INVITED REVIEW

INVITED REVIEW
ABSTRACT: Treatment of neuropathic pain is the primary focus of management for many patients with painful peripheral neuropathy. Antidepressants and anticonvulsants are the two pharmacological classes most widely
studied and represent first-line agents in the management of neuropathic
pain. The number of pharmacological agents that have demonstrated effectiveness for neuropathic pain continues to expand. In the current review, we
summarize data from randomized, controlled pharmacological trials in painful peripheral neuropathies. Although neuropathic pain management remains challenging because the response to therapy varies considerably
between patients, and pain relief is rarely complete, a majority of patients
can benefit from monotherapy using a well-chosen agent or polypharmacy
that combines medications with different mechanisms of action.
Muscle Nerve 30: 3–19, 2004
PAINFUL PERIPHERAL NEUROPATHY AND ITS
NONSURGICAL TREATMENT
GIL I. WOLFE, MD, and JAYA R. TRIVEDI, MD
Department of Neurology, University of Texas Southwestern Medical Center,
5323 Harry Hines Blvd., Dallas, Texas 75390-8897, USA
Accepted 16 February 2004
Neuropathic
pain is conventionally defined as pain
initiated or caused by injury or dysfunction of the
nervous system.58 The injury or dysfunction may involve peripheral or central nervous system structures.
Neuropathic pain is common, estimated to affect 1.5%
of the United States population.12 When including
disorders that are not categorized as conventional neuropathic pain states, the prevalence is even higher.92
Poorly controlled neuropathic pain is associated with
mood and sleep disturbance and an impaired ability to
work and participate in social and recreational activities.26 It is expected that neuropathic pain will be a
growing burden on health care and society resources
as the aged population increases worldwide.
Peripheral nerve disorders are the major cause of
neuropathic pain encountered by neurologists and
other clinicians.25 Neuropathic pain is a prominent
feature of many generalized, symmetrical polyneuropathies. Even after extensive evaluation, a cause for the
polyneuropathy may remain unknown in most pa-
Abbreviations: 5-HT, 5-hydroxytryptamine; ART, antiretroviral therapy; CI,
confidence interval; CNS, central nervous system; FDA, Food & Drug Administration; GABA, ␥-aminobutyric acid; HIV, human immunodeficiency virus;
NMDA, N-methyl-D-aspartate; NNT, number needed to treat; SSRI, selective
serotonin reuptake inhibitor; VAS, visual analogue scale
Key words: anticonvulsants; antidepressants; neuropathic pain; peripheral
neuropathy; treatment
Correspondence to: G. I. Wolfe; e-mail: gil.wolfe@utsouthwestern.edu
© 2004 Wiley Periodicals, Inc.
Published online 26 April 2004 in Wiley InterScience (www.interscience.wiley.
com). DOI 10.1002/mus.20057
Treatment of Painful Neuropathy
tients, especially when small fibers are exclusively or
predominantly involved.45,69 In such settings, a diagnosis of idiopathic or cryptogenic sensory polyneuropathy
is made.35,36,99 Of identifiable etiologies, diabetes is the
most common cause of painful polyneuropathy, but
there are many other potential etiologies for painful
polyneuropathies and mononeuropathies.101 For simplicity, the current review at times uses the terms “neuropathy” and “peripheral neuropathy” (which have no
specific implications) in place of “polyneuropathy,”
which implies a generalized, symmetrical disorder of
peripheral nerves.
The frequency, intensity, and quality of neuropathic pain, though subject to individual variability,
differ between etiologies. Postherpetic neuralgia is defined by a neuropathic pain experience, and 90% of
patients with Fabry disease have pain48 that classically is
lancinating and lightning-like, aggravated by cold or
exertion. Neuropathic pain is present in 65– 80% of
idiopathic polyneuropathies100 and up to one third of
diabetic patients25 and patients with acquired immunodeficiency syndrome82 but is uncommon in paraprotein-associated neuropathies. Although chronic therapy is required for many types of neuropathic pain,
Guillain–Barre´ syndrome and toxic neuropathies typically require only short-term intervention.
SYMPTOMS AND SIGNS OF NEUROPATHIC PAIN
The symptoms of neuropathic pain are often referred to as the “positive” symptoms of peripheral
MUSCLE & NERVE
July 2004
3
neuropathy. “Negative” sensory symptoms and signs
of peripheral neuropathy refer to reports of numbness and the finding of reduced or absent sensation
on sensory examination. Spontaneous (stimulusindependent) and stimulus-evoked pain, which can
be distinguished by history and sensory examination,
often coexist in individuals and are likely to represent different pathophysiological mechanisms.104
Spontaneous pain may be constant or intermittent.
It is common for patients to experience both persistent burning pain and superimposed episodes of
shooting or lancinating discomfort.
Paresthesias are abnormal spontaneous or stimulus-independent sensations, often described as tingling or compared to a limb that has fallen “asleep.”
Descriptors of spontaneous painful sensation vary
widely in patients and include burning, stabbing,
stinging, squeezing, aching, cramping, shooting, and
freezing. “Pins and needles,” “broken glass,” and
“vicelike” sensations may be elicited by history. Stimulus-evoked pain is also common and is experienced
in a variety of forms. Dysesthesia refers to an unpleasant abnormal sensation that can be spontaneous or
evoked; allodynia, to pain following contact by a
normally nonnoxious stimulus; and hyperalgesia, to
exaggerated pain from a noxious stimulus.58 Hyperpathia is a complex sensory experience characterized by an abnormally painful reaction to a stimulus,
especially a repetitive stimulus, in a patient who initially perceives the stimulus as less intense, due to an
increased threshold. A variety of positive symptoms
often coexist in an individual. Given the lengthdependent pattern of many peripheral neuropathies, neuropathic pain symptoms tend to predominate in the distal limbs, typically involving the feet to
a greater degree than the hands.99 Sensory neuropathy appears to be the most common cause for the
painful or burning-foot presentation. In a cohort of
117 patients presenting with painful, burning feet,
89% had objective evidence of peripheral neuropathy based on a variety of studies including electrophysiological testing and intraepidermal nerve fiber
density on punch skin biopsy.69
NEUROPATHIC PAIN MECHANISMS
The pathophysiological basis of neuropathic pain is
complex and not fully understood. Some background, however, is helpful in strategizing treatment
approaches. Peripheral mechanisms include altered
sensitivity and activation of C nociceptor terminals
resulting in ectopic discharges in damaged or regenerating fibers, recruitment of silent nociceptors, and
spontaneous discharges in more proximal segments
4
Treatment of Painful Neuropathy
of the sensory nerve, including the dorsal root ganglion.64,104 Changes in expression and permeability
of voltage-gated sodium channels appear to be common events in these peripheral alterations,20 and
several agents (tricyclic antidepressants, carbamazepine, topiramate, lamotrigine, mexiletine) have activity at these ion channels. Damaged peripheral
nerve fibers express ␣-adrenoreceptors and exhibit
heightened sensitivity to sympathetic stimulation,
raising the possibility of a sympathetically mediated
component to neuropathic pain states.5
Waves of increased peripheral nerve activity move
centrally, producing central sensitization in secondand third-order neurons. It is the process of central
sensitization that alters the way neurons respond to
subsequent sensory input.32,103 The alterations include
the enlargement of peripheral receptive fields to stimuli, enhanced responses to suprathreshold inputs, and
generation of action potentials by previously subthreshold inputs. Central sensitization appears to result from
increased and prolonged release of excitatory amino
acids such as glutamate and neuropeptides.104 For instance, enhanced release of substance P as a result of
prolonged activity along nociceptive pathways can potentiate activation of postsynaptic N-methyl-d-aspartate
(NMDA) receptors. Subsequently, additional ion channels open, intracellular calcium concentrations build,
and action potential generation is potentiated in central sensory pathways.6 Neuropeptides may diffuse
through the dorsal horn, sensitizing neurons that
would otherwise be “bystanders,” producing the phenomenon of enlarged peripheral receptive fields, thus
causing a perception of pain over a wider distribution
and of greater intensity. Some of the newer agents used
for neuropathic pain (gabapentin, lamotrigine, topiramate, tramadol, venlafaxine) are thought to inhibit
central sensitization by blocking the activity of glutamate, excitatory neuropeptides, and presynaptic calcium channels and enhancing inhibitory pathways
such as those mediated by ␥-aminobutyric acid
(GABA) and its receptors.
A variety of pathophysiological processes may be
at work in an individual patient, and the same mechanisms may not be present in all patients who share
a specific neuropathic pain state. This pathophysiological variability likely accounts for some of the
heterogeneity of patient responses to therapeutic
interventions.24
CLINICAL TRIALS AND DRUG INDICATIONS
Most randomized, controlled pharmacological studies in neuropathic pain have evaluated antidepressants and anticonvulsants. Clinical trials of treatment
MUSCLE & NERVE
July 2004
for neuropathic pain in peripheral neuropathy share
a number of challenges and shortcomings. The response to placebo is considerable, typically observed
in one third3,33,51 and at times in more than one half
of subjects.10 Although statistically significant differences may be demonstrated between active treatment and placebo arms, the actual clinical benefit of
a 1- or 2-point drop on a 10-point visual analogue
scale (VAS) for pain intensity may be a point of
debate. Although they provide objective data, neurophysiological outcome measurements have not
been helpful.87 There is conflicting efficacy data for
some agents.14,40,47,76 Active treatment durations in
studies are short, usually ranging from 6
weeks21,33,51,78 to 8 weeks.3,10 Although studies demonstrate a favorable pharmacological effect commencing in a matter of days to weeks,87 long-term
efficacy remains uncertain. Furthermore, the effect
of medications on different aspects of neuropathic
pain (e.g., steady versus episodic, spontaneous versus
stimulus evoked) is rarely analyzed.89 There are very
few studies using combinations of agents. A study to
determine whether combined therapy with an antidepressant and anticonvulsant is superior to either
agent alone has not been performed.
Another consideration for United States clinicians is that the use of the agents in neuropathic
pain states related to polyneuropathy is “off-label.”
Labeled neuropathic pain indications in the United
States are limited to carbamazepine for trigeminal
neuralgia and gabapentin and lidocaine patches for
postherpetic neuralgia. Some countries permit more
liberal indications that cover neuropathic pain in
general, whereas others require labeling for only
specific forms.15 In some countries, including Japan,
off-label use of medication is not permitted, influencing medication options. As a result, Japanese
clinicians rarely prescribe tricyclic antidepressants
for neuropathic pain.
A variety of outcome measures have been utilized
in neuropathic pain studies. Visual analogue scales
or 10-point and 11-point scales such as the Likert
scale (0 ⫽ no pain, 10 ⫽ worst possible pain) are
conventional primary outcome measures. Patients
record their pain levels in daily diaries, and mean
values over a specified interval are compared with
baseline values obtained prior to randomization.
The short-form McGill pain questionnaire,56 which
consists of 15 pain descriptors (11 sensory [throbbing, shooting, stabbing, sharp] and four affective
[tiring-exhausting, sickening, fearful, punishingcruel]) graded from 0 to 3, has served as either a
primary or secondary outcome.
Treatment of Painful Neuropathy
Although the instruments provide reliable and
valid measurements of pain intensity and unpleasantness, they do not address other aspects of the
neuropathic pain experience.27 As a result, a variety
of quality-of-life and daily activity measures have
been introduced, especially in more recent trials.
The Wisconsin Brief Pain Questionnaire—a survey
that includes 11-point rating scales for worst pain,
pain right now, and average pain but also assesses
the effect of pain on mood, sleep, and daily activities— has been used on occasion.18 Other secondary
outcome measures provide global impressions of
change from the standpoint of both study subject
and clinician. Quality-of-life instruments employed
in neuropathic pain studies include the General
Health Self-Assessment form and the Short Form–36
Quality-of-Life Questionnaire. Galer and Jensen27 recently developed and validated the Neuropathic
Pain Scale, the first survey designed primarily for
neuropathic pain. The scale includes items that address pain intensity, temporal patterns, and ratings
for various descriptors of the neuropathic pain experience. The Neuropathic Pain Scale can generate
distinct patterns for different neuropathic pain syndromes, a finding that has potential implications for
underlying pain mechanisms and treatment.
TRICYCLIC ANTIDEPRESSANTS
Tricyclic antidepressants presumably exert their
analgesic effect by modulating voltage-gated sodium channels and inhibiting the reuptake of the
biogenic amines norepinephrine and serotonin.
They are the agents most extensively studied for
neuropathic pain, especially in diabetic neuropathy.8,24 Randomized, controlled trials for the tricyclics in painful peripheral neuropathy are outlined in Table 1. Efficacy for the individual agents
is roughly similar,51,90 although tricyclics with
mixed serotonergic and noradrenergic reuptake
inhibition (e.g., amitriptyline, imipramine, and
clomipramine) have been marginally more effective than those with relatively selective noradrenergic effects (desipramine, nortriptyline, and maprotiline).96 Patients may preferentially respond
to one tricyclic antidepressant over another, so
that sequential therapeutic trials may be needed.50
Tricyclics have been effective in relieving pain in
both depressed and nondepressed patient subgroups, with an analgesic action that is independent
of mood alteration and that becomes clinically evident as early as 1 to 2 weeks.49,55 Tricyclics have been
effective in both diabetic and nondiabetic forms of
painful neuropathy.96 The degree of analgesic re-
MUSCLE & NERVE
July 2004
5
Table 1. Randomized, placebo-controlled trials of tricyclic antidepressants.*
Ref.
no.
Cause of
neuropathy
Daily dose
(mg)
n
Design
44
DM
Imipramine
100
12
60
18
DM
Nortriptyline (⫹
fluphenazine)
Amitriptyline†
90 (mean)
29
Crossover
5 wk
Crossover
30 days
Crossover
6 wk
30
DM
49
87
DM
Imipramine
200 (mean)
20
88
DM
Clomipramine
75
19
88
DM
Desipramine
200
19
Crossover
2 wk
50
DM
Desipramine†
201 (mean)
20
91
DM
Imipramine
150 (mean)
18
96
Amitriptyline
75
33
Maprotiline
75
33
80
DM and
non-DM
DM and
non-DM
HIV
Amitriptyline
75
136
40
HIV
100
145
85
Various
Amitriptyline vs.
mexiletine
Imipramine
150
32
Crossover
6 wk
Crossover
2 wk
Crossover
4 wk
Crossover
4 wk
Parallel
14 wk
Parallel
10 wk
Crossover
4 wk
96
Drug
Crossover
2 wk
Crossover
2 wk
Primary
outcome
Result of
primary
outcome
Improved
on active
drug (%)
Improved
on placebo
(%)
Six-item scale
P ⬍ 0.10
58
0
VAS score
P ⬍ 0.01
89
6
Numeric
global
assessment
VAS score
P ⬍ 0.0001
79
3
P ⬍ 0.0002
89
15
P ⬍ 0.05
74
5
0.05 ⬍ P ⬍
0.10
53
5
P ⬍ 0.01
55
20
P ⫽ 0.03
44
11
P ⫽ 0.002
67
24
P ⫽ 0.053
42
24
P ⫽ 0.99
47
51
P ⫽ 0.38
50
48
P ⫽ 0.0005
48
7
Six-item
observer
scale
Six-item
observer
scale
Pain intensity
score
Six-item scale
10-step verbal
scale
10-step verbal
scale
Pain intensity
score
Pain intensity
score
10-point rating
scales
Abbreviations: DM, diabetes mellitus; N/A, not available.
*Main adverse events were mouth dryness (up to 90%), sedation (up to 66%), and dizziness (up to 28%).
†
Placebo was infused with benztropine ⫾ diazepam, to mimic tricyclic side effects.
sponse has correlated directly with serum tricyclic
levels in some studies49,88 but not in others.50,51,91,96
Tricyclics have demonstrated greater therapeutic effects than selective serotonin reuptake inhibitors
such as paroxetine, but suboptimal plasma concentrations may be partly to blame for this observation.87
The nontricyclic antidepressant mianserin, a drug
that blocks 5-hydroxytryptamine (5-HT) receptors
and that possesses only weak noradrenergic reuptake
inhibition, was not effective in relieving painful diabetic neuropathy.91 Of note, neither amitriptyline at
doses up to 100 mg/day nor a standardized acupuncture regimen— either alone or in combination—was
more effective than placebo in randomized trials of
human immunodeficiency virus (HIV)–related painful neuropathy (Table 1).40,80 Possible explanations
for the negative trials include mechanistic factors in
HIV-related neuropathy that are more resistant to
tricyclic actions, the modest doses used, and failure
of amitriptyline to have a persistent benefit in longer
duration studies.
6
Treatment of Painful Neuropathy
The clinical impression that antidepressants are
more effective for burning pain whereas anticonvulsants are preferred for shooting, lancinating pain
has not been verified in clinical trials; the benefit of
tricyclics is not dependent on the quality of pain.51,55
Shortcomings of studies include dropout rates of
30% or more in some trials, often the result of
adverse events,49,87 and treatment durations as short
as 2 weeks (Table 1). Also, many of the earlier crossover trials did not employ washout periods between
the various interventions.44,50,87,88 As is true for most
agents, the use of tricyclic antidepressants in neuropathic pain is off-label. Low doses (10 –25 mg) can
be given at bedtime and slowly increased by 10 to 25
mg every 1 to 2 weeks up to 100 –150 mg as tolerated.
Slower titration rates may be better tolerated by the
elderly. Daily tricyclic doses between 75 and 150 mg
are likely to fall within the effective range for most
patients.51
The main side effects of the tricyclics include dry
mouth, sedation, urinary retention, cardiac arrhyth-
MUSCLE & NERVE
July 2004
Table 2. Randomized, placebo-controlled trials of other antidepressants.*
Drug
Daily
dose
(mg)
n
Design
DM
Paroxetine
40
20
51
DM
Fluoxetine†
40
46
86
DM
Citalopram
40
15
78
Various
Bupropion
SR
300
41
Crossover
2 wk
Crossover
6 wk
Crossover
3 wk
Crossover
6 wk
85
Various
Venlafaxine
225
32
Ref.
no.
Cause of
neuropathy
87
Crossover
4 wk
Primary outcome
Result of
primary
outcome
Improved
on active
drug (%)
Improved
on placebo
(%)
VAS score
P ⫽ 0.0121
50
15
Pain intensity
score
Six-item observer
scale
Wisconsin Brief
Pain
questionnaire
10-point rating
scales
P ⫽ 0.34
48
41
P ⫽ 0.02
N/A
N/A
P ⬍ 0.001
73
10
P ⫽ 0.004
27
7
Abbreviations: DM, diabetes mellitus; N/A, not available.
*Main adverse events were mouth dryness (up to 37%), fatigue (up to 28%), and insomnia (up to 20%).
†
Placebo was infused with benztropine, to mimic side effects.
mias, orthostatic hypotension, dizziness, constipation, and weight gain.25,101 The secondary amines
(nortriptyline, desipramine) tend to be less sedating
and have less anticholinergic activity. Tricyclic antidepressants are contraindicated in patients with cardiac arrhythmias, congestive heart failure, recent
myocardial infarction, drug sensitivity, narrow-angle
glaucoma, and urinary retention from prostatic hypertrophy or other causes. Drug interactions may
occur from concurrent use of central nervous system
depressants or anticholinergic agents. The agents
should be used with caution in elderly patients, who
often are especially sensitive to adverse effects.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Selective serotonin reuptake inhibitors (SSRIs) have
been less effective than tricyclic antidepressants in
controlled studies of neuropathic pain (Table 2).
Although both imipramine and paroxetine demonstrated benefit compared with placebo in painful
diabetic neuropathy, the tricyclic was significantly
more efficacious than paroxetine on both an observer and self-rating scale.87 Scores for dysesthesia,
hypesthesia, and sleep disturbance did not improve
on paroxetine. However, paroxetine was better tolerated by patients. Citalopram was of mild benefit in
painful diabetic neuropathy.86 No relation between
drug level and analgesic effect was observed. In another trial, fluoxetine was no more effective than
placebo in providing pain relief except in a subgroup of patients with depression.51 Because fluoxetine has an active metabolite with a very long halflife, the study’s crossover design may have clouded a
distinction between the active drug and placebo.90
Treatment of Painful Neuropathy
Adverse events for the SSRIs tend to be mild and
include somnolence or insomnia, asthenia, nausea,
diarrhea, sweating, dry mouth, decreased libido, and
impotence. Because neuropathic pain trials suggest
that the rate of major side effects for SSRIs is half
that observed for the tricyclics,55 the SSRIs bear
some clinical relevance despite lower efficacy.86 The
SSRIs may be particularly beneficial in depressed
patients with neuropathic pain.
ATYPICAL ANTIDEPRESSANTS
Prominent adverse events and poor tolerability of
tricyclic antidepressants have prompted investigation of atypical antidepressants with unique pharmacological profiles (Table 2). Bupropion is a
second-generation nontricyclic antidepressant that
specifically inhibits neuronal norepinephrine uptake. It is a weak inhibitor of dopamine reuptake.
Unlike tricyclic agents, it does not have significant
affinity for muscarinic, histaminergic, or ␣-adrenergic receptors, and it is often better tolerated.1 The
sustained-release form of bupropion has been subjected to a double-blind randomized crossover trial
in 41 patients with various forms of painful neuropathy.78 Among the patients, 70% had either idiopathic, diabetic and paraprotein-related neuropathies, or lumbar radiculopathy. Pain relief was
significant at week 2 and persisted through week 6 of
the study (Table 2). A 30% reduction in pain scores
relative to placebo was observed, similar to tricyclic
studies. Quality-of-life measures also improved, and
the drug was relatively well tolerated. Only two patients (5%) dropped out of the study because of side
effects related to sustained-release bupropion.78 Of
MUSCLE & NERVE
July 2004
7
Table 3. Randomized, placebo-controlled trials of gabapentin.*
Ref.
no.
Cause of
neuropathy
Daily dose
(mg)
n
Design
Primary
outcome
3
DM
900–3600
135
31
DM
900
40
67
GBS
15 mg/kg
18
79
Various
2400
232
Parallel
8 weeks
Crossover
6 weeks
Crossover
16 days
Parallel
8 weeks
11-point Likert
scale
McGill Pain
Questionnaire
Numeric pain
score
Average daily
pain score
Result of
primary
outcome
Improved on
active drug
(%)
Improved on
placebo (%)
P ⬍ 0.001
59
33
P ⫽ 0.03
43
23
P ⬍ 0.001
N/A
N/A
P ⫽ 0.048
N/A
N/A
Abbreviations: DM, diabetes mellitus; GBS, Guillain–Barre´ syndrome; N/A not available.
*Main adverse events were dizziness (up to 24%) and somnolence (up to 23%).
the 11 patients enrolled in the study who had previously discontinued tricyclics because of side effects,
only one was unable to tolerate buproprion.
The main side effects of bupropion are dry
mouth, headache, nausea, insomnia, and tremor.
Bupropion is contraindicated in patients with a
known seizure disorder, those taking a monoamine
oxidase inhibitor, and those with known hypersensitivity to the medication. Buproprion should not be
used in individuals with a current or prior diagnosis
of bulimia or anorexia nervosa because of a higher
incidence of seizures in this population.102
Venlafaxine is an antidepressant that strongly inhibits the reuptake of both serotonin and norepinephrine but has minimal muscarinic and histaminergic activity compared with tricyclics.37 In a
preliminary report of a large study of 244 patients,
venlafaxine extended-release was superior to placebo in nondepressed patients with painful diabetic
neuropathy.42 Effective doses were 150 –225 mg/day.
A double-blinded, placebo-controlled study showed
significantly improved pain reduction, mood, and
quality of life when venlafaxine was added to gabapentin in painful diabetic neuropathy.81 Doses of up
to 150 mg/day were used.
Recently, venlafaxine was compared with imipramine in a randomized, double-blinded, placebo-controlled, three-way crossover study (Table 2). At the
end of the 4-week treatment periods, both venlafaxine and imipramine were superior to placebo in
reducing pain scores.85 There was no statistical difference between venlafaxine and imipramine in efficacy. This is one of the few studies to compare
responses in diabetic and nondiabetic subgroups.
There was a trend for diabetic patients to experience
greater pain relief than subjects with other forms of
painful neuropathy, although this has not been the
experience from other trials.90
8
Treatment of Painful Neuropathy
Side effects of venlafaxine include nausea, dizziness, somnolence, insomnia, sexual dysfunction, and
dry mouth. Prior hypersensitivity and concomitant
use of monoamine oxidase inhibitor are contraindications to using this drug. Tolerability of venlafaxine
may not be superior to tricyclics, as side-effect severity was similar in the comparative trial with imipramine.85 In fact, more patients withdrew from the
study as a consequence of venlafaxine.
ANTICONVULSANTS
Gabapentin is a popular first-line anticonvulsant used in treatment of neuropathic pain.90
Gabapentin was developed as a structural GABA analogue, and recent in vivo studies demonstrated increased cerebral GABA concentrations within hours
after administration of a single dose43 and with
longer-term administration in healthy subjects and
patients with epilepsy.43,70 Several other cellular
mechanisms of action have been proposed, including competition with l-type amino acids for active
transport, high-affinity binding to the ␣2␦ subunit of
voltage-activated calcium channels, inhibition of
voltage-activated sodium channels, increased serotonin concentrations, reduction in monoamine neurotransmitters, and prevention of neuronal death.95
The primary mechanism responsible for gabapentin’s analgesic effect remains uncertain.
Several randomized, double-blinded, placebocontrolled studies of gabapentin use in painful peripheral neuropathy have been conducted (Table
3). Backonja et al.3 studied 165 patients with painful
diabetic neuropathy. Seventy of 84 patients (83%)
receiving gabapentin and 65 of 81 (80%) receiving
placebo completed the 8-week study. Gabapentin
was titrated from 900 to 3600 mg/day over a period
of 4 weeks or to the maximally tolerated dosage. The
Gabapentin.
MUSCLE & NERVE
July 2004
Table 4. Randomized, placebo-controlled trials of lamotrigine.*
Cause of
neuropathy
Daily
dose
(mg)
n
Design
53
Various
200
74
83
HIV
300
29
Parallel
8 wk
Parallel
14 wk
21
DM
400
46
82
HIV
400–600
92 ART; 135
non-ART
Ref.
no.
Parallel
8 wk
Parallel
11 wk
Primary
outcome
Result of
primary
outcome
Improved on
active drug (%)
Improved on
placebo (%)
VAS score
P ⫽ NS
N/A
N/A
modified
Gracely pain
scale
Numerical pain
scale
Gracely pain
scale
P ⫽ 0.03
N/A
N/A
P ⬍ 0.001
73
52
P ⫽ 0.004 for
ART patients;
P ⫽ NS for
non-ART patients
53 for ART
patients
60 for non-ART
patients
39
Abbreviations: ART, antiretroviral therapy; DM, diabetes mellitus; N/A, not available; NS, non significant.
*Main adverse events were rash (up to 25%), nausea (up to 11%), and infection (up to 11%).
primary outcome measure was daily pain severity as
measured on an 11-point Likert scale. Mean daily
pain scores were significantly lower in the gabapentin-treated group (P ⬍ 0.001).3 All secondary outcome measures assessing sleep, mood, and quality of
life also improved significantly in the gabapentin
arm.
Other randomized, double-blinded, placebo-controlled studies of gabapentin produced conflicting
results.67,79 Serpell et al.79 enrolled patients with a
variety of neuropathic pain syndromes, the majority
being complex regional pain syndrome (28%); only
2% had diabetic neuropathy. Pain scores did not
improve after 6 weeks. In a study of 18 patients with
Guillain–Barre´ syndrome admitted to an intensive
care unit, there was a significant decrease in fentanyl
requirements over a 7-day period in those receiving
gabapentin as opposed to placebo.67
Two studies, one open-label and the other a randomized, double-blinded crossover trial, compared
gabapentin with tricyclics.17,59 In the open-label
study,17 gabapentin was superior to amitryptiline in
pain reduction (P ⬍ 0.026), whereas the blinded
trial found the two drugs to be equivalent in reducing pain.59
A recent analysis of five randomized, placebocontrolled trials provides direction on gabapentin
dosing for neuropathic pain. The conclusion was
that gabapentin should be started at 300 mg on day
1, 600 mg on day 2, and 900 mg on day 3. Subsequent titration to 1800 mg/day was recommended
to achieve greater efficacy, with doses up to 3600
mg/day needed in some patients.4 However, doses as
low as 900 mg/day were effective in a placebo-controlled, crossover study of painful diabetic neuropathy.31
Treatment of Painful Neuropathy
Gabapentin is usually well tolerated. Side effects
include sedation, fatigue, dizziness, confusion,
tremor, weight gain, peripheral edema, and headache. Contraindications and drug interactions are
few. It is eliminated by renal excretion, and its clearance is reduced in patients with renal insufficiency,
especially those with a creatinine clearance below 60
ml/min.3 Cimetidine alters the renal excretion of
gabapentin. Bioavailability is reduced by concomitant administration of magnesium or aluminumbased antacids.101
Lamotrigine is a novel anticonvulsant
that acts on voltage-sensitive sodium channels to
stabilize neuronal membranes and inhibit neurotransmitter release, principally glutamate.46 Several
randomized, placebo-controlled, double-blinded
studies of lamotrigine have been performed in various painful neuropathies (Table 4). Although there
are some inconsistencies, most trials support its use
in neuropathic pain management. An early placebocontrolled, double-blinded study of 100 patients with
undefined causes of neuropathic pain failed to demonstrate an analgesic benefit at a dose of 200 mg/
day.53 However, individual disease subgroups were
not analyzed. Subsequent studies have evaluated the
efficacy of lamotrigine in HIV-related82,83 and diabetic neuropathy.21 The first trial in painful HIV
neuropathy enrolled 20 subjects in the placebo arm
and only 9 on lamotrigine.83 Patients receiving up to
300 mg/day of lamotrigine had a greater reduction
in average pain compared with the placebo group
(P ⫽ 0.03). However, an overestimation of the treatment effect was possible, because 11 of 20 patients
randomized to the active arm dropped out. Nearly
half of the dropouts left the study because of skin
Lamotrigine.
MUSCLE & NERVE
July 2004
9
Table 5. Randomized, placebo-controlled trials of other anticonvulsants.*
Ref.
no.
Cause of
neuropathy
74
Improved
on active
drug (%)
Improved
on
placebo
(%)
N/A
93
63
P ⬍ 0.05
70
23
P ⫽ NS
N/A
N/A
Result of
primary
outcome
Drug
Daily dose
(mg)
n
Design
Primary outcome
DM
Carbamazepine
200–600
30
98
DM
Carbamazepine
600
40
76
DM
Phenytoin
300
12
14
DM
Phenytoin
300
40
74
26
Various
Phenytoin
15 mg/kg
20
Subjective changes
in pain intensity
10-cm analogue
scale
Linear analogue
self-assessment
Six-category
outcome scale
0–10 linear VAS
P ⬍ 0.02
54
P ⬍ 0.005
70
0
41
DM
Sodium
valproate
1200
52
Crossover
2 wk
Crossover
1 wk
Crossover
23 wk
Crossover
2 wk
Crossover
2 wk
Parallel
4 wk
SF-MPQ
P ⬍ 0.05
N/A
N/A
Abbreviations: DM, diabetes mellitus; N/A, not available; NS, nonsignificant; SF-MPQ, short-form McGill pain questionnaire.
*Main adverse events were somnolence (up to 53%), dizziness (up to 52%), gait changes (up to 42%), and nausea/vomiting (up to 40%).
rash. This investigator group performed a larger HIV
neuropathy trial in which patients were stratified
according to whether they were using neurotoxic
antiretroviral therapy (ART; didanosine, zalcitabine,
or stavudine).82 Lamotrigine was titrated to a dose of
400 mg/day, but a slower titration was used. The
change in the Gracely pain scale slope for average
pain indicated that lamotrigine was more effective in
reducing pain in patients receiving neurotoxic ART
(P ⫽ 0.004) but was no more effective than placebo
in patients not on these agents. The drug was well
tolerated, with adverse events, including rash, being
similar to placebo. No serious rash was reported, in
contrast to the prior study, possibly because of the
slower titration. In a diabetic neuropathy study, lamotrigine was beneficial at a daily dosage of 200 to 400
mg, and adverse events were not problematic using a
slow titration.21
Recommended lamotrigine dosing is 25 mg at
night for 2 weeks, increasing weekly by 25 to 50 mg
to a maximum dose of 400 mg/day. Side effects
include mild to serious rash, including Stevens–
Johnson syndrome, dizziness, unsteadiness, drowsiness, and diplopia.101 Rashes are more common in
children and with rapid titration. Lamotrigine
should be discontinued at the first sign of a drugrelated rash. If concomitantly used with valproic
acid, titration should be even slower, beginning at 25
mg every other day, with maintenance dosing generally not exceeding 200 mg/day.
Carbamazepine is an iminostilbene derivative chemically related to the tricyclic
antidepressants.2 It stabilizes membranes by inhibitCarbamazepine.
10
Treatment of Painful Neuropathy
ing voltage-gated sodium channels.57 Although it has
been studied extensively in trigeminal neuralgia and
is labeled for this indication, data regarding its effect
in peripheral neuropathy are limited (Table 5). Two
early double-blind crossover studies found carbamazepine to be effective in painful diabetic neuropathy at doses of 600 mg/day.74,98 However, these are
small studies, and each treatment phase lasted only
1–2 weeks, casting doubt on the results. Moreover,
validated primary outcome measures were not used.
Adverse events were frequent, although they were
minor and transient. They included somnolence,
dizziness, nausea, vomiting, gait changes, and urticaria. Other side effects of carbamazepine include
hyponatremia, leukopenia, thrombocytopenia, and
hepatic dysfunction.101
Oxcarbazepine is structurally similar to carbamazepine but has distinct pharmacokinetic and pharmacodynamic properties.52 Like carbamazepine, oxcarbazepine slows the recovery rate of voltage-activated
sodium channels, but it also inhibits high-threshold Nand P-type calcium channels and reduces glutamatergic transmission. As a result, it has the potential to
modulate both peripheral and central neuropathic
pain pathways. Whereas carbamazepine is metabolized
via oxidation to 10-11-epoxide—the metabolite responsible for most side effects— oxcarbazepine undergoes
reductive metabolism to a 10-monohydroxy derivative.52 This reductive metabolism results in minimal
involvement of hepatic cytochrome P-450– dependent
enzymes, less autoinduction, and fewer drug interactions. As a result, oxcarbazepine boasts a safety advantage over carbamazepine. Unlike carbamazepine, ox-
MUSCLE & NERVE
July 2004
Table 6. Randomized, placebo-controlled trials of analgesics.*
Ref.
no.
Cause of
neuropathy
Daily dose
(mg)
n
31
DM
Tramadol
210 (mean)
131
84
Various
Tramadol
200–400
34
29
DM
Oxycodone
37 (mean)
159
Drug
Design
Parallel 6 wk
Crossover 4 wk
Parallel 6 wk
Primary
outcome
5-point
Likert
scale
10-point
rating
scale
11-point
rating
scale
Result of
primary
outcome
Improved
on active
drug (%)
Improved
on placebo
(%)
P ⬍ 0.001
68
36
P ⫽ 0.001
32
9
P ⫽ 0.002
N/A
N/A
Abbreviations: DM, diabetes mellitus; N/A, not available.
*Main adverse events were tiredness (up to 56%), mouth dryness (up to 50%), constipation (up to 42%), dizziness (up to 44%), and nausea (up to 36%).
carbazepine does not have a “black box” warning for
aplastic anemia or agranulocytosis and is generally better tolerated.68 Evidence is accumulating that oxcarbazepine is effective in treating neuropathic pain. Data
from an open-label prospective study indicate that oxcarbazepine significantly improves pain scores in diabetic neuropathy patients.11 Several trials to assess efficacy and define dosing are under way in Japan.
Phenytoin, like many other anticonvulsants, exerts its membrane-stabilizing effect by blocking sodium channels.38 It is no longer a popular
choice for neuropathic pain, because the few studies
available are conflicting and adverse events are frequent. Furthermore, phenytoin inhibits insulin secretion, a potential problem in the diabetic population.33 In a double-blind crossover study in patients
with diabetic polyneuropathy, there was no significant benefit for phenytoin 300 mg/day over placebo
(Table 5).76 This is in contrast to the findings of
Chadda et al.14 of significant improvement in diabetic patients on the same dose. A single intravenous
infusion of phenytoin at 15 mg/kg was shown to
have an analgesic effect in acute flare-ups of neuropathic pain. The relief persisted beyond both the
infusion time and plasma half-life of the drug.54
Phenytoin.
Valproic acid was shown to increase
GABA content in the brain and to prolong the repolarization phase of voltage-sensitive sodium channels.38 There is only one randomized, controlled
trial in painful peripheral neuropathy (Table 5).
The study of 52 diabetic neuropathy patients demonstrated a significant improvement in pain in the
valproate-treated group as compared with placebo at
the end of 1 month.41 Valproate was well tolerated at
1200 mg/day in divided doses; only one patient deValproic Acid.
Treatment of Painful Neuropathy
veloped elevated liver enzymes. Other clinical trials
are needed to reproduce these favorable results.
TRAMADOL
Tramadol, a centrally acting nonnarcotic analgesic
medication with monoaminergic and opiate effects,
has been used in Europe since the late 1970s and was
first marketed in the United States in 1995. It has
low-affinity binding to ␮-opioid receptors coupled
with mild inhibition of norepinephrine and serotonin reuptake.71 Development of tolerance and dependence appear to be unusual events with tramadol.72 Tramadol has been effective in blinded,
placebo-controlled studies of painful diabetic neuropathy and other forms of painful neuropathy (Table 6).33,84 Pain relief was manifest as early as 2
weeks, showing even greater effect by 4 weeks before
a plateau was observed.33 Overall health and social
functioning improved significantly, although sleep
indices did not. In a 6-month open-label extension
that enrolled 120 patients from the randomized trial,
tramadol was found to provide sustained relief of
neuropathic pain.34 Eighty-five patients completed
the 6-month extension. By 30 days, average pain
intensity scores for the former placebo patients were
similar to those who had always received active drug.
The frequency and severity of adverse events did not
appear to increase with time. In a smaller placebocontrolled crossover study (Table 6), tramadol produced significant reductions in ratings for spontaneous and touch-evoked pain as well as dynamic
allodynia by electronic toothbrush stimulation.84 Although side effects from tramadol were frequent in
this trial, they tended to be mild and did not correlate with the primary analgesic response.
MUSCLE & NERVE
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11
Tramadol dosing usually begins at 50 mg twice
daily. The dose can be titrated upward at increments
of 50 mg every 3 to 7 days, using a schedule in which
medication is taken three of four times daily. The
maximum recommended dose is 100 mg four times
daily.
Frequently reported side effects include constipation, headache, and nausea. Sedation and dizziness are less common, reported by less than 15% of
patients,33,34 suggesting that tramadol may be better
tolerated than tricyclics in some individuals. Tramadol is contraindicated in patients with a previous
hypersensitivity to opioid analgesics. It should be
avoided in the setting of ongoing alcohol abuse,
hypnotics, centrally acting analgesics, opioids, or psychotropic drugs. Increased risk of central nervous
system depression or seizures has been described
with concurrent use of other centrally acting drugs
including neuroleptics and all major families of antidepressants. Other potential drug interactions include carbamazepine, digoxin, and warfarin. The
abuse potential of tramadol appears to be low, but
the agent is best avoided in patients with a prior
history of addiction.34 Because tramadol undergoes
hepatic metabolism and is partially excreted unchanged in the urine, dosing should be reduced in
patients with either hepatic (maximum dose of 50
mg twice daily) or renal insufficiency (maximum
dose of 100 mg twice daily).
OPIOID ANALGESICS
Although the efficacy of opioids in neuropathic pain
was disputed into the 1990s,89 recent studies support
an emerging role for opioid analgesics as a reasonable therapeutic alternative (Table 6). Prior to 2003,
controlled data for opiates in neuropathic pain
states was limited to postherpetic neuralgia.97 Controlled-release oxycodone up to 60 mg/day was superior to placebo for steady and brief pain and
allodynia in this crossover trial of 38 patients. Recently, controlled-release oxycodone demonstrated
efficacy in painful diabetic neuropathy in a doubleblinded, placebo-controlled study.29 Oxycodone dosing ranged between 10 and 99 mg/day. Significant
improvement in all pain outcomes and sleep quality
was seen within 1 week of oxycodone therapy, excluding the worst pain category. The reduction in
pain intensity occurred in the setting of relatively low
average daily doses (37 mg), one third of the maximum allowed per study protocol. The median time
to achieve mild pain (an average pain intensity rating of ⱕ4 on the 11-point scale) was 6 days for
oxycodone and 17 days for placebo. Measures for
12
Treatment of Painful Neuropathy
physical function and both general and mental
health did not differ significantly between the two
treatment arms, however.
In a second randomized, double-blinded trial
that included 81 patients with either refractory
chronic peripheral or central neuropathic pain, reduction of pain intensity was significantly greater
with high-strength (0.75 mg) than low-strength (0.15
mg) doses of levorphanol.73 The degree of pain
reduction was 36% in the high-strength group versus
21% in patients receiving the low-dose capsules. The
level of pain reduction was not associated with prior
opioid use. A major drawback of high-strength dosing was the greater degree of adverse events. Only
patients receiving the high-dose tablets reported anger, irritability, mood or personality change, generalized weakness, confusion, and dizziness. The study
withdrawal rate of 35% was also greater in the highstrength group.73 Withdrawal rates between 20%
and 25% are typical in opioid studies.29,97
Not surprisingly, the frequency of adverse events
is high in patients treated with opiate analgesics,
ranging from 76%97 to 96%29 in these studies. Constipation, sedation, and nausea are most commonly
reported. Neither opioid tolerance nor physical dependence was observed,29 although longer-term
studies have yet to be performed. Similar to tramadol, opioids should be used with extreme caution in
patients with a history of addictive behavior. Patients
should be counseled on the potential for drug tolerance and addiction, although such behavior has
been uncommon in the experience of specialists
using chronic opioids in this population.25 Longeracting agents are preferred for chronic therapy, including extended-release oxycodone, morphine,
and methadone. Dosing varies depending on the
agent. In general, the dose should be slowly titrated
upward until there is pain relief and improvement in
function. Effective daily doses may be relatively low:
30 to 60 mg for extended-release oxycodone and 1 to
15 mg for methadone. Prophylactic laxative therapy
should be considered when starting these agents.
Opioids are contraindicated in patients with
prior hypersensitivity, significant respiratory depression, obstructive pulmonary disease, and paralytic
ileus. Opioids interact with central nervous system
depressants; therefore, concomitant use should be
avoided.
MEXILETINE
Trials of mexiletine, a class IB antiarrhythmic agent
and oral analogue of lidocaine, have generated conflicting data in studies involving patients with dia-
MUSCLE & NERVE
July 2004
Table 7. Randomized, placebo-controlled trials of mexiletine.*
Cause of
neuropathy
Daily
dose
(mg)
n
Design
19
DM
10 mg/kg
16
93
DM
450–675
95
65
DM
126
39
HIV
225, 450,
675
600
40
HIV
600
126/145
Crossover
10 weeks
Parallel
5 weeks
Parallel
3 weeks
Crossover
6 weeks
Parallel
10 weeks
Ref.
no.
22
Primary
outcome
Result of
primary
outcome
Improved on
active drug
(%)
Improved on
placebo (%)
FIS, 94
VAS, 63
N/A
FIS, 13
VAS, 0
N/A
FIS; VAS
P ⬍ 0.02
McGill VAS
score
VAS score
P ⫽ NS
P ⫽ 0.029
74
65
VAS score
P ⫽ 0.78
31
31
Gracely pain
intensity
scale
P ⫽ 0.38
46
48
Abbreviations; DM, diabetes mellitus; FIS, five-item symptom score scale; N/A, not available; NS, nonsignificant.
*Main adverse events were nausea (up to 29%) and vomiting (up to 24%).
betic,19,65,93 alcoholic,61 and HIV-related39,40 neuropathy (Table 7). In a crossover study of diabetic
painful neuropathy in which mexiletine was titrated
up to a daily dose of 10 mg/kg, the VAS score and
clinical symptom scale showed significant improvement (P ⬍ 0.02 and P ⬍ 0.01, respectively) compared with placebo.19 A larger study involving 126
diabetic patients also suggested improvement in
sleep disturbances and nocturnal pain at 675 mg/
day.65 In contrast, Stracke et al.93 failed to differentiate between mexiletine and placebo in either the
VAS or McGill pain scales, although a subanalysis did
suggest that stabbing or burning pain, heat sensations, and formication improved. Clinical trials that
enrolled patients with HIV-related neuropathy failed
to demonstrate any benefit for mexiletine at doses
up to 600 mg/day.39,40
The recommended starting dose is 150 mg/day,
and this can be titrated up to 10 mg/kg per day
divided into three daily doses. Main side effects include nausea, vomiting, dizziness, tremor, nervousness, headache, and liver function abnormalities
(Table 7). Mexiletine is contraindicated in patients
with second- or third-degree atrioventricular blockade or cardiogenic shock.102
CAPSAICIN
Capsaicin, an alkaloid extracted from chili peppers
that depletes substance P from sensory nerves, has
had a significant effect in most diabetic neuropathy
trials but not in other painful neuropathies (Table
8). In diabetic neuropathy studies, the proportion of
patients with improved pain control has ranged from
60% to 90%.10,77,94 Ability to sleep, work, and perform other daily activities also improved significantly
Treatment of Painful Neuropathy
on capsaicin.9,77 In a small open-label extension, at a
mean follow-up of 22 weeks approximately 50% of
patients had improved, 25% were unchanged, and
25% were worse.94 However, more than half the 18
patients who entered the open-label study dropped
out during the 48-week extension. Six of the dropouts left the study because of lack of relief. A major
concern raised with regard to capsaicin trials is inadequate blinding from the burning sensation induced during early capsaicin application. The one
study that used an “active” placebo as a control failed
to demonstrate a significant effect for capsaicin.47
However, only 18% of subjects in the study had
diabetic neuropathy. Interestingly, another study
found capsaicin to be no more effective than placebo in painful HIV-associated distal symmetrical
peripheral neuropathy.66 In fact, significantly higher
pain scores were reported in the capsaicin group at
the end of the first week of the 4-week trial.
In contrast, in the Capsaicin Study Group trial—
the largest study that favored capsaicin over placebo—treatment outcomes were similar regardless
of whether diabetic subjects developed burning sensations.10 Capsaicin was equally effective as amitriptyline in reducing pain and improving daily activities
in a double-blind randomized comparison study of
235 patients with diabetic neuropathy.7 The systemic
side effect profile favored capsaicin.
Favorable response rates have been very high for
vehicle placebos in capsaicin studies. In the Capsaicin
Study Group trial, more than 50% of patients receiving
placebo were believed to have improved on a physician
global evaluation scale.10 The patients reported a 45%
mean percentage of pain relief. In the study that employed a placebo vehicle containing methyl nicotinate
MUSCLE & NERVE
July 2004
13
Table 8. Randomized, placebo-controlled trials of capsaicin cream (0.075% applied qid).*
Ref.
no.
Cause of
neuropathy
n
Design
Primary outcome
13
DM
46
Pain severity scale
9
DM
252
Parallel
4 weeks
Parallel
8 weeks
77
DM
49
Parallel
8 weeks
94
DM
20
Parallel
8 weeks
47
Various
39
66
HIV
20
Parallel
8 weeks†
Parallel
4 weeks
Six step
physician’s
global
evaluation
Six step
physician’s
global
evaluation
Six step
physician’s
global
evaluation
Verbal pain relief
evaluation
Brief pain
inventory
Result of
primary
outcome
Improved on
active drug
(%)
Improved
on placebo
(%)
P ⫽ NS
71
50
P ⫽ 0.007
71
51
P ⫽ 0.005
89
50
P ⫽ 0.038
60
20
P ⫽ NS
59
67‡
P ⫽ NS
N/A
N/A
Abbreviations: DM, diabetes mellitus; N/A, not available; NS, nonsignificant.
*Main adverse events were burning (up to 73%), sneezing/coughing (up to 12%), and skin redness/rash (up to 10%).
†
One leg received active drug; one leg, placebo.
‡
Methyl nicotinate used in initial placebo tube to induce stinging, erythema
to induce stinging and erythema, the percentage of
limbs that improved at 12 weeks on a global scale was
near 60% for both the active and placebo arms, even
after a 4-week placebo wash-out phase.47
Substance P is considered the primary neurotransmitter for polymodal nociceptive afferent fibers. In addition to substance-P depletion, capsaicin
may cause epidermal nerve fiber degeneration, contributing to its analgesic effects.63
Capsaicin 0.075% cream is available over the
counter and should be applied to the painful region
three to four times daily. It should be used in wellventilated areas, and patients should avoid rubbing
their eyes after use. Nonsteroidal anti-inflammatory
agents may be used if the initial burning from capsaicin is intense. This side effect is reported by a
majority of patients but usually improves over several
weeks as nociceptor membranes become desensitized and substance-P levels are depleted.23,77,94
Other side effects include sneezing, coughing, rash,
and skin irritation (Table 8). Capsaicin should not
be used if there is known prior hypersensitivity to the
cream or to hot chili peppers. There are no significant interactions with other medications.
LEVODOPA
There has been only one double-blind placebo-controlled study of levodopa in painful neuropathy.22
14
Treatment of Painful Neuropathy
The study enrolled 25 patients with diabetic peripheral neuropathy. Compared with placebo, VAS
scores dropped significantly in the active arm by
week 2, persisting through week 4 (P ⫽ 0.004). The
levodopa dosage used in the study was 100 mg/day
three times a day. No adverse events were reported.
DEXTROMETHORPHAN
Dextromethorphan is a low-affinity NMDA glutamate receptor antagonist. A crossover study that enrolled 14 patients with diabetic neuropathy revealed
a significant improvement in pain at a mean dose of
dextromethorphan 381 mg/day compared with placebo (P ⫽ 0.014).60 Adverse events were frequent in
the active arm, including sedation, dizziness, lightheadedness, and ataxia. Among patients in the trial,
16% dropped out because of sedation or ataxia.
There were virtually no adverse events reported on
placebo, suggesting that patients may have been unblinded to the treatment.60 A recent parallel study of
19 patients that used lorazepam as a sedating placebo demonstrated a trend for dextromethorphan
in reducing pain intensity, but this was not statistically significant.75 In the responder subgroup, however, a dose-response effect on pain intensity was
seen at higher doses. Sedation occurred in 71% of
patients receiving dextromethorphan.
MUSCLE & NERVE
July 2004
Table 9. Number-needed-to-treat analysis for ⱖ50% pain relief.
Pharmacological class
Neuropathic pain*
Antidepressants, tricyclic antidepressants
2.6 (2.2–3.3)
Antidepressants, SSRIs
6.7 (3.4–435)
Venlafaxine
Gabapentin
Carbamazepine
Phenytoin
Tramadol
Oxycodone
Capsaicin
Mexiletine
Levodopa
Dextromethorphan
5.2 (2.7–5.9)㛳
3.7 (2.4–8.3)
3.3 (2.0–9.4)
2.1 (1.5–3.6)
3.4 (2.3–6.4)
2.5 (1.6–5.1)¶
5.9 (3.8–13)
10 (3.0–infinity)
3.4 (1.5–infinity)
1.9 (1.1–3.7)
Painful diabetic neuropathy†
3.0 (2.4–4.0)
Balanced reuptake inhibitors,‡ 2.0 (1.7–2.5)
Noradrenergic reuptake inhibitors,§ 3.4 (2.3–6.6)
6.7 (3.4–435)
Paroxetine, 2.9
Citalopram, 7.7
—
3.7 (2.4–8.3)
3.3 (2.0–9.4)
2.1 (1.5–3.6)
3.1
—
5.9 (3.8–13)
10 (3.0–infinity)
3.4 (1.5–infinity)
1.9 (1.1–3.7)
Values in parentheses are 95% CI.
*Composite analysis that combined studies with different causes of neuropathic pain.90
†
From Ref.89
㛳
From Ref.85
¶
From Ref.97
‡
Balanced reuptake inhibition of both serotonin and norepinephrine (amitriptyline, imipramine, colmipramine).
§
Includes desipramine and maprotiline.
NUMBER-NEEDED-TO-TREAT ANALYSES
Increasing emphasis is being placed on the translation of evidence-based medicine into clinical practice. Along these lines, randomized placebocontrolled studies in neuropathic pain have
been subjected to number-needed-to-treat analyses
(NNT).16 This methodology provides the clinician
with a measure of efficacy that can be more readily
translated into routine practice situations. The NNT
refers to the number of subjects that need to be
treated in order to achieve a defined clinical response in a single patient. In the context of pain
studies, a 50% or greater reduction in the self-report
of pain is considered clinically relevant and is used as
the defined response.90 For studies that do not specifically employ a 50% reduction as an outcome
measure, “excellent/good/moderate” pain relief or
“no/slight pain” intensity grades may be categorized
as satisfying this degree of pain reduction.55 The
NNT can be performed only on placebo-controlled
studies, because a correction for placebo responders
is included in the calculation. The formula is expressed as the reciprocal of the absolute risk reduction:
NNT ⫽ 1/ [response achieved active/total active]
⫺ [response achieved placebo/total placebo]. 16
The 95% confidence interval (CI) for the NNT is
obtained by taking the reciprocal value of the 95%
Treatment of Painful Neuropathy
CI for the absolute risk reduction. Although the
NNT approach is only a coarse measure of a drug’s
effectiveness and does not account for study duration, it does inform on the rate and magnitude of the
analgesic effect and allows for a reasonable comparison of different agents (Table 9).15,57 Given the
scarcity of head-to-head trials in neuropathic pain,
the NNT can serve as a helpful guide in the choice of
first- and second-line agents. Table 9 summarizes
NNT data for various pharmacological agents. For
studies of painful diabetic neuropathy, the NNT for
50% pain relief for amitriptyline was 2.1; paroxetine,
6.7; carbamazepine, 3.3; dextromethorphan, 1.9;
and tramadol, 3.4.62,90 Based on these findings, tricyclic antidepressants were recommended as firstline therapy for neuropathic pain.90 Leading alternatives were gabapentin, carbamazepine, and
tramadol. It should be noted that these recommendations preceded the publication of randomized,
controlled trials of third-generation anticonvulsants
and atypical antidepressants mentioned earlier.
GENERAL TREATMENT GUIDELINES
Pain management should begin with an effort to
identify the etiology of the neuropathy, as directed
therapy may help alleviate the symptoms. Prior to
the initiation of any therapy, the physician and patient should discuss the goals and expectations of
treatment. It is important that the patient have a
realistic view of therapy and understand that re-
MUSCLE & NERVE
July 2004
15
Table 10. Pharmacological therapy for neuropathic pain in peripheral neuropathy.
Medication
First line
Gabapentin
Tricyclic antidepressants
Tramadol
Second line
Lamotrigine
Carbamazepine
Bupropion SR
Venlafaxine XR
Opiate analgesics
Topical Agents
Capsaicin 0.075%
Starting doses
100–300 mg tid
10–25 mg qhs
50 mg qd or bid
25 mg qd or bid
100–200 mg qd or bid
150 mg qd
75 mg qd
Varying doses: initiate with
short-acting agent qid pm
Apply tid or qid
Maintenance doses and comments
Increase by 300–400-mg increments every 5–7 days to 3600 mg daily
divided in 3–4 doses
Increase by 10–25 mg increments every 7 days to 100–150 mg qhs;
titration can continue following blood levels (stay below 500 ng/ml) and
electrocardiogram
Increase by 50-mg increments every 5–7 days to a maximum of 100 mg qid
After 2 weeks, increase by 25-mg increments weekly to 100–200 mg bid
Increase by 100–200 mg every 7 days to 600 mg qd in divided doses;
titration can continue following blood levels; Extended-release forms can
be given on a bid schedule
After 1 week, increase to 150 mg bid
Increase by 75-mg increments every 7 days to 150–225 mg qd
After 1–2 weeks, replace with longer-acting agent on a qd or bid schedule;
careful titration is necessary.
Continue with starting dose; may be considered for first-line or adjunctive
therapy
sponses may vary from person to person and that
pain relief is rarely complete. Some physicians find it
helpful to have patients monitor their pain level
using simple 5- or 10-point rating scales that they can
complete at home or in the clinic and bring to their
appointment. Pharmacological agents should be initiated at low doses and titrated using small increments over several weeks until an adequate clinical
response is observed or intolerable side effects appear.25 Tolerance of agents with sedating profiles
may be enhanced by starting the medication in a
single bedtime dose. Slow titrations are especially
important in elderly patients who receive other medications for chronic medical illness.
Polypharmacy or multidimensional therapy may
be considered when one drug provides partial relief
but higher doses produce troublesome side effects.
In this setting, a rational intervention would be to
add a medication with a different mechanism of
action or initiate a nonpharmacological approach.
Two common reasons for treatment failure in the
neuropathic pain population are stopping titrations
before effective dosing levels are reached and immediate initiation of polypharmacy.25 A drug trial of at
least 4 to 6 weeks is recommended before switching
to or adding another medication.
Recommendations for first- and second-line
pharmacological agents are provided in Table 10.
The recommendations are based on the weight of
evidence from randomized, controlled trials, taking
adverse effect risks into account. Other considerations when choosing between the agents include
16
Treatment of Painful Neuropathy
cost, underlying medical illness, and potential drug
interactions. Although many patients with neuropathic pain are treated simultaneously with two or
more of the agents listed, systematic evaluations of
combination therapy have not been performed. As
mentioned earlier, whether some medication classes
are more effective than others in treating certain
qualities of neuropathic pain has not been addressed
in convincing fashion.89
The future of neuropathic pain management is
promising. Pharmacological options continue to
grow, and new agents are actively being investigated.
An increasing number of FDA-approved indications
are expected in the near future. Still, even current
knowledge and available therapies appear underutilized. In a recent survey of 151 patients referred to a
tertiary center, 25% had never received any of the
conventional agents known to have efficacy in neuropathic pain.28 Over 70% had never been prescribed anticonvulsants. Offering educational programs and raising awareness among health-care
professionals are of critical importance if advances in
neuropathic pain management are to reach this
large group of patients.
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