to central
nervous system structures may alter
sensory processing.
ContinuumJournal.com 515
 Neuropathic Pain
KEY POINTS
h Prior to beginning
pharmacotherapy, it is
important to validate
the patient’s pain and
jointly set realistic
treatment goals.
h Tricyclic antidepressants
are effective in treating
several different types
of neuropathic pain.
h The analgesic effect of
tricyclic antidepressants
is independent of their
antidepressant effect,
and the analgesic effect
is achieved by much
lower doses in
comparison to the
antidepressant effect.
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TREATMENT
Establishing realistic goals is an impor-
tant first step in treatment. The vast
majority of patients will not achieve
complete pain relief but can expect the
pain to be made tolerable. In general, a
30% reduction of pain on an 11-point
numerical rating scale is considered to
be clinically important and constitutes
‘‘moderate relief’’ or ‘‘much improved.’’12
It is also important to recognize and
treat comorbidities such as anxiety and
depression, and secondary treatment
goals may include improving sleep,
advancing function, and enhancing
overall quality of life. These goals are
best achieved when pharmacologic ther-
apy is just one component of a multi-
disciplinary approach to treatment.
Most randomized controlled drug
trials in neuropathic pain have been in
painful diabetic neuropathy and post-
herpetic neuralgia, and the US Food
and Drug Administration (FDA) has
approved six medications for three
neuropathic pain syndromes: trigemi-
nal neuralgia (carbamazepine), posther-
petic neuralgia (gabapentin, pregabalin,
5% lidocaine patch, capsaicin cream, and
capsaicin 8% patch), and painful diabetic
neuropathy (pregabalin, duloxetine, and
capsaicin cream) (Table 8-4). Although
the results from one neuropathic pain
syndrome cannot directly be applied to
another, most first-line therapies have
been found to be effective in multiple
types of neuropathic pain,9 which is
TABLE 8-4 Neuropathic Pain Medications Approved by the US Food
and Drug Administration
Indication
Trigeminal neuralgia
Painful diabetic neuropathy
Postherpetic neuralgia
illustrated in Case 8-1. The exception
to this is trigeminal neuralgia. For
more information on management of
trigeminal neuralgia, refer to the article
‘‘Trigeminal Neuralgia’’ by Giorgio
Cruccu, MD,13 in this issue of Contin-
uum. Recommendations for first-line
pharmacotherapy of neuropathic pain
are summarized in Table 8-5.
Tricyclic Antidepressants
The analgesic effect of tricyclic antide-
pressants is due to inhibition of norepi-
nephrine reuptake at the spinal dorsal
synapses, with secondary activity at so-
dium channels.14 Amitriptyline is rela-
tively balanced in its ability to inhibit
norepinephrine and serotonin reuptake
while nortriptyline, which has similar
efficacy but fewer side effects, demon-
strates greater inhibition of norepineph-
rine reuptake. Tricyclic antidepressants
are effective for several different types
of neuropathic pain, mainly painful
diabetic neuropathy and postherpetic
neuralgia. Tricyclic antidepressants are
considered effective in treating central
pain, but there are limited data in spe-
cific central pain etiologies. Tricyclic
antidepressants are also efficacious in
treating depression, but their analgesic
effect is independent of their antide-
pressant effect, and the analgesic effect
is achieved by much lower doses in com-
parison to the antidepressant effect.
Tricyclic antidepressants should be
initiated at low dosages (10 mg/d to
Medication
Carbamazepine
Duloxetine, pregabalin, capsaicin cream
Gabapentin, pregabalin, topical lidocaine,
capsaicin 8% patch, capsaicin cream
April 2017
 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
can be increased every 3 to 7 days by
10 mg/d to 25 mg/d as tolerated. The
goal dose is 75 mg/d to 150 mg/d;
before prescribing higher doses, an
ECG should be performed if not
already performed, and blood levels
should be monitored. In patients with
a history of heart disease, the dose
should be limited to less than 100 mg/d.
An adequate trial of a tricyclic antide-
pressant should last 6 to 8 weeks with
1 to 2 weeks at the maximum toler-
ated dose.
Adverse effects are the main problem
with use of tricyclic antidepressants.
Common side effects include sedation
and anticholinergic effects (eg, dry
mouth, blurred vision, constipation,
urinary retention, and postural hypo-
tension). They must be used with
caution in patients with a history of
heart disease (a screening ECG for
conduction abnormalities is recom-
mended before beginning treatment),
glaucoma, urinary retention, or auto-
nomic neuropathy. Caution is advised
when a risk exists for suicide or
overdose because of the risk of fatal
cardiac dysrhythmias and serotonin
syndrome. Nortriptyline is generally
recommended rather than amitripty-
line in elderly patients because it is
usually better tolerated.
Calcium Channel !2% Ligands
Gabapentin and pregabalin are effective
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-
erated with few medication interactions
but can cause sedation and dizziness.
Gabapentin. Gabapentin is a ,-
aminobutyric acid (GABA) analog, but
it has no proven effect on GABA re-
ceptors. It is thought to work by
modulation of voltage-gated calcium
channels to inhibit neurotransmitter
release. Gabapentin is FDA approved

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for the treatment of postherpetic neu-
ralgia. Gabapentin and pregabalin have
the most evidence-based data for the
treatment of painful diabetic neuro-
pathy. Gabapentin has also been
shown to be effective in phantom limb
pain, pain in Guillain-Barré syndrome,
and pain from spinal cord injury.
The typical starting dose is 100 mg
to 300 mg 3 times a day, and it is ti-
trated up every 1 to 7 days by 100 mg/d
to 300 mg/d as tolerated up to a target
dose of 1800 mg/d to 3600 mg/d. To
reduce side effects, practitioners may
start with a single bedtime dose, in-
crease to twice a day, and then in-
crease to 3 times daily. Although 3 times
a day dosing is ideal, occasionally a
higher dose is given at bedtime to limit
daytime sedation. An adequate trial of
gabapentin would include 3 to 8 weeks
for titration and development of toler-
ance to adverse effects, plus 1 to 2 weeks
at the maximum tolerated dose. Dosage
adjustment is necessary in patients with
renal impairment.
In general, gabapentin is well toler-
ated with few drug interactions. Com-
mon side effects of dizziness and
sedation are dose dependent and can
be reduced by starting with lower
doses and using a slow titration sched-
ule. Other side effects include gait and
balance problems, gastrointestinal symp-
toms, and peripheral edema. Gaba-
pentin has been found to have a similar
efficacy to nortriptyline, but difficulty
concentrating was reported more often
with gabapentin, and dry mouth was
seen more often with nortriptyline.15
Gabapentin enacarbil. Gabapentin
enacarbil is an extended release form
of gabapentin. It has been found to be
effective and well tolerated in treating
postherpetic neuralgia. However, it
was not found to be effective in
treating painful diabetic neuropathy.16
Gabapentin enacarbil is given once or
twice a day with a larger dose at night.
Continuum (Minneap Minn) 2017;23(2):512–532
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KEY POINTS
The starting dose is 600 mg/d for h Starting with a single
3 days and then is increased to 600 mg bedtime dose of
twice a day. Dosage adjustment is gabapentin can help to
necessary in patients with renal impair- reduce side effects.
ment. Side effects include sedation, h Pregabalin has linear
dizziness, headache, and, less com- pharmacokinetics and an
monly, edema and nausea. easier dosing schedule
Pregabalin. Pregabalin is also calcium than gabapentin.
channel "2& ligand and is closely h Pregabalin has
related to gabapentin. However, it has dose-dependent effects
linear pharmacokinetics, a higher af- with several negative
finity for the presynaptic calcium studies for 150 mg/d and
channel than gabapentin, and an positive results for total
easier dosing schedule than gaba- daily doses of 300 mg/d
pentin. Pregabalin is FDA approved to 600 mg/d. However,
for the treatment of painful diabetic total daily doses of more
neuropathy and is also effective in than 300 mg/d may not
postherpetic neuralgia and spinal cord be more effective and
are often associated with
injury and other causes of central neuro-
increased side effects.
pathic pain. Pregabalin has dose-
dependent effects and is typically
not effective at the starting dose of
150 mg/d. The initial dose is either
50 mg 3 times daily or 75 mg 2 times
a day, which can be increased to a
total dose of up to 300 mg/d after
1 to 2 weeks. If a patient tolerates
300 mg/d, but has persistent pain,
the dose can be increased to a total
dose of 600 mg/d. However, total
daily doses of more than 300 mg/d
are not necessarily more effective and
are associated with a higher rate of side
effects. The dose should be adjusted
in patients with renal impairment.
Pregabalin has a similar side effect
profile to gabapentin, but patients tend
to tolerate a more rapid dose titration.
The most common side effects include
dizziness, somnolence, weight gain,
peripheral edema, and diplopia. Pre-
gabalin is a schedule V controlled sub-
stance that can cause feelings of euphoria
and has the potential for abuse. In addi-
tion, all antiepileptics, including pregab-
alin, have been shown to be associated
with an increased risk of suicidal thoughts
or actions, and patients should be mon-
itored for changes in behavior.
ContinuumJournal.com 519
 Neuropathic Pain
KEY POINTS
h Serotonin norepinephrine
reuptake inhibitors treat
major depressive disorder
and generalized anxiety
disorder in addition to
neuropathic pain.
h The most frequent side
effect of duloxetine and
venlafaxine is nausea.
The extended release
formulation of
venlafaxine may be
better tolerated than
the immediate release
formulation. No
additional benefit has
been found from taking
more than 60 mg/d of
duloxetine, and higher
total daily dosages are
associated with more
side effects.
h First-line medications for
the treatment of
neuropathic pain include
tricyclic antidepressants
(amitriptyline or
nortriptyline),
anticonvulsants
(gabapentin or
pregabalin), serotonin
norepinephrine reuptake
inhibitors (duloxetine
or venlafaxine), and
topical lidocaine.
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Serotonin Norepinephrine
Reuptake Inhibitors
Serotonin norepinephrine reuptake in-
hibitors (SNRIs) inhibit the reuptake
of serotonin and norepinephrine. Dulo-
xetine is a balanced inhibitor of seroto-
nin and norepinephrine reuptake,
while venlafaxine inhibits serotonin
reuptake at lower dosages and inhibits
the reuptake of both neurotransmitters
at higher dosages of 150 mg/d or more.
Duloxetine. Duloxetine is FDA ap-
proved for the treatment of painful
diabetic neuropathy and has also been
found to be effective in chemotherapy-
induced painful neuropathy. Based on
a meta-analysis, its efficacy is similar
to that of gabapentin and pregabalin.17
It has not been found to be effective
in central neuropathic pain. However,
it is also effective in the treatment
of major depression and generalized
anxiety disorder. The typical starting
dose is 60 mg/d, but starting at 30 mg/d
may reduce the incidence of nausea.
The usual total daily dose is 60 mg/d
to 120 mg/d, but no additional benefit
has been found from taking dosages
of more than 60 mg/d.
Nausea is the most common adverse
effect. Additional side effects include
increased sweating, somnolence, dry
mouth, constipation, diarrhea, and diz-
ziness. Cardiac conduction abnormali-
ties and blood pressure increases have
been reported, so caution is advised
when prescribing this medication to
patients with cardiac disease. Cases of
hepatotoxicity have also been reported,
so its use is not recommended in
patients with hepatic insufficiency, but
routine liver function monitoring is not
recommended.
Venlafaxine. Venlafaxine is FDA ap-
proved for the treatment of major
depression, but it has been studied
and found to be effective in the treat-
ment of painful diabetic neuropathy as
well as in painful polyneuropathies of
various etiologies. Venlafaxine is avail-
able in short- and long-acting formu-
lations. The starting dose for venlafaxine
immediate release is 75 mg/d in 2 or
3 divided doses, and it can be in-
creased as tolerated up to 225 mg/d.
Venlafaxine extended release is started
at 37.5 mg or 75 mg once a day and
is increased over 2 to 4 weeks to
150 mg/d to 225 mg/d. Increased
sweating is a frequent side effect.
Cardiac conduction abnormalities and
blood pressure increases have been
reported, so caution is advised when
prescribing this medication to patients
with cardiac disease. Patients taking
venlafaxine immediate release should
be cautioned not to abruptly stop this
medication because of the risk of a
withdrawal syndrome, which can occur
upon abrupt discontinuation of any
selective serotonin reuptake inhibitor
(SSRI) or SNRI but is of concern with
venlafaxine immediate release because
of its short half-life.
Topical Lidocaine
Topical lidocaine acts locally by antag-
onizing sodium channels and reducing
spontaneous ectopic nerve discharges.
The 5% lidocaine patch is FDA ap-
proved for the treatment of posther-
petic neuralgia, but the treatment
effect is moderate. It also has been
shown to be efficacious in allodynia
due to different types of peripheral
neuropathic pain. Lidocaine gel (5%) is
less expensive and is effective in
treating postherpetic neuralgia and
allodynia. Patches should be applied
directly to painful sites and can be cut
as needed. No more than 3 patches
should be worn concurrently for a
maximum of 12 hours. In patients
with normal hepatic function, blood
levels are minimal; however, systemic
absorption must be considered in
patients taking Class I antiarrhythmic
medications. No titration is needed,
April 2017

and an adequate trial would be for
2 to 4 weeks. Side effects are minimal
and include skin reactions at the
application site.
Topical Capsaicin
Capsaicin is a hot chili pepper ex-
tract, and its mechanism of action in
treating neuropathic pain is not well
understood, but it is thought to result
in desensitization of sensory axons
and epidermal denervation.18
High-concentration capsaicin patches.
The high-concentration capsaicin 8%
patch has been shown to be effective
in postherpetic neuralgia and painful
human immunodeficiency virus (HIV)-
associated neuropathy. A single treat-
ment, which must be applied by a health
care provider, can provide a sustained
reduction in pain for up to 12 weeks. It
is generally safe and well tolerated, but
it often requires the preapplication of a
local anesthetic because of an intense
burning sensation. Long-term repeat
applications have unclear effects, and a
possible risk exists of transient epider-
mal denervation and resultant loss of
heat pain sensation.
Capsaicin cream. Capsaicin creams
(0.075%) are moderately effective in
postherpetic neuralgia, but inconsistent
results have been seen in the treatment
of neuropathic pain due to peripheral
neuropathy. The creams are available in
a range of potencies, can be difficult to
apply, must be applied multiple times a
day to the entirety of the painful area,
and often cause painful sensations
during the first few weeks of use.
Adverse effects at the application site
include pain and erythema.
Tramadol and Opioid Analgesics
Tramadol and opioid analgesics are
effective in different types of neuropathic
pain but are generally not recommended
as first-line treatments because of con-
cerns about long-term safety. Instead,
Continuum (Minneap Minn) 2017;23(2):512–532
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
they are typically recommended for h A single application of
patients who do not respond to first- capsaicin 8% patch
line medications. However, they are can be effective for
recommended as first-line treatments in up to 12 weeks, but
acute neuropathic pain, neuropathic the effects from
pain due to cancer, and episodic repeat applications
exacerbations of severe neuropathic are unknown.
pain. They are also used while a first- h Because of concerns
line medication is being titrated when about long-term safety,
immediate pain relief is needed. opioid narcotics are
Tramadol. Tramadol has a dual generally recommended
mechanism of action: as a central only for patients who
opioid agonist at the mu receptor and do not respond to
as an inhibitor of norepinephrine and first-line medications.
serotonin reuptake. Tramadol has been h Tramadol should be
shown to be effective in several neuro- avoided in patients with
pathic pain conditions, including painful a history of substance
diabetic neuropathy and mixed neuro- abuse, and it is
increasingly being
pathic pain syndromes. Although it has
misused or abused.
generally been considered to be a safer
Tramadol can also
alternative to other narcotic analgesics, lower the seizure
it is a schedule IV controlled substance threshold and should
and is increasingly being misused or be avoided in individuals
abused. Tramadol should be avoided with a history of
in patients with a history of substance seizure disorders.
abuse. Tramadol should be started at
a low dose, 50 mg once or twice a
day, and titrated every 3 to 7 days
by 50 mg/d to 100 mg/d in divided
doses as tolerated. The maximum dose
is 100 mg 4 times a day (maximum
total daily dose 300 mg/d in patients
older than 75 years). An adequate trial
is 4 weeks. The dosage should be re-
duced in patients with renal or hepatic
impairment.
Adverse effects of tramadol include
dizziness, nausea, constipation, som-
nolence, and orthostatic hypotension.
The tramadol/acetaminophen combi-
nation may be better tolerated. Impor-
tantly, tramadol can lower the seizure
threshold, and seizures can occur if
high doses are used. A risk exists of
the serotonin syndrome if tramadol is
used simultaneously with other sero-
tonergic medications.
Opioid analgesics. Strong opioids
that are used in chronic pain include
ContinuumJournal.com 521
 Neuropathic Pain
KEY POINT
h The American Academy
of Neurology position
paper and Centers for
Disease Control and
Prevention guidelines
both stress that
nonpharmacologic and
nonopioid pharmacologic
therapy are preferred for
chronic pain, and if
opioids are used, they
should be part of a
multidisciplinary approach
to pain management.
522 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
codeine, morphine, oxycodone, and
fentanyl. Their use in treating a variety
of neuropathic pain conditions is
controversial, and the use of opioids
to treat chronic noncancer pain is a
public health concern given the rising
number of deaths related to prescrip-
tion opioids in the United States. Opi-
oids have been shown to be efficacious
in patients with painful diabetic neu-
ropathy with at least moderate pain for
a minimum of 3 months as well as
in patients with postherpetic neural-
gia.19,20 However, as discussed in the
AAN position paper on opioids for
chronic noncancer pain, evidence for
long-term pain relief or improved
function is lacking, and serious risks
of overdose, dependence, or addiction
exist.21 It is difficult to assess which
patients will benefit from chronic treat-
ment with opioids, and for some
patients the risks of chronic opioid
therapy outweigh any potential bene-
fits. The AAN position paper and CDC
guidelines both stress that nonphar-
macologic and nonopioid pharmaco-
logic therapy are preferred for chronic
pain, and if opioids are used, they
should be part of a multidisciplinary ap-
proach to pain management.21Y23
Opioid prescribing guidelines have
been published.23 In general, immediate-
release opioids should be started at
the lowest effective dosage. The ben-
efits and harms of opioid therapy
should be reexamined with the pa-
tient every 3 months or within 1 to
4 weeks after starting opioids or chang-
ing the dose. Additional best practices
when using opioids for chronic pain
include: (1) using a patient treatment
agreement, (2) screening for sub-
stance abuse or misuse as well as
depression, (3) random urine drug
screening prior to starting opioid
therapy and periodically thereafter,
(4) tracking pain and function as well
as daily morphine equivalent dose at
every visit, (5) using a state prescrip-
tion drug monitoring program to mon-
itor prescriptions, and (6) consulting
with a pain management specialist if the
daily morphine equivalent dose reaches
80 mg/d to 120 mg/d.21,22
Additional Medications
This category includes medications that
have been shown to be effective in a
single randomized controlled trial or
inconsistently in multiple randomized
controlled trials. Carbamazepine is FDA
approved for the treatment of trigeminal
neuralgia and is the first-line medication
for treatment in this neuropathic pain
condition. However, small studies in pain-
ful neuropathy have not demonstrated
clear efficacy. In addition, carbamaze-
pine has poor tolerability and multiple
pharmacokinetic interactions. Side ef-
fects include skin rash, hyponatremia,
decreased bone density, and hemato-
poietic issues. Similar to carbamaze-
pine, conflicting results exist regarding
the efficacy of oxcarbazepine in treating
painful diabetic neuropathy. However,
it is significantly better tolerated than
carbamazepine and has fewer drug in-
teractions than carbamazepine. Patients
should be monitored for hyponatremia.
Divalproex sodium has been found
to have a beneficial effect in treating
painful diabetic neuropathy and trigem-
inal neuralgia but lacks efficacy in
reducing overall pain or improving
quality of life.24,25 Lamotrigine is the
only drug that has been found to be
moderately effective in patients with
HIV-associated neuropathy who were
receiving antiretroviral treatment. How-
ever, overall, no convincing evidence
exists that lamotrigine is effective in
treating other forms of neuropathic
pain.26 A slow titration schedule is
required because of risk of a severe
rash and Stevens-Johnson syndrome.
Lacosamide, topiramate, zonisamide,
and phenytoin have also been studied
April 2017

in painful diabetic neuropathy, but only
inconclusive evidence exists for their
use in the treatment of neuropathic pain.
SSRIs have been shown to have
efficacy in the treatment of neuro-
pathic pain in small studies, but
pooled data failed to show a signifi-
cant difference in pain relief com-
pared to placebo.27 A weak analgesic
effect has been found for citalopram,
paroxetine, and escitalopram, but not
fluoxetine. SSRIs must be used with
caution alongside tricyclic antidepres-
sants because of an increased risk for
serotonin syndrome.
Mexiletine is an oral analog of
lidocaine that has shown efficacy in
only small studies of neuropathic pain.
It is generally not recommended for
use in neuropathic pain because of its
side effects, which include agranulocy-
tosis, hepatotoxicity, and toxic epider-
mal necrosis. Its use is contraindicated
in patients with second- and third-
degree atrioventricular block, and pa-
tients should be monitored with
complete blood cell count, ECG, and
liver function tests.
Cannabinoids have been found to
be effective in treating neuropathic
pain associated with multiple sclerosis
and in neuropathic pain with allodynia,
but overall the results of clinical trials
have been inconsistent, and legal and
regulatory issues surround its use.
They are recommended as third-line
analgesics for the treatment of neuro-
pathic pain by the Canadian Pain
Society.8 The use of cannabinoids is
limited by many negative effects that
include dizziness, nausea, dry mouth,
sedation, gastrointestinal effects, and
oral discomfort. Cannabinoids should
be used with caution in patients with a
history of heart disease or seizures and
are not recommended for patients with
psychiatric disorders because of a risk
of psychosis.28 Controversy exists about
their long-term use and the potential
Continuum (Minneap Minn) 2017;23(2):512–532
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
for negative effects on cognition and h A combination of two
mood as well as the risk of tolerance first-line medications
and dependency. may be more
efficacious than either
Combination Therapy medication alone.
Although multiple drugs are often used
in combination to treat neuropathic
pain in patients who have a partial re-
sponse to monotherapy, only a few
studies have examined the efficacy of
this strategy. In theory, combination
pharmacotherapy may improve the
analgesic efficacy and reduce side
effects of individual drugs, but not
enough evidence exists to recommend
a specific drug combination. This is a
frequent strategy in clinical practice
and is illustrated by Case 8-2. Com-
pared to monotherapy, the combina-
tion of gabapentin and morphine or
gabapentin and nortriptyline was found
to provide better pain relief at lower
dosages in patients with painful dia-
betic neuropathy and postherpetic
neuralgia.15,29,30 However, there have
been conflicting results from similar
trials of pregabalin and oxycodone.31,32
In addition, a large study in painful
diabetic neuropathy did not find a
significant difference in efficacy be-
tween high-dose monotherapy with
pregabalin or duloxetine compared to
combination therapy.33
SPECIFIC CONDITIONS
Different types of neuropathic pain
may respond well to a particular
medication or class of medications.
This section will provide specific treat-
ment recommendations for select
neuropathic pain conditions.
Painful Peripheral Neuropathy
As stated previously, the efficacy of most
of the medications discussed in the
treatment of neuropathic pain has
been established in studies of painful
diabetic neuropathy. The 2011 AAN
evidence-based guideline on the
ContinuumJournal.com 523
 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-
athy found that pregabalin was effec-
tive in the treatment of painful diabetic
neuropathy, and venlafaxine, duloxetine,
amitriptyline, gabapentin, valproate,
opioids, and capsaicin were probably
effective.4 Limited evidence exists on
the efficacy of oral "-lipoic acid, an
antioxidant, but it is often prescribed in
painful diabetic neuropathy because of
its potential benefits and low side
effect profile. It is typically dosed at
600 mg once or twice daily and should
be used with caution in patients who are
at risk of hypoglycemia.
In general, the treatment options
for diabetic and nondiabetic painful
peripheral neuropathy are similar, and
recommendations for common condi-
tions are outlined in Table 8-6. The
exception is for HIV-associated neu-
ropathy and chemotherapy-induced
neuropathy, which tend to be relatively
refractory to first-line neuropathic
pain treatments. In HIV-associated
neuropathy, no evidence exists to
recommend treatment with amitrip-
tyline, pregabalin, or topical lido-
caine. Some benefit has been seen
in studies of lamotrigine, gabapentin,
cannabinoids, and high-concentration
(8%) capsaicin patches.
Neuropathic Pain in Patients
With Cancer
Patients with cancer often experi-
ence more than one type of pain,
and the World Health Organization
has published guidelines for the
treatment of non-neuropathic can-
cer pain. 34 However, neuropathic
cancer pain may respond poorly to
opioids, and very few clinical trials
have been performed to help guide
clinical management in this scenario.
Gabapentin and tricyclic antidepres-
sants may be effective in treating neuro-
pathic pain from cancer, and pregabalin
is often used because of its rapid
titration schedule and tolerability.35
Postherpetic Neuralgia
In general, tricyclic antidepressants,
gabapentin, and pregabalin are the
drugs of first choice in the treat-
ment of postherpetic neuralgia. Other

524 ContinuumJournal.com April 2017

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

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

Continuum (Minneap Minn) 2017;23(2):512–532 ContinuumJournal.com 525

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Neuropathic Pain
KEY POINTS
h A recent systematic
review did not find any
effective treatments for
central poststroke pain.
h Pregabalin is often the
drug of choice in
neuropathic pain
associated with spinal
cord injury.
h The treatment of
complex regional pain
syndrome requires
multidisciplinary care
with a focus on
functional therapies,
and pharmacotherapy
is often required to
enable patients to
participate in
these therapies.
526 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
pain have been carried out. Despite this,
central neuropathic pain is generally
responsive to the same medications as
peripheral neuropathic pain. One ex-
ception to this is the use of topical lido-
caine and capsaicin, which are thought
to be only effective in peripheral neu-
ropathic pain. In central poststroke
pain, amitriptyline and lamotrigine are
typically recommended as first-line
medical therapies. However, a recent
systematic review of therapies for cen-
tral poststroke pain found that all
therapies examined (anticonvulsants,
an antidepressant [amitriptyline], an
opioid antagonist [naloxone], repetitive
transmagnetic stimulation, and acu-
puncture) had little or no effect on
pain.36 In spinal cord injury, pregabalin
has been shown to be effective in treat-
ing neuropathic pain. Other medication
options for treating central neuropathic
pain associated with spinal cord injury
include gabapentin, tricyclic antidepres-
sants, SNRIs, and opioids.
Posttraumatic Neuropathy and
Phantom Limb Pain
Gabapentin and pregabalin have been
shown to affect neuropathic pain asso-
ciated with posttraumatic neuropathy,
and some evidence supports the use of
tricyclic antidepressants and SNRIs.
However, results for topical capsaicin
have been inconsistent. In the treatment
of post-thoracotomy pain, there have
been varying results from the use of
tricyclic antidepressants or gabapentin,
but caution must be used when pre-
scribing tricyclic antidepressants in pa-
tients with a history of cardiac disease.
In the treatment of postmastectomy
pain, amitriptyline and venlafaxine pro-
vided moderate pain relief, although
venlafaxine did not have an effect on
the primary end point of the study.37 In
the treatment of phantom limb pain,
opioids and tramadol have been found
to be effective. In addition, gabapentin
has been shown to be beneficial, but
no reduction in neuropathic pain was
found from amitriptyline.
Complex Regional Pain
Syndrome
Complex regional pain syndrome
(CRPS) is characterized by intense neu-
ropathic pain that includes allodynia or
hyperalgesia. CRPS can be difficult to
diagnose, which has led to a lack of
evidence-based recommendations for
treatment. Multidisciplinary care with a
focus on functional therapies is often
recommended, and pharmacotherapy
is often required to enable patients to
participate in these therapies. Cortico-
steroids can be used within the first
3 months of CRPS to treat inflammation
and have been found to have a benefi-
cial effect in the prevention and treat-
ment of CRPS.38,49 Other medications
used to treat neuropathic pain in CRPS
include tricyclic antidepressants, gaba-
pentin, pregabalin, duloxetine, bisphos-
phonates, calcitonin, topical lidocaine
or capsaicin, and opioids. Bisphospho-
nates, which are used to treat osteopo-
rosis, may be effective in treating
neuropathic pain in patients with early
CRPS who have abnormal uptake on a
bone scan.40,41 Calcitonin, a hormone
secreted in the thyroid that inhibits
bone resorption, has also been found
to possibly provide pain relief in pa-
tients with CRPS.41 Opioids are occa-
sionally used in patients with CRPS
whose neuropathic pain is refractory to
other therapies or who require opioids
for pain relief in order to participate
in therapy.
Low Back Pain and Lumbar
Radiculopathy and Failed Back
Surgery Syndrome
Low back pain and lumbar radiculo-
pathy are addressed in the article ‘‘Low
Back Pain’’ by Jinny O. Tavee, MD, and
Kerry H. Levin, MD, FAAN,42 in this
issue of Continuum.
April 2017

INTERVENTIONAL TECHNIQUES
In the treatment of chronic neuro-
pathic pain, interventional techniques
are typically used if medical manage-
ment fails to provide adequate pain
control (Table 8-6). However, for many
interventional treatments, a lack of evi-
dence exists to recommend their use
because of a lack of high-quality trials.
Herpes Zoster and Postherpetic
Neuralgia
The use of steroid injections in the
treatment of herpes zoster and post-
herpetic neuralgia is based on their
ability to reduce inflammation at the
dorsal root ganglion. Only weak evi-
dence recommends their use, and
not all studies use the same technique
for the injections, so the ideal number
and frequency of procedures remains
unknown. Epidural injections of local
anesthetic and steroids have been
found to reduce acute pain in herpes
zoster,43 but conflicting results exist on
whether they can reduce the progres-
sion of acute herpes zoster to post-
herpetic neuralgia. 43,44 Therefore,
epidural or paravertebral local anes-
thetic and steroid injections are an
option for the treatment of acute pain
associated with herpes zoster, but there
is a lack of high-quality evidence.45 A
single study exists, which could not be
reproduced, which found that intrathe-
cal injections of methylprednisolone
acetate and lidocaine reduced pain
intensity in postherpetic neuralgia.46,47
However, because of the potential risks
associated with intrathecal methyl-
prednisolone administration and the
inconsistencies in the literature, this
treatment has not been recommended.45
Sympathetic blockade has also been
performed for short-term pain relief in
herpes zoster and postherpetic neural-
gia, but very few data demonstrate a
beneficial effect, and the Neuropathic
Continuum (Minneap Minn) 2017;23(2):512–532
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
Pain Special Interest Group from the h Epidural or paravertebral
International Association for the Study local anesthetic and
of Pain recommends that sympathetic steroid injections are
nerve blocks be generally avoided in used for the treatment
postherpetic neuralgia.45 Similarly, in- of acute pain associated
trathecal medication delivery, spinal with herpes zoster, but
cord stimulation, deep brain stimula- a lack of high-quality
tion, and radiofrequency ablation have evidence exists to
all been reported as treatments for recommend this
postherpetic neuralgia, but these thera- treatment. Intrathecal
pies lack randomized trials. steroid administration is
not recommended.
Trigeminal Neuralgia
For a discussion of interventional pro-
cedures in trigeminal neuralgia, refer
to the article ‘‘Trigeminal Neuralgia’’
by Giorgio Cruccu, MD,13 in this issue
of Continuum.
Painful Peripheral Neuropathies
There are several small, prospective
studies on the effect of spinal cord
stimulation on refractory painful dia-
betic neuropathy that have demon-
strated a beneficial effect on pain and
quality of life.48,49 Weak evidence sup-
ports a beneficial effect of deep brain
stimulation in peripheral neuropathic
pain.50 Surgical decompression, other
than for compressive mononeuro-
pathies, in patients with painful dia-
betic neuropathy remains unproven and
cannot be recommended until further
high-quality studies are completed.51,52
Central Neuropathic Pain
Only case series have examined the
use of spinal cord stimulation in the
treatment of neuropathic pain associ-
ated with spinal cord injury. Likewise,
intrathecal medication delivery, deep
brain stimulation, and dorsal root entry
zone lesioning have not been well
studied in patients with spinal cord
injury with chronic neuropathic pain.
Evidence from case series has sug-
gested a benefit from motor cortex
stimulation and deep brain stimulation
for the treatment of central poststroke
pain. Spinal cord stimulation has also
ContinuumJournal.com 527
 Neuropathic Pain
only been examined by case series, but
the results were unfavorable.53
Radiculopathy
Epidural injections of a local anesthetic
and steroid are among the most com-
mon procedures to treat radicular pain.
Their widespread use is based on the
fact that an inflammatory response to
foreign proteins that are released from
the nucleus pulposus into the spinal
canal causes nociceptors to be more
sensitive to mechanical stimulation.
However, the efficacy of epidural ste-
roid injections is controversial, and the
evidence to support their use is lim-
ited. Likewise, much of the evidence
for other procedures such as facet
injections, radiofrequency ablation,
intradiscal electrothermal therapy, and
adhesiolysis are limited by small num-
bers or lack of a placebo.
Failed Back Surgery Syndrome
Failed back surgery syndrome is a hete-
rogeneous condition that is character-
ized by the presence of persistent back
or leg pain despite the patient having
undergone spinal surgery. In patients
with prominent radicular symptoms,
epidural steroid injections may be at-
tempted, despite the lack of evidence,
prior to recommending more invasive
procedures. Adhesiolysis has been stud-
ied in failed back surgery syndrome and
has proven to be effective, but its effect
on neuropathic versus musculoskeletal
pain is unclear.45
Spinal cord stimulation is thought to
work by stimulating large-diameter,
non-nociceptive sensory fibers in the
dorsal column to cause the release of
GABA, which leads to decreased activa-
tion of the small diameter nociceptive
fibers. It has been studied in patients
with failed back surgery syndrome with
prominent radicular symptoms and is
FDA approved for use in chronic pain
associated with failed back surgery
528 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
syndrome. In comparison to conven-
tional medical management, spinal cord
stimulation was found to be superior at
6 and 12 months, but almost one-third
of the patients required surgical revi-
sion of the generator.54 One study
found that, compared to reoperation,
spinal cord stimulation was more effec-
tive in terms of pain relief and was a
cost-effective treatment option.55
Complex Regional Pain
Syndrome
In patients with CRPS who have failed
medical therapy, interventional proce-
dures may include regional sympathetic
nerve block, spinal cord stimulation, or
chemical or mechanical sympathectomy.
The published literature for these
methods is limited, but often practi-
tioners will begin with sympathetic
nerve blocks and try spinal cord stim-
ulation in patients who do not re-
spond. No randomized controlled trials
have examined the long-term effect of
sympathetic blockade in CRPS, and the
quality of evidence for their efficacy is
low, but because of the lack of treat-
ment options in this condition and the
relative safety of the procedure, it is
generally considered a reasonable
treatment option in patients who are
early in the disease course and
have pain that is refractory to medical
management. Spinal cord stimulation
is a more invasive treatment option,
but it has been shown to be beneficial
in CRPS type 1. The benefit may de-
crease over time, and patients may re-
quire reoperation, but the majority of
patients were happy with their initial
decision to undergo the procedure.56,57
Because of the benefits that are often
seen with sympathetic blockade,
chemical and surgical ablative pro-
cedures of autonomic structures have
been performed (sympathectomy).
However, weak evidence supports
these procedures, and the risk of
April 2017

adverse events is relatively high.
These risks include the potential to
develop postablation pain that is
worse than the original pain. Repeated
ketamine infusions have been shown
to be of benefit in CRPS, but because
of the risks associated with the treat-
ment, it is not recommended outside
of clinical trials.45 Not enough evidence
exists to recommend intrathecal baclo-
fen for the treatment of dystonia
associated with CRPS, and a large risk
for potential complications exists.
NONPHARMACOLOGIC
TREATMENT
The multidisciplinary care of patients
with chronic neuropathic pain ideally
includes physical and occupational
therapy as well as psychotherapy. Ran-
domized controlled trial evidence is
lacking for therapy-based treatment ap-
proaches, but, in general, they are safe
and may decrease pain and the use of
medications, increase function, and im-
prove overall quality of life. As a general
rule, physical therapy is appropriate
once the primary impairments to activ-
ity restriction have been determined. In
patients with neuropathic pain, the
primary impairment is typically pain,
and the goal of physical therapy is to
maximize function while minimizing
pain. Therapists often accomplish this
by addressing fear of movement and
sensory impairments. Aquatic therapy
may be particularly useful because of
the pain-relieving effects of the warm
water and the ease of movement while
in water. Occupational therapy can help
to maximize function by addressing
limitations in performing activities of
daily living and activities at work or
leisure. Occupational therapists teach
patients how to adapt a task or their
environment to optimize productivity
and minimize pain. Acupuncture is also
often used in the management of
chronic neuropathic pain. Challenges in
Continuum (Minneap Minn) 2017;23(2):512–532
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
studying the effect of acupuncture in the h Spinal cord stimulation
treatment of neuropathic pain include has been shown to be
the fact that many different acupuncture beneficial in failed back
techniques are used and a strong surgery syndrome and
placebo effect from both acupuncture complex regional pain
and sham acupuncture seems to exist. syndrome. Spinal cord
However, both acupuncture and sham stimulation may be
acupuncture appear to be superior to helpful in painful
no treatment. Overall, there seems to peripheral neuropathy
be a small positive effect in the treat- and spinal cord injury.
ment of chronic pain, but the results h Individuals will
of studies have been inconsistent.58 experience pain and
Questions remain about whether on- respond to treatment
going benefits from acupuncture exist in very different ways.
An individualized
and if habituation and tolerance de-
treatment approach and
velop over time. In general, acupunc-
use of a multidisciplinary
ture is considered to be very safe, and team can help to
practitioners are required to use dis- improve outcomes.
posable sterile needles.
Pain, and especially chronic pain, is
a biopsychosocial experience, and pain
psychology and the use of cognitive-
behavioral therapy is an integral part
of its treatment. Psychosocial disorders
affect not only how a person perceives
pain but how they respond to treat-
ment, so identifying and addressing
depression and anxiety, which are very
common in patients with chronic pain,
is essential to a successful treatment
plan. In cognitive-behavioral therapy,
patients are taught to conceptualize
their thoughts about the meaning
of their pain with the goal of managing
their pain better, improving their mood,
increasing their level of activity, and
reducing their overall disability.
CONCLUSION
Neuropathic pain is a common but
often difficult to treat condition that is
affected by multiple patient comor-
bidities. It is important to set realistic
treatment expectations together with
the patient and to approach manage-
ment with a multidisciplinary team.
Treatment algorithms for neuropathic
pain typically start with pharmacotherapy
and recommend tricyclic antidepressants,
ContinuumJournal.com 529
 Neuropathic Pain
gabapentin, pregabalin, duloxetine,
venlafaxine, or topical lidocaine as first-
line therapies and reserve opioid anal-
gesics for second-line therapy. Aside
from painful diabetic neuropathy and
postherpetic neuralgia, a lack of high-
quality evidence exists to recommend
treatment for other causes of neuro-
pathic pain. The lack of randomized
controlled trials is especially problem-
atic for interventional therapies. Ad-
vances in the treatment of neuropathic
pain have been made with the inclusion
of treatment outcomes such as quality
of life, sleep, and mood; the introduc-
tion of new treatments; studies of
combination therapies; and a focus on
mechanism-based treatment strategies
and responder profiles in order to
personalize treatment according to
the quality of neuropathic pain (ie, the
pain phenotype).
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