Neuropathic Pain:
Treatment Options Report
November 2006
Neuropathic Pain:
Treatment Options Report
Prepared for:
CALIFORNIA HEALTHCARE FOUNDATION
Prepared by:
UC Davis Center for Health Services Research in Primary Care
Authors:
Erika D. Cutler, Pharm.D.
Kenneth T. Furukawa, M.D.
November 2006
Acknowledgments
The authors would like to thank MaryLynn McPherson,
Pharm.D., B.C.P.S., C.D.E., and James Barrett, M.D., for
their careful review and critique of an earlier draft of this document. Additional thanks are due to Diane Romac, Pharm.D.,
Robert Mowers, Pharm.D., B.C.P.S., and Jeff King, Pharm.D.,
for their contributions and input.
About the Authors
Erika D Cutler, Pharm.D., is a pharmacist at the University of
California, Davis Health System. Kenneth T. Furukawa, M.D.,
is an associate professor in the Department of Medical
Anesthesiology at the University of California, Davis.
About the Foundation
The California HealthCare Foundation, based in Oakland,
is an independent philanthropy committed to improving
California’s health care delivery and financing systems. Formed
in 1996, our goal is to ensure that all Californians have access to
affordable, quality health care. For more information about
CHCF, visit us online at www.chcf.org.
ISBN 1-933795-18-2
Copyright © 2006 California HealthCare Foundation
Contents
4
I. Description of Condition
Definition
Classification
Epidemiology
Causes and Risk Factors
Pathophysiology
Natural History and Prognosis
Diagnosis
7
II. Management
Nonpharmacologic Treatment
Alternative and Complimentary Medicines
Prescription Drug Treatment
21
III. Summary
22
Appendix 1. Pathophysiology
24
Appendix 2. Assessment
26
Endnotes
I. Description of Condition
Definition
THE INTERNATIONAL ASSOCIATION FOR THE
Study of Pain defines neuropathic pain as “pain initiated or
caused by a primary lesion or dysfunction in the nervous
system”.1 Neuropathic pain may be caused by any disease or
injury to the nervous system. It is a broad category composed
of numerous types of painful disorders, each with varying causes, presentations, durations, and pain characteristics.
The vagueness associated with the term “dysfunction” has led
some authors to advocate reclassifying neuropathic pain
based on presumed pain mechanisms.2
Regardless of mechanism, the symptoms suggesting a diagnosis
of neuropathic pain include numbness, tingling, itching,
burning, subjective change in temperature, increased sensitivity
to repetitive noxious stimuli (hyperpathia), the interpretation
of non-noxious stimuli as painful (allodynia), and the altered
perception of stimuli that normally induce mild pain as severe
pain (hyperalgesia).3 Such symptoms can be experienced
continuously, intermittently, or in any combination. Other
nonspecific common symptoms include stiffness, tightness or
swelling, sleep disturbance, and fatigue.3 Signs of neurologic
damage may be present and include tremor, muscle atrophy,
reduced motor strength, frank paresis, and impaired sensation
to stimuli (fine touch, sharp-dull, pressure, temperature,
position, and vibration).3
Classification
Neuropathic pain can be classified according to the underlying
disease (e.g., diabetic neuropathy, multiple sclerosis), the site
of the lesion (e.g., peripheral nerve, spinal cord), or the underlying mechanism.4,5 Chronic pain may also be classified based
on expert opinion, anatomy, duration, presumed cause, body
system, severity, and presumed mechanism.6,7 Each of these taxonomies has its shortfalls in clinical and research applications,
and no single system is accepted as the “gold standard.”1,2,6,7
Thus, identifying neuropathic pain as a component of a
painful syndrome depends on understanding of the underlying
pathology and dysfunction.
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Epidemiology
In the United States, an estimated 1.5% of the
general population has neuropathic pain. This
figure underestimates the true incidence because
it does not include neuropathic pain experienced
by patients with cancer, degenerative diseases,
or neurologic conditions.8 More than 3 million
people have painful diabetic neuropathy,
and 1 million have postherpetic neuralgia.9,10
According to the National Institute of Neurological Disorders and Stroke, 30% to 40% of
patients with diabetes have symptoms suggesting
neuropathy, compared with only 10% of people
without diabetes.11 A UK study found little risk
of postherpetic neuralgia in people with acute
herpes zoster who were under the age of 50 years;
however, postherpetic neuralgia developed in
20% of people aged 60 to 65 years and in 34%
of people 80 years or older.12 The annual
incidence of trigeminal neuralgia in the United
States is 5.9 per 100,000 women and 3.4 per
100,000 men.13
Causes and Risk Factors
The underlying causes of neuropathic pain can
be categorized into trauma, endocrine, autoimmune, neurologic dysfunction, inflammatory,
neurotoxin exposure, tumor, and infectious
diseases.3,11 As with all chronic disease processes,
neuropathic pain syndromes have associated
contributing risk factors. Some of the more common risk factors for different neuropathic pain
syndromes are described below.
■
Smoking, age greater than 40 years, longstanding diabetes mellitus, and uncontrolled blood glucose levels are risk factors
for diabetic neuropathy.10,11
■
Age greater than 50 years, severe acute pain,
rash, sensory impairment, psychological
distress, or prodrome are risk factors
for postherpetic neuralgia.10,12
■
Female sex, older age, multiple sclerosis, and
female sex with hypertension are risk factors
for trigeminal neuralgia.13
Pathophysiology
Transduction, transmission, modulation, and
perception of sensory stimuli result from the
complex interactions between multiple pathways
and mechanisms, from the peripheral receptor to
the brain cortex and multiple points along the
way.14 This complex interplay is known as
“nociception” when it is related to stimuli that
are actually or potentially harmful. Transduction
involves the conversion of heat, cold, or mechanical forces into action potentials in peripheral
nerve endings.14 For the most part, transduction
involves A-beta, A-delta, and C axons. The
action potential is transmitted through the dorsal
root ganglion of the spinal cord to second-order
neurons in the spinal cord.14 From here, different
projections follow multiple tracts (such as the
spinothalamic tract) to the brainstem and midbrain structures. The final leg of transmission
follows neurons to various structures in the
cortices. The action potential can be modulated
at multiple levels along the pathway, with the
dorsal horn of the spinal cord being one of the
major sites.14 Both amplification and dampening
occur to any given action potential. The final
subjective sensation is then perceived, and
usually an action or recognition follows.14 See
Appendix 1 for additional information on the
pathophysiology of pain.
Neuropathic Pain: Treatment Options Report |
5
Natural History and Prognosis
Diagnosis
Chronic neuropathic pain follows its own course
in terms of presentation, duration, and pain
characteristics, depending on the disease process.
The usual course of a neuropathic pain condition
is slow and steady progression of pain and neurologic manifestations of disease. Occasionally,
symptoms level off for months or years, whereas
some worsen over time. Consistent reevaluation
is necessary to establish whether the changing
pain is related to progression of the primary
disease or is a manifestation of another process.
Pain tends to progress with worsening of the primary disease. For example, patients with chronic
diabetes may experience greatly worsened pain
when hyperglycemic control is not adequate, and
such loss of control may be a sign of worsened
pancreatic function or insulin response. If euglycemia can be maintained, pain and neurologic
complaints generally improve.
The diagnosis of neuropathy is based on a
thorough medical history, review of systems,
physical examination, and appropriate laboratory
and diagnostic studies.3 Particular attention must
be paid to any neurologic abnormalities.4 Diagnostic tests are determined, and often justified,
by the findings during the initial examination.
When describing pain that is thought to be neuropathic, specialized terminology can be helpful,
but careful description and drawings explaining
the physical findings can be even more revealing.
Careful quantification of symptoms and signs
is important during the initial evaluation.3,4 Any
discrepancies should be examined fully before
committing them to the medical record.
Common tools, such as the visual analog scale
(VAS) for pain and symptom assessment, must
be administered properly if they are to accurately
reflect the patient’s pain.18 In fact, these tools
are often improperly applied and documented.
A concise discussion concerning pain assessment
tools is available from the Agency for Healthcare
Quality and Research.18
The evaluation of chronic neuropathic pain
should also focus on psychological and social
factors that may contribute to the condition.3
As with all chronic pain states, the roles of mind,
body, and person cannot be isolated, and successful treatment and management depend on identifying pertinent psychosocial factors. Appendix 2
has additional information and details on the
diagnosis of neuropathic pain.
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CALIFORNIA HEALTHCARE FOUNDATION
II. Management
NEUROPATHIC PAIN CAN BE MANAGED WITH
nonpharmacologic and pharmacologic agents. The complexity
of neuropathic pain mechanisms means that any single combination of medications is unlikely to be adequate in every
case. All the transmitters, channels, receptors, and messengers
noted above perform a multitude of other critical functions, in
addition to creating neuropathic pain. As a result, all analgesics
are plagued by side effects and limited effectiveness.
Nonpharmacologic treatments include exercise, transcutaneous
electrical nerve stimulation (TENS), and acupuncture. Overthe-counter, alternative, and complementary medicines used in
treating neuropathic pain have not been extensively evaluated.
Prescription drugs are the treatment of choice, offering a variety of drug classes with different mechanisms of action, including antidepressants, antiepileptics, opioids, local and topical
anesthetics, and N-methyl-D-aspartate (NMDA) antagonists.
The goal of treatment is a 50% reduction in pain on the
numerical rating scale, which corresponds to a “very much
improved” score on the Clinical Global Impression for
Change. On this instrument, a 30% reduction in pain score
is considered to be clinically important.4 This reduction may
also be reliably indicated as a 2-point reduction on a standard
11-point VAS scale (0-10).
Nonpharmacologic Treatment
Nonpharmacologic treatments for neuropathic pain are often
perceived as harmless, noninvasive procedures. Patients may
accept them more readily than medications, especially if they
have experienced untoward adverse effects. Unfortunately,
these options have not been extensively studied for treating
neuropathic pain. Most studies have evaluated only a few
patients with diabetic neuropathy. Therefore, nonpharmacologic therapies should be used with caution when employed
as treatment for other forms of neuropathic pain.
Neuropathic Pain: Treatment Options Report |
7
Exercise
A 2005 Cochrane Review of the effect of exercise
on functional ability in patients with peripheral
neuropathy found inadequate evidence to evaluate efficacy.24 The results of three trials, only one
of which met the inclusion criteria and lasted
longer than 8 weeks, could not be pooled
because of heterogeneity between groups and
outcomes. Strengthening or endurance exercise
programs did not affect functional ability;
however, some evidence suggests that exercise
programs moderately increased the strength of
targeted muscles. Although the literature offers
no compelling support for exercise and physical
therapy in treating these heterogeneous conditions, the use of exercise as part of the treatment
for neuropathic pain is well accepted.
Electrical Nerve Stimulation
TENS is the application of electrical current to
the skin over the painful or adjacent body region.
The electrodes are usually placed with adhesive,
and the portable generator has user-selected
settings to adjust skin sensations. The stimulus
can be modulated to be apparent as a generalized
buzzing or as an identifiable pulse of variable
intensity and character.
A 1999 review of three studies evaluated the use
of TENS in patients with diabetic neuropathy.25
One study reported a 44% improvement in
painful symptoms for more than 1 year. The
other two studies evaluated the efficacy of TENS
alone and in combination with amitriptyline,
and found a 52% reduction in painful symptoms
in patients treated with TENS for 2 to 3 weeks,
a 26% reduction in pain in those treated with
amitriptyline alone for 4 weeks, and a 66%
reduction in pain in those receiving both TENS
and amitriptyline therapy.
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CALIFORNIA HEALTHCARE FOUNDATION
Percutaneous electrical nerve stimulation
(PENS) stimulates peripheral nerves through
the use of disposable acupuncture-like needles
connected to electrodes. One randomized
placebo-controlled, crossover trial compared
PENS, administered three times a week,
30 minutes per session, with sham treatment
in 50 patients with diabetic neuropathy.26 More
than 90% of patients reported benefits during
the active-treatment phase. Pain and nonopioid
analgesic use were substantially reduced, and
sleep quality and mood were markedly better
during the PENS phase.
A newer, if not well-studied, electrotherapy
option for treating neuropathic pain is frequencymodulated electromagnetic neural stimulation
(FREMS). This therapy uses sequences of modulated electrical stimuli that vary automatically in
terms of pulse frequency, duration, and voltage
amplitude. A 2005 randomized, double-blind,
crossover trial of 31 patients found FREMS to be
effective in treating diabetic neuropathic pain.27
After 3 weeks of therapy, daytime pain, nighttime pain, and measures of peripheral neurologic
function improved substantially. Four-month
follow-up showed continued benefit in FREMStreated patients.
Acupuncture
Acupuncture effectively reduces diabetic neuropathy pain.28,29 A 1998 uncontrolled, 10-week
study of 46 patients (of whom 44 completed the
study) evaluated the use of six acupuncture treatment sessions in relieving diabetic neuropathy
pain.28 Symptoms resolved in 21% of patients.
Patients whose symptoms did not resolve nevertheless decreased their use of pain medications.
After 1 year, eight of the 34 patients who
experienced marked pain relief required further
acupuncture treatment sessions to maintain this
relief. Another trial conducted in 40 diabetic
neuropathy patients reported improvements in
pain, sleep, mobility, and mood with 20-minute
acupuncture sessions, held once a week for 2 to 3
months.29 Acupuncture also reduces neuropathic
pain caused by spinal cord injury.30 A retrospective chart review of 36 individuals found
improvement in 24 patients with electroacupuncture therapy.30 Patients with constant (P = 0.005),
bilateral (P = 0.01), or symmetric (P = 0.03) pain
were more likely to improve with acupuncture
than were patients with nonconstant, unilateral,
or asymmetric pain.
Other Nonpharmacologic Treatments
The uses of magnet therapy, polyurethane films,
low-intensity laser therapy, and near-infrared
treatment have been studied for the relief of
painful diabetic neuropathy. Magnet therapy
improved foot pain and other symptoms in 260
patients (68% of the original 377) who completed
a large multicenter, randomized, double-blind
study.31 Magnet therapy insoles, compared with
sham insoles, significantly reduced burning
(-12% vs. -3%, P <0.05), numbness and tingling
(-10% vs. 1%, P <0.05), and foot pain (-12%
vs. -4%, P <0.05).
Polyurethane film was studied for 3 months
in a controlled trial of 33 patients with bilateral
diabetic neuropathy.32 The polyurethane
(OpSite®) was placed on one of the painful legs
for 4 weeks and provided substantial reductions
in pain in the treated leg as compared with in
the untreated leg.
Low-intensity laser therapy improved weekly
mean pain scores in 50 patients with diabetic
neuropathy when compared with sham therapy.33
In a small, 27-patient, sham-controlled, doubleblind study, near-infrared therapy improved
sensations in the feet of diabetic patients by
decreasing both the number of insensitive sites
and neuropathic pain symptoms as measured
with the Michigan neuropathy screening instrument.34 Pain decreased on a 10-point VAS, from
4.2 at initiation to 3.2 after six treatments, and
to 2.3 after 12 treatments (P <0.03).
Alternative and Complementary
Medicines
Herbal and dietary supplements for treating
chronic neuropathic pain have not been extensively studied. The few studies available involved
patients with diabetic neuropathy, except for one
randomized controlled trial using St. John’s wort.
St. John’s wort was evaluated against placebo
in a trial of 94 patients with polyneuropathy.35
It was found to be more effective than placebo,
with nine of 47 patients responding to St. John’s
wort, whereas only two of 47 patients on placebo
had a complete or good response. Other agents
shown to have minimal benefit in small trials
at relieving pain in diabetic neuropathy include
alpha-lipoic acid,36-39 evening primrose oil,40,41
and vitamin B12.42,43
Prescription Drug Treatment
Prescription drugs are the best-studied treatment
for patients with neuropathic pain. Although
the drug of choice for treating neuropathic pain
remains controversial, neither opioids nor
nonsteroidal anti-inflammatory drugs (NSAIDs)
are recommended for long-term treatment. In a
recent study of 55,686 patients, more than 50%
were receiving opioids and approximately 40%
were receiving NSAIDs.44 Only five medications
are currently approved by the Food and Drug
Administration (FDA) for treating neuropathic
pain syndromes: duloxetine and pregabalin
for painful diabetic neuropathy; carbamazepine
for trigeminal neuralgia; and the 5% lidocaine
patch, gabapentin, and pregabalin for postherpetic neuralgia. However, gabapentin, pregabalin,
tricyclic antidepressants (TCAs), serotonin and
norepinephrine reuptake inhibitors, and the 5%
lidocaine patch are recommended as first-line
therapy for neuropathic pain.3,45
Neuropathic Pain: Treatment Options Report |
9
TCAs and other antidepressants have been
used as first-line therapy for many years, and the
literature supports their use in treating neuropathic pain syndromes. Gabapentin has become
popular for treating neuropathic and other pain
syndromes, owing to its relative effectiveness and
perceived safety. Unfortunately, the antidepressants and antiepileptics may require a long titration period to reach effective therapeutic levels;
therefore, other medications, such as opioid
analgesics, tramadol, and the lidocaine 5% transdermal patch, may be more convenient to use
initially. Pregabalin was recently approved for
use in neuropathic pain management, and may
be easier to titrate than gabapentin or carbamazepine for antineuropathic activity. Other
medications to consider after first-line therapy
include other antiepileptics, antidepressants,
and analgesics. Adjuvant therapy with clonidine,
dextromethorphan, capsaicin, and mexiletine
should be considered, but results with these
agents have been mixed.
The choice of first-line agent should be based
on a patient’s comorbidities, the drug’s side
effects and contraindications, and the patient’s
clinical condition, and not on the drug’s mechanism of action.46 In patients who do not respond
to an adequate trial of a first-line agent, clinicians
should follow the recommendations listed
below:46
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■
First, change to another first-line agent with
a different mechanism of action.
■
Second, change to a second-line agent with
a different mechanism of action.
■
Third, add another first- or second-line
agent with different mechanisms of action,
considering possible synergies and potential
additive adverse reactions.
CALIFORNIA HEALTHCARE FOUNDATION
Antidepressants
Antidepressants were the first drug class proven
to treat neuropathic pain, although the mechanism by which they do so is unknown
(Table 1).47 The class as a whole can be subdivided into TCAs (e.g., amitriptyline, imipramine,
clomipramine, desipramine, doxepin, nortriptyline), selective serotonin reuptake inhibitors
(SSRIs; e.g., citalopram, fluoxetine, paroxetine,
sertraline), serotonin norepinephrine reuptake
inhibitors (SNRIs; e.g., duloxetine, venlafaxine),
and other antidepressants (e.g., bupropion,
L-tryptophan, phenelzine, trazodone). However,
duloxetine is the only antidepressant approved
by the FDA for use in treating neuropathic pain,
and even then its indication is only for diabetic
neuropathy.
A 2002 meta-analysis of 15 randomized controlled trials investigating the use of nine antidepressants in 359 patients found antidepressants
to be substantially more effective than placebo in
relieving pain in patients with diabetic neuropathy or postherpetic neuralgia.48 Antidepressants
provided at least 50% pain relief in 69% of
patients with diabetic neuropathy, whereas
placebo provided similar relief in only 39% of
patients. In postherpetic neuralgia, 59% of
patients taking antidepressants experienced 50%
pain relief, whereas 10% of placebo patients
had at least 50% pain relief. TCAs effectively
relieved pain, but SSRIs were statistically not
more effective than placebo.
A 2005 Cochrane Review identified 50 studies
evaluating the effect of antidepressants in relieving neuropathic pain among 2,515 patients.35
TCAs were evaluated in 25 randomized, placebocontrolled trials, 14 of which had measures of
pain relief, allowing a meta-analysis of these
studies. TCAs were significantly better than
placebo (relative risk [RR]: 2.37; 95% confidence
interval [CI]: 1.96 to 2.87). Three of these
studies—two evaluating human immunodefi-
ciency virus (HIV)-related neuropathies and one
evaluating chronic intractable pain without a
specific organic cause—found no benefit of TCAs
over placebo in relieving pain. Amitriptyline,
the most studied TCA, had a number needed to
treat (NNT)* of 2.0 (95% CI: 1.7 to 2.5), with
doses ranging up to 150 mg/day for moderate
pain relief.
Four trials found SSRIs to be superior to placebo
in relieving idiopathic facial pain (one study in
98 patients receiving fluoxetine 20 mg or 40 mg)
and diabetic neuropathy (three studies: one study
of 54 patients receiving fluoxetine 20 mg or 40
mg and two small studies of patients taking
citalopram 40 mg or paroxetine 40 mg).35 One
small study of 26 patients compared paroxetine
40 mg with imipramine in doses of up to 350
mg/day and found that both drugs reduced
diabetic neuropathy better than did placebo.
In the same Cochrane Review, other antidepressants were compared with placebo in eight
trials, five of which had pain relief measures that
allowed for meta-analysis.35 Intention-to-treat
analysis found a significant effect for antidepressants over placebo (RR: 2.31, 95% CI: 1.61 to
3.31). Three of the five studies found other antidepressants to be superior to placebo (one study
of 40 patients with atypical facial pain taking
phenelzine, one study of 82 patients with
different neuropathic pain syndromes taking
bupropion, and one study of 94 patients with
polyneuropathy taking St. John’s wort).
The SNRIs duloxetine and venlafaxine are
efficacious in patients with diabetic neuropathy,
and their use is supported by findings from
randomized controlled trials. Duloxetine, 60 mg
and 120 mg daily, significantly reduced weekly
average pain scores, night pain scores, Brief Pain
Inventory severity scores, and interference scores
(P <0.05) in patients with diabetic neuropathy.49
Another randomized controlled trial of patients
with diabetic neuropathy also found that duloxetine significantly improved the worst pain severity and night pain scores (P = 0.01).50 However,
patients taking duloxetine 60 mg daily or 60 mg
twice daily reported significantly more nausea,
vomiting, constipation, somnolence, hyperhidrosis, and anorexia than did those receiving placebo. These adverse effects led to a withdrawal of
2.6%, 4.3%, and 12.1% of patients receiving
placebo, duloxetine 60 mg daily, and duloxetine
60 mg twice daily, respectively (P = 0.05).50
Venlafaxine, in one study of patients with
diabetic neuropathy, was associated with a percentage reduction from baseline in VAS pain
intensity of 27% with placebo, 32% with the
75-mg dose, and 50% with the 150- to 225-mg
dose (P <0.001 vs. placebo).51 In another study
of venlafaxine compared with imipramine,
venlafaxine was found to be efficacious (sum of
the individual pain scores during Week 4 of
treatment was lower with venlafaxine [80% of
baseline score, P = 0.006] and imipramine [77%,
P = 0.001] compared with placebo [100%]).51,52
There was no statistical difference between venlafaxine and imipramine (P = 0.44 for use in
painful neuropathies).
In a 2005 review of pharmacologic agents used
to treat neuropathic pain, 26 trials of antidepressants found that TCAs with norepinephrine and
serotonin reuptake properties (e.g., amitriptyline,
imipramine, clomipramine) were more efficacious than TCAs with primarily norepinephrine
properties (e.g., desipramine, nortriptyline) for
both painful polyneuropathies (NNT: 2.1 [95%
CI: 1.8 to 2.6] vs. 2.5 [95% CI: 1.9 to 3.6]) and
for postherpetic neuralgia (NNT: 2.5 [95% CI:
1.8 to 3.9] vs. 3.1 [95% CI: 2.2 to 5.5]).45 The
SSRIs had an overall NNT of almost 7 and the
SNRI venlafaxine had an NNT of almost 4 for
painful polyneuropathies.45
* The number needed to treat (NNT) is the number of
patients that need to be treated to prevent one additional
unwanted outcome (e.g., death, stroke).
Neuropathic Pain: Treatment Options Report |
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Table 1. Probable Mechanisms of Action of Pharmacologic Agents Used
to Treat Neuropathic Pain47
Medication
Mechanism of Action
Antidepressants
Tricyclic antidepressants
Norepinephrine and or serotonin reuptake inhibitors in the
descending pathway and sodium channel modulators in the PNS
Serotonin norepinephrine
reuptake inhibitors
Serotonin and norepinephrine reuptake inhibitors in the
descending pathway
Selective serotonin
reuptake inhibitors
Selective serotonin reuptake inhibitors in the descending
pathway
Antiepileptics
Carbamazepine
Sodium channel modulator affecting PNS
Gabapentin
Calcium channel inhibitor affecting CNS
Lamotrigine
Sodium and calcium channel modulator affecting PNS and CNS
Levetiracetam
Calcium channel inhibitor affecting CNS
Oxcarbazepine
Sodium and calcium channel modulator affecting PNS and CNS
Phenytoin
Sodium channel modulator affecting PNS
Pregabalin
Calcium channel inhibitor affecting CNS
Topiramate
Sodium channel modulator affecting PNS
Opioids
All
Opioid receptors (m, d, and k) in the descending pathway
Methadone
NMDA-glutamate antagonist affecting CNS
Tramadol
Opioid m receptor and weak inhibition of norepinephrine and
serotonin reuptake in the descending pathway
Anesthetics
Lidocaine
Sodium channel modulator affecting PNS
Mexiletine
Sodium channel modulator affecting PNS
Others
Capsaicin
Initial short-term vanilloid receptor activation, then long-term
calcium-dependent desensitization
Dextromethorphan
NMDA-glutamate antagonist affecting CNS
Ketamine
NMDA-glutamate antagonist affecting CNS
Memantine
NMDA-glutamate antagonist affecting CNS and sodium
channel modulator affecting PNS
CNS, central nervous system; NMDA: N-methyl D-aspartate; PNS, peripheral nervous system.
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CALIFORNIA HEALTHCARE FOUNDATION
The majority of side effects experienced by
patients taking antidepressants are antimuscarinic
effects (e.g., dry muth, constipation, blurred
vision) and central nervous system effects (e.g.,
dizziness, somnolence, gait disturbance).48
Amitriptyline and clomipramine have the greatest affinity for muscarinic receptors and therefore
the greatest propensity for causing antimuscarinic
adverse effects.46 This affinity is less with TCAs
such as nortriptyline and desipramine.46 A 2005
meta-analysis of 50 trials in 2,515 patients treated
with antidepressants found that the number
needed to harm (NNH)** for a minor adverse
event was 4.6, whereas the NNH for major
adverse events was 16.35 To minimize adverse
events and to increase patient adherence, TCAs
should be initiated at a low dose, titrated every
3 to 7 days, and given as a single dose before
bedtime, as tolerated.3,53 The SSRIs and SNRIs
have fewer adverse effects, are less sedating, and
are usually better tolerated than are the TCAs.54,55
Table 2 has more details on the dosing of
antidepressants.3,46,56-65
The TCAs should be used with caution in the
elderly because of anticholinergic and cardiovascular adverse effects, as well as the potential
to cause balance problems and cognitive impairment.3 These drugs must also be used with
caution in patients at risk of overdose, or who
have glaucoma, hypertension, or cardiac abnormalities.3,46 Duloxetine should be used with
caution in patients with hepatic insufficiency
because of markedly decreased metabolism and
an increased risk of liver toxicity.46,66
Antiepileptics
Antidepressants and antiepileptics have been
used for years to treat neuropathic pain,
but which class should be first-line remains
uncertain. Systematic reviews have found no
differences in efficacy or in the incidence of
adverse events between them in relieving diabetic
neuropathy.48,67 Carbamazepine is FDA approved
for treating trigeminal neuralgia, gabapentin
is approved for treating postherpetic neuralgia,
and pregabalin is approved for treating diabetic
peripheral neuropathy and postherpetic neuralgia. Most use of antiepileptics for treating pain,
however, is “off label.” Other antiepileptic agents
used in treating neuropathic pain include lamotrigine, tiagabine, topiramate, oxcarbazepine,
valproic acid, zonisamide, and phenytoin. See
Table 3 for a summary of the evidence for the
efficacy of different antiepileptic medications for
different types of neuropathic pain.3,45,68,69
Intraclass Comparisons Among Antiepileptics
An extensive review of the safety, efficacy, and
tolerability of antiepileptics was recently completed by the Oregon Evidence-based Practice
Center’s Drug Effectiveness Review Project
(DERP).70 The DERP report concluded that
most of the fair-quality trials of neuropathic pain
proved the efficacy of gabapentin, with little
or no evidence to support the use of other
antiepileptics for use in neuropathic pain. In
terms of adverse events, no strong conclusions
regarding differences between antiepileptic
medications could be drawn. Carbamazepine,
phenytoin, and gabapentin all had similar safety
and tolerability. Limited, indirect evidence found
gabapentin to be better tolerated than lamotrigine, although the evidence for lamotrigine
was inconsistent. The evidence was insufficient
to determine whether one antiepileptic drug was
more effective or associated with fewer adverse
events based on patient characteristics, other
medications, or comorbidities.
** The number needed to harm (NNH) is the number of
patients that will likely be treated for each patient who
experiences an adverse event from the treatment.
Neuropathic Pain: Treatment Options Report |
13
Table 2. Dosing Guidelines for Agents Used to Treat Neuropathic Pain3,46,56 -65
Drug
FDA-Approved Indication
Other Evidence-Based Indications
Dose
Diabetic peripheral neuropathic pain,
postherpetic neuralgia, poststroke
pain, postmastectomy pain syndrome, other painful neuropathies;
except HIV-related neuropathies,
pain from spinal cord injuries,
cisplatin-induced neuropathy, and
chronic intractable pain without
specific organic cause
10 to 25 mg/day as a
single dose before bedtime;
titrate up by 10 to 25 mg/
day every 3 to 7 days, as
tolerated, to a maintenance
dose of 75 to 150 mg/day
as a single dose before
bedtime
Antidepressants
Tricyclic antidepressants
Not applicable
Amitriptyline
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
Serotonin norepinephrine reuptake inhibitors
Diabetic peripheral neuropathic pain,
Diabetic peripheral
Duloxetine
postmastectomy pain syndrome,
neuropathic pain
other painful neuropathies
Diabetic peripheral neuropathic pain
75 to 225 mg/day
Diabetic peripheral neuropathic pain
20 to 40 mg/day
Trigeminal
neuralgia
Diabetic peripheral neuropathic pain
100 mg BID; titrate up as
tolerated by 100 mg BID
to 400 to 800 mg/day
divided BID
Gabapentin
Postherpetic
neuralgia
Postherpetic neuralgia, diabetic
peripheral neuropathic pain, mixed
neuropathic pain syndromes,
phantom-limb pain, Guillain-Barré
syndrome, acute and chronic neuropathic pain from spinal cord injuries
100 to 300 mg/day as single
dose before bed or divided
TID; titrate up by 100 to 300
mg/day divided TID as tolerated every 1 to 7 days to
maximum of 3,600 mg/day
divided TID
Lamotrigine
Not applicable
HIV sensory neuropathy, diabetic
peripheral neuropathic pain, central
poststroke pain, neuropathic pain
from spinal cord injuries
25 mg/day; titrate up as
tolerated to maximum dose
of 400 mg/day
Oxcarbazepine
Not applicable
Diabetic peripheral neuropathic pain
300 mg BID; titrate up every
3 days as tolerated by 300
mg/day to 600 mg BID
Venlafaxine ER
Not applicable
Selective serotonin reuptake inhibitors
Citalopram
Not applicable
Paroxetine
Antiepileptics
Carbamazepine
14 |
40 to 60 mg/day
CALIFORNIA HEALTHCARE FOUNDATION
Table 2. Dosing Guidelines for Agents Used to Treat Neuropathic Pain (cont.)3,46,56 -6
Drug
FDA-Approved Indication
Other Evidence-Based Indications
Dose
Diabetic peripheral
neuropathic pain,
postherpetic
neuralgia
Diabetic peripheral neuropathic pain,
postherpetic neuralgia
150 mg/day; double dose
every 7 days as tolerated
to 300 to 600 mg/day
Topiramate
Not applicable
Diabetic peripheral neuropathic pain
50 mg/day; titrate every
7 days as tolerated to
200 mg BID
Zonisamide
Not applicable
Diabetic peripheral neuropathic pain
100 mg/day; titrate up
every 7 days by 100 mg/day
as tolerated up to maximum
of 600 mg/day, can be
divide BID
Oxycodone CR
Morphine CR
Not applicable
Postherpetic neuralgia, diabetic
peripheral neuropathic pain, phantom-limb pain
Initiate with short-acting
opioid 5 to 15 mg every
4 hours; after 1 to 2 weeks
of treatment, total the
patient’s daily dosage of
short-acting analgesic and
convert to one of the
long-acting opioids
Methadone
Not applicable
Painful neuropathies
10 to 20 mg/day as a single
dose
Tramadol
Not applicable
Diabetic peripheral neuropathic pain,
painful neuropathies
50 mg/day to BID; titrate
up by 50 to 100 mg/day,
divided doses, every 3 to
7 days as tolerated to a
maximum of 100 mg QID
Lidocaine
Postherpetic
neuralgia
Diabetic peripheral neuropathic pain,
painful neuropathies
Maximum of three patches
daily placed over painful
sight for 12 hours; no
titration
Capsaicin
Postherpetic
neuralgia
Diabetic peripheral neuropathic
pain as adjunctive therapy, painful
neuropathies
Apply 0.075% cream to
painful area three to four
times daily
Antiepileptics
Pregabalin
Opioids
Anesthetics
FDA, Food and Drug Administration; HIV, human immunodeficiency virus.
Neuropathic Pain: Treatment Options Report |
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The text that follows is intended to supplement the
DERP report:
A 2002 meta-analysis of five trials investigating
three antiepileptics in 456 patients found
antiepileptics to be more effective than placebo
in relieving pain in patients with diabetic neuropathy or postherpetic neuralgia.48 Antiepileptics
provided at least 50% pain relief in 63% of
patients with diabetic neuropathy, whereas placebo provided such relief in only 24% of patients.
In a single trial of gabapentin, 43% of 229
patients with postherpetic neuralgia experienced
50% pain relief, whereas 12% of patients receiving placebo reported at least 50% pain relief.48
Gabapentin, phenytoin, or carbamazepine did
not differ from placebo in the incidence
of major adverse events, but both gabapentin
and phenytoin were associated with higher incidences of minor adverse events than was placebo.
Data on carbamazepine and its minor adverse
events were unavailable.
A 2005 Cochrane Review of 12 studies in 404
patients found that carbamazepine relieved
chronic neuropathic pain in approximately 66%
of patients.69 In small studies, carbamazepine
was effective in treating trigeminal neuralgia,
diabetic neuropathy, postherpetic neuralgia, and
poststroke pain. The combined NNT for moderate pain relief was 2.5 (95% CI: 1.8 to 3.8).
The NNH for major harm did not differ from
that of placebo.15 The NNH for minor harm
with the use of carbamazepine was 3.7 (95%
CI: 2.4 to 7.8).
Another 2005 Cochrane Review of 15 studies
in 1,468 patients found that approximately 40%
of patients who took gabapentin experienced
effective neuropathic pain relief.68 Gabapentin
was effective in postherpetic neuralgia, diabetic
neuropathy, cancer-related pain, phantom-limb
pain, Guillain-Barré-related pain, spinal cord
injury pain, and various neuropathic pain
syndromes. The combined NNT for moderate
pain relief in this meta-analysis with the use of
gabapentin was 4.3 (95% CI: 3.5 to 5.7). The
NNH for major harm was not significantly
different than that for placebo. The NNH for
minor harm was 3.7 (95% CI: 2.4 to 5.4).
Table 3. Evidence for the Efficacy of Different Antiepileptics for
Different Types of Neuropathic Pain3,45,68,69
Type of
Neuropathic Pain
EVIDENCE FOR EFFICACY
Carbamazepine
Gabapentin
Lamotrigine
Pregabalin
Postherpetic neuralgia
✚
✚✚
–
✚✚
Diabetic neuropathy
✚
✚✚
✚✚
✚✚
Trigeminal neuralgia
✚✚
–
✚
–
✚✚ good evidence for efficacy based on multiple randomized controlled trials or meta-analyses
✚ weak evidence of efficacy based on few randomized controlled trials
– not tested or studied
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The antiepileptic pregabalin is a newer agent
for treating neuropathic pain, and it therefore
has not yet been evaluated in meta-analyses. In a
recent review of drugs for treating neuropathic
pain, pregabalin in doses of 150 to 600 mg had
a combined NNT for postherpetic neuralgia
and diabetic neuropathy of 4.2 (95% CI: 3.4 to
5.4).45 The combined NNH leading to withdrawal of pregabalin was 11.7 (95% CI: 8.3 to 19.9).
As a result of side effects, such as dizziness, somnolence, and other central nervous system
adverse effects, pregabalin should be used with
caution in patients with depression or in those
with fall or balance problems.46
The mechanisms by which this drug class provides pain relief are unclear, and although some
block sodium channels and others block calcium
channels, they have multiple mechanisms
(Table 1).47 The most common adverse effects
for this drug class include edema, weight gain,
diarrhea, dizziness, headache, nausea, rash,
and somnolence.48 However, more important
adverse effects can include severe hematologic,
endocrinological, hepatic, metabolic, and dermatologic reactions. To decrease the incidence of
adverse effects and to increase patient adherence,
the dose of most antiepileptics should be started
low and titrated slowly (Table 2).3,46,56-65
Multiple randomized controlled trials show lamotrigine to be efficacious in treating HIV-related
sensory neuropathy, diabetic neuropathy, and
central poststroke pain.3,45 In a recent review of
drugs for neuropathic pain, lamotrigine had an
NNT of 2.1 (95% CI: 1.3 to 6.1) for trigeminal
neuralgia as add-on therapy to carbamazepine or
phenytoin, and an NNT of 4.0 (95% CI: 2.1 to
42.0) for diabetic neuropathy.45 Lamotrigine is
not considered a first-line agent because it must
be titrated slowly to minimize the risk of rash
and Stevens-Johnson syndrome.3
Opioids
Another treatment option for neuropathic pain
is opioids, several of which are available by prescription. The potency, speed of onset, and
duration of activity differ between each drug.
Examples of opioid analgesics studied for the
treatment of neuropathic pain include oxycodone, morphine, methadone, levorphanol,
codeine, and meperidine. Opioid analgesics
that are partial agonists-antagonists can simultaneously produce analgesia and precipitate
withdrawal. Examples of these drugs include
buprenorphine, butorphanol, nalbuphine,
and pentazocine. However, their use in chronic
neuropathic pain has not been well studied.
The use of methadone could have possible
advantages over other opioids as a result of its
NMDA receptor effect.71,72 See Table 1 for
additional information on the mechanism of
action of opioids.47
Because antiepileptics have multiple mechanisms
of action, nonresponse to one antiepileptic does
not mean nonresponse to the entire drug class.3,47
Gabapentin and pregabalin are recommended
as the first-line antiepileptics for treating neuropathic pain because they are the most well
studied and the most tolerable.45 Lamotrigine is
recommended as the second-line antiepileptic
for neuropathic pain.3 Other second-line antiepileptics include carbamazepine and phenytoin.3
Other antiepileptic medications (e.g., levetiracetam, oxcarbazepine, tiagabine, topiramate,
zonisamide) remain alternatives for patients who
do not respond to the other agents, primarily
because randomized placebo-controlled trials of
these drugs have been limited.3
The goal of opioid use in treating chronic
neuropathic pain is to decrease pain and improve
patient function.54 A European expert panel
recommends that opioids should not be used as
monotherapy in treating chronic noncancer
pain.73 Combining the use of opioids with other
pain therapies will optimize therapy and reduce
the need for opioids.73
Neuropathic Pain: Treatment Options Report |
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A 2005 systematic review of opioid analgesics
for treating neuropathic pain of nonmalignant
origin identified eight intermediate-length trials
(median, 28 days; range, 8 to 56 days), all of
which documented the efficacy of long-acting
morphine, oxycodone, and methadone in
treating neuropathic pain.74 Six of these trials,
combined in a meta-analysis, showed a significant reduction in pain intensity after opioid
treatment, as compared with placebo (14 points
lower on a VAS scale, 95% CI: -18 to -10 points,
P <0.001).
In a 2005 review of pharmacologic agents for
treating neuropathic pain, 11 trials examined
opioids and found morphine to be superior to
placebo for treating postherpetic neuralgia,
phantom-limb pain, and painful diabetic neuropathy (NNT: 2.5, 95% CI: 1.9 to 3.4), whereas
oxycodone was superior to placebo for treating
postherpetic neuralgia and diabetic neuropathy
(NNT: 2.6, 95% CI: 1.9 to 4.1).45 The NNH
was nonsignificant for both agents compared
with placebo. Codeine, meperidine, and levorphanol for treating neuropathic pain have only
been studied in short-term (less than 24 hours),
randomized controlled trials.
The most common adverse effects of opioids
reported in a recent meta-analysis include nausea
(NNH: 3.6), vomiting (NNH: 6.2), constipation
(NNH: 4.6), drowsiness (NNH: 5.3), and dizziness (NNH: 6.7).54 Tolerance to these adverse
effects occurs with time, except for constipation.
More serious adverse effects include respiratory
depression and addiction.
Treatment with an opioid analgesic should be
initiated with a short-acting medication in an
equianalgesic dose to morphine sulfate, 5 to
15 mg given orally every 4 hours.3 After titrating
the dose to achieve pain relief, followed by
1 to 2 weeks of stabilization, the total daily dose
should be converted to a long-acting opioid
analgesic. See Table 2 for additional dosing
information.3,46,56-65
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Unfortunately, fear of abuse and addiction
are still concerns when using opioids for treating
chronic pain. Further randomized controlled
trials are needed to assess the long-term efficacy
and safety of chronic opioid use in neuropathic
pain.
Tramadol
Tramadol is a norepinephrine and serotonin
reuptake inhibitor with a metabolite that acts as
a µ opioid agonist (Table 1).47 It is another
alternative for treating neuropathic pain. The
most common adverse events include dizziness,
nausea, constipation, somnolence, and orthostatic hypotension.3 More severe adverse effects
include serotonin syndrome and an increased risk
of seizures in patients with a history of seizures,
or in patients also taking medications that lower
the seizure threshold (e.g., SSRIs, TCAs, other
pain medications, muscle relaxants).3 To decrease
the incidence of adverse effects and to increase
patient adherence to treatment, therapy should
be initiated at a low dose.3 See Table 2 for
additional dosing information.3,46,56-65
A 2004 Cochrane Review of five trials concluded
that tramadol is effective in treating neuropathic
pain.76 Three trials found a significant reduction
in neuropathic pain with tramadol compared
with placebo. Two of these trials were combined
into a meta-analysis (n = 161), which revealed an
NNT of 3.5 (95% CI: 2.4 to 5.9) to achieve
at least a 50% reduction in pain relief. The
NNH for adverse effects resulting in withdrawal
from the study was 7.7 (95% CI: 4.6 to 20.0).
The remaining two trials compared tramadol
with clomipramine and morphine; however, the
authors concluded that there was insufficient
evidence to determine the efficacy of tramadol as
compared with clomipramine or morphine.
A 2005 review of drugs for treating neuropathic
pain included two trials of tramadol for treating
painful polyneuropathy and one trial for treating
postherpetic neuralgia.45 The pooled NNT for
pain relief was 3.9 (95% CI: 2.7 to 6.7) and the
overall NNH was 9.0 (95% CI: 6.0 to 17.5).
Anesthetics
The use of systemic local anesthetics with an
analgesic effect when given orally or parentally
is another treatment option for people with
neuropathic pain. Safety concerns limit the
medications with local anesthetic properties
administered for chronic neuropathic pain to
lidocaine, mexiletine, and flecainide. See Table 1
for their mechanisms of action.47 Lidocaine is a
first-line option because of its excellent safety
profile and tolerability.3,45 It can be administered
intravenously or topically by patches or cream,
and the 5% lidocaine patch is FDA approved for
use in postherpetic neuralgia. Flecainide and
mexiletine are oral antiarrhythmics with local
anesthetic properties.
A 2005 Cochrane Review of 32 controlled
clinical trials found intravenous lidocaine and
oral mexiletine to be superior to placebo.77
Limited evidence indicates no difference in
efficacy or adverse event rates when compared
with carbamazepine, amantadine, gabapentin, or
morphine. Pre- and post-treatment pain scores
were available from 11 lidocaine and nine mexiletine trials (n = 750). Both lidocaine and mexiletine, when compared with placebo, reduced
chronic neuropathic pain in both the random
and fixed-effects models (weighted mean difference: -11 mm [on a 0- to 100-mm VAS], 95%
CI: -15 to -7 mm, P <0.0001). The intravenous
dose of lidocaine varied among studies from
1 to 5 mg/kg. The dose of mexiletine ranged
from 300 to 1,200 mg/day, with a median dose
of 600 mg/day.
In a recent review of drugs for treating neuropathic pain, mexiletine had mixed results, lacking
efficacy in HIV-related neuropathy, spinal cord
injury, and neuropathic pain dominated by allodynia.45 The overall NNT for diabetic neuropathy was nonsignificant, but in peripheral nerve
injury was 2.2 (95% CI: 1.3 to 8.7). Topical 5%
lidocaine gel applied directly to the painful skin
area improved postherpetic neuralgia in a small,
double-blind, randomized controlled trial of
39 patients.77 For cranial postherpetic neuralgia,
lidocaine gel was applied to 16 patients without
occlusion for 8 hours, and all patients reported
pain relief at 30 minutes and at 2, 4, and 8
hours. For torso or limb postherpetic neuralgia,
lidocaine gel was applied to 23 patients with
occlusion for 24 hours, and decreased pain
intensity was reported at 8 hours; the 23 patients
reported pain relief and decreased pain intensity
at 24 hours.
The lidocaine patch has established efficacy in
postherpetic neuralgia,78,79 although there is
limited evidence to support its use in refractory
neuropathic pain conditions (e.g., post-thoracotomy pain, stump neuroma pain, diabetic
polyneuropathy, intercostal neuralgia, postmastectomy pain).80 Of 32 patients with postherpetic
neuralgia, the topical lidocaine patch was preferred by 25, the placebo patch by three, and
four had no preference (P <0.001).79 The other
randomized controlled trial in 35 patients
with postherpetic neuralgia found a significant
reduction in VAS pain scores at all time periods
from 30 minutes to 12 hours after application,
compared with observational treatment
(P <0.001 to P = 0.02, depending on the time
period) and a significant reduction in VAS pain
scores at 4, 6, 9, and 12 hours after lidocaine
patch application, compared with vehicle
(placebo) patch (P <0.001 to P = 0.04).78
Neuropathic Pain: Treatment Options Report |
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The lidocaine patch is placed directly over the
area of pain and can be cut to fit if needed.3,54
Three patches can be applied simultaneously for
12 hours in any 24-hour period. The most
common adverse effects of topical lidocaine are
minimal because accumulation does not occur
with a dosing schedule of 12 hours on, 12 hours
off.3 These adverse effects are limited to localized
skin reactions (e.g., erythema, rash, swelling) and
usually dissipate within 3 hours after the anesthetic is removed from the skin.3,54 Mexiletine has
proarrhythmic effects and adverse events that
often limit its use at high doses. See Table 2 for
additional information on dosing.3,46,56-65
Capsaicin
Several other topical analgesics have been studied
for use in neuropathic pain, including EMLA
cream (a mixture of the local anesthetics lidocaine 2.5% and prilocaine 2.5%), which is no
longer available, and capsaicin. Capsaicin is
FDA approved for use in postherpetic neuralgia.
Topical capsaicin is a last-line alternative according to an expert panel citing clinical experience
and inconsistent clinical trial results.3
A 2004 systematic review of six double-blind,
placebo-controlled trials of 656 patients found a
relative benefit of 1.4 (95% CI: 1.2 to 1.7) and
an NNT of 5.7 (95% CI: 4.0 to 10.0) in patients
who had a 50% reduction in pain who were
receiving topical capsaicin 0.075%, as compared
with placebo, for a variety of neuropathic pain
conditions.65 Approximately 54% of patients
using capsaicin experienced local adverse events,
compared with 15% of placebo-treated patients.
The NNH for a patient with a local adverse
event to capsaicin was 2.5 (95% CI: 2.1 to 3.1).
In a recent review of drugs for treating neuropathic pain, topical capsaicin was efficacious in
three of five trials for postherpetic neuralgia, diabetic neuropathy, nerve injury pain, and mixed
neuropathic pains, with a combined NNT of
6.7 (95% CI: 4.6 to 12.0) and an NNH of 11.5
(95% CI: 8.1 to 19.8).45
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CALIFORNIA HEALTHCARE FOUNDATION
Capsaicin is a compound found in chili peppers.
It may bind to nociceptors in the skin, causing
excitation of neurons and a period of increased
sensitivity often perceived as itching, pricking, or
burning as a result of vasodilation.64 This sensation is followed by a period of reduced sensitivity
and, with repeated applications, persistent desensitization. See Table 1 for additional information
of mechanisms of action.47 Adverse effects to
this medication are specific to the application site
and include burning, stinging, and erythema.64
Systemic effects are rare. See Table 2 for dosing
information.3,46,56-65
Other Drug Treatment Options
Other treatments for neuropathic pain are lastline options because of mixed findings in a few,
small clinical trials. These treatments include a2adrenergic agonists, clonidine or tizanidine,
NMDA antagonists, dextromethorphan, and
memantine or ketamine. In a recent review of
drugs for treating neuropathic pain, high-dose
dextromethorphan was efficacious in treating
diabetic neuropathy, having an NNT of 2.5
(95% CI: 1.6 to 5.4); however, it was not
effective in treating postherpetic neuralgia, and
had an NNH of 8.8 (95% CI: 5.6 to 21.1).45
Memantine, in doses of 20 to 30 mg daily, is not
efficacious for treating postherpetic neuralgia,
diabetic neuropathy, and phantom-limb pain.
III. Summary
A
BETTER UNDERSTANDING OF THE
pathophysiologic mechanisms of neuropathic pain will
help define individual treatments. Untreated, persistent
neuropathic pain damages the nervous system and causes
impairment and disability. It may also precipitate
disabling emotions and psychosocial or other medical
comorbidities. Therapy should be determined by diagnosis, response to previous therapies, pain mechanisms,
adverse-effect profiles, toxicity risk, possible synergy of
combination agents, ease of use, and cost. Medications
may need to be used in combination so that their different mechanisms of action can improve pain relief
and increase functional outcomes optimally.
Neuropathic Pain: Treatment Options Report |
21
Appendix 1. Pathophysiology
ALONG THE COMPLEX AND MULTI-TIERED
response, multiple receptors and secondary messenger
chemicals come into play.14 An incomplete list includes:
■
Neurotransmitters: substance P, glutamate, acetylcholine,
aspartate, calcitonin gene related peptide, serotonin,
norepinephrine, calcium, g-aminobutyric acid (GABA),
glycine
■
Ion channels: sodium, potassium, chloride, calcium
■
Excitatory receptors: NK1, NK2, glutamate NM,
glutamate KA, glutamate AM, N-methyl D-aspartate
(NMDA), DL-a-amino-3-hydroxy-5-methyl-isoxazole
propionic acid (AMPA), serotonin (5HT)
■
Inhibitory receptors: GABA-A, GABA-B, glycine,
magnesium, serotonin (5HT), acetylcholine M, acetylcholine N, norepinephrine (a-2)
■
Other mechanisms: prostaglandin E2-mediated inflammation, cyclooxygenase (COX) 1 and 2-mediated
sensitization, nitric oxide, opioid receptor.
For as yet unknown reasons, even a trivial trauma can lead
to a variety of peripheral, central, and even autonomic nervous
system processes leading to persistent pain and neural dysfunction.3 Peripheral sensitization, characterized by hyperexcitable
afferent nociceptors, may result. This state is initially heralded
by local hyperalgesia in the primary receptive zone, which,
by itself, is not abnormal. However, in certain circumstances,
centrally mediated inhibition fails to prevent facilitation and
persistence of the nociceptive input, and receptive neural structures become hyperexcitable. This state of central sensitization
then leads to altered processing of non-nociceptive stimuli with
conversion to the sensation of pain. Ectopic and spontaneous
discharges, ephaptic transmission, abnormal neuronal sprouting, and reorganization of the dorsal root ganglia may be the
resultant peripheral changes, whereas spinal receptive field
reorganization, cortical reorganization, and altered descending
inhibition may result from segmental central sensitization.2
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CALIFORNIA HEALTHCARE FOUNDATION
Some of these actions may be related to actual
remodeling of the dorsal horn of the spinal cord
with alterations of the standard nerve transmission pathways at multiple levels, especially the
laminae of the substantia gelatinosa.15-17A result
of such reorganization is related to the “wind-up”
phenomenon, in which the temporal summation
of noxious stimulation via C fibers leads to a
gradually increased perception of pain (hyperpathia). 7 The above changes are examples of the
plasticity of the peripheral, central, and autonomic nervous systems in response to persistent
pain signaling. The goal of all therapies is to
minimize, ablate, or reverse such neuroplastic
changes that contribute to chronic and ongoing
pain states.
Conditions associated with the development
of neuropathic pain include trauma, neurovascular events, neurodegenerative diseases, metabolic
deficiencies and disease processes, neurovascular
compression, inflammation, and tumor effects.
History, physical examination, and diagnostic
testing may reveal classic time courses and
findings for many syndromes, such as painful
diabetic peripheral neuropathy, postherpetic
neuralgia, or post-thalamic stroke pain. Although
confirming a neurological lesion helps to confirm
a suspicion of neuropathic pain, current diagnostic methods and technology cannot identify a
focus in many patients, so neuropathic pain cannot be excluded from the differential diagnosis.3
Neuropathic Pain: Treatment Options Report |
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Appendix 2. Assessment
SEVERAL NEUROPATHIC PAIN SCALES AND SHORT
inventories have been developed from larger generalized questionnaires. Although not as simple to use as the Faces Scale
by Bieri or the visual analog scale (VAS), the following tools
also provide information that may help to determine pathophysiology or even to diagnose neuropathic pain:19
■
The Neuropathic Pain Scale (NPS) consists of ten items
that assist in determining the varying qualities of symptoms associated with neuropathic pain, and these descriptors appear to identify changes that occur with therapy.20
■
The Neuropathic Pain Symptom Inventory (NPSI) is
a similar tool used to evaluate patients with previously
suspected or diagnosed neuropathic pain.
■
The Neuropathic Pain Questionnaire (NPQ) consists
of subgrouped VASs to help distinguish neuropathic pain
from nociceptive pain.21
■
The French DN4 consists of ten questions and suggests
that a score of 4 or more is needed to diagnose neuropathic pain.22
■
The Leeds Assessment of Neuropathic Symptoms
and Signs (LANSS), a slightly more complicated tool,
also helps distinguish neuropathic pain from nociceptive
pain.23
The NPS and NPSI are used to further define and follow the
treatment of patients already diagnosed as having neuropathic
pain, whereas the LANSS, NPQ, and DN4 are more suited
to determine the presence of neuropathic pain when evaluating
patients.19
Careful neurologic examination should look for sensory or
motor deficits. Nerve conduction velocity (NCV) and electromyography (EMG) evaluations are valuable for identifying
large peripheral nerve patterns but not for those related to the
smaller myelinated (A-delta) and unmyelinated (C) sensory
fibers. Hence, EMG or NCV testing may not yield any findings in predominantly sensory-only situations. Specialized
equipment and testing procedures may be needed to quantitate
responses to tactile or thermal stimuli.3
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CALIFORNIA HEALTHCARE FOUNDATION
Anatomic imaging, such as standard radiograph
series, computed tomography, and magnetic
resonance imaging (MRI), of primary and related
structures should be performed to identify any
potential neurologic lesions and their associated
musculoskeletal or vascular structures.3,4
Functional MRI, single positron emission
computed tomography, and positron emission
tomography scanning are used in some centers
to better define functional and anatomic changes
related to both acute and chronic neuropathic
pain.3,4 Neural biopsies may be needed to further
define the anatomic pathology.
Neuropathic Pain: Treatment Options Report |
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Endnotes
1. Merskey H, Bogduk N. Classification of Chronic Pain:
Descriptions of Chronic Pain Syndromes and Definitions of
Pain Terms. 2nd ed. Seattle, Washington: IASP Press;
1994.
2. Backonja M. Defining neuropathic pain. Anesth Analg.
2003;97:785-790.
16. Swarm RA, Karanikolas M, Kalauokalani D. Pain
treatment in the perioperative period. Curr Probl Surg.
2001;38:833-920.
3. Dworkin R, Backonja M, Rowbotham M. Advances in
neuropathic pain diagnosis, mechanisms, and treatment
recommendations. Arch Neurol. 2003;60:1524-1534.
17. Terman GW, Bonica JJ. Spinal Mechanisms and
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