REVIEW ARTICLE

Neuropathic Pain and Pharmacological

Treatment

Joost L. M. Jongen, MD, PhD*,†; Guy Hans, MD, PhD‡;

Honorio T. Benzon, MD, FIPP§; Frank Huygen, MD, PhD, FIPP¶; Craig T.
Hartrick, MD, FIPP**
*Department of Neurology, Erasmus MC, Rotterdam, The Netherlands; †Department of
Anesthesiology, Erasmus MC, Rotterdam, The Netherlands; ‡Department of Anesthesiology and
Multidisciplinary Pain Center, Antwerp University Hospital, Edegem, Belgium; §Department of
Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
¶
Department of Anesthesiology and Pain Medicine, Erasmus MC, Rotterdam, The Netherlands;
**Departments of Biomedical Sciences and Anesthesiology, Oakland University William
Beaumont School of Medicine, Rochester, Michigan, U.S.A

& Abstract: Neuropathic pain is a serious chronic condition Key Words: evidence-based medicine, review, neuropathic
strongly affecting quality of life, which can be relieved but pain, clinical diagnosis, pharmacological management, poly-
cannot be cured. Apart from symptomatic management, pharmacy
treatment should focus on the underlying disorder. The
estimated prevalence is at least 1% to 5% of the general
population. Neuropathic pain is characterized both by spon-
taneous and evoked pain. A diagnosis of neuropathic pain INTRODUCTION
can usually be established based solely on history and Until recently, the International Association for the
neurological examination. Ancillary investigations may
Study of Pain (IASP) defined neuropathic pain as pain
include EMG and computerized tomography/magnetic reso-
nance imaging scans, depending on the localization of the
that is initiated or caused by a primary lesion or
suspected lesion. A limited number of agents, primarily dysfunction of the nervous system. Because normal
directed at symptom control, are currently approved for use plasticity of the nociceptive system is also included as a
in neuropathic pain. A mechanism-based approach to phar- dysfunction of the nervous system, and because only
macological intervention supports the use of polypharmacy conditions of the somatosensory part of the nervous
in neuropathic pain. & system can cause neuropathic pain, a new definition has
recently been adopted by the IASP. Neuropathic pain is
Address correspondence and reprint requests to: Joost L. M. Jongen,
now defined as pain that is a direct result of a lesion or
MD, PhD, Departments of Neurology and Anesthesiology, Erasmus Med- disease of the somatosensory system.1,2 The exact
ical Centre, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
incidence and prevalence of neuropathic pain are
E-mail: [email protected].
Disclosure: Nagy Mekhail, MD, PhD served as Editor-in-Chief for this unknown, but the overall prevalence is conservatively
manuscript. estimated to be 1% to 5% of the general population.3–5
Submitted: September 21, 2012; Revision accepted: April 26, 2013
DOI. 10.1111/papr.12085 The individual prevalence of common neuropathic pain
states has been reviewed elsewhere.6 The prevalence of
© 2013 World Institute of Pain, 1530-7085/14/$15.00
neuropathic pain that is refractory to treatment has been
Pain Practice, Volume 14, Issue 3, 2014 283–295 estimated to be 1.5% of the population.7
284  JONGEN ET AL.

Neuropathic pain can be located in the central PATHOPHYSIOLOGY

nervous system (central neuropathic pain) as well as in
Only the principal issues concerning the pathophysio-
the peripheral nervous system (peripheral neuropathic
logy of neuropathic pain are addressed here. Neuro-
pain). Table 1 presents the causes of central and
pathic pain is characterized by 2 phenomena: increased
peripheral neuropathic pain that occurs most fre-
sensitivity of neurons and abnormal impulse genera-
quently.8 Neuropathic pain may thus be regarded as a
tion.11 Increased sensitivity of neurons occurs in primary
symptom of neurological disease. It is important to
afferent neurons as well as in neurons of the central
identify this underlying disease because the optimal
nervous system. In the former case, we refer to it as
treatment of neuropathic pain consists of treatment or
peripheral sensitization, which leads to primary hyper-
prevention of the underlying disease as well as symp-
algesia, that is, increased sensitivity in the injured region
tomatic treatment of the pain. We will use a patient with
itself. The latter case is termed central sensitization,12
burning foot pain as an example. This pain may be the
which leads to secondary hyperalgesia or increased
first symptom of diabetic neuropathy and/or diabetes
sensitivity outside of the primary painful region. Abnor-
mellitus. It is obvious that symptomatic treatment of the
mal impulse generation takes place in neuromas, regen-
pain should be accompanied by regulating patients’
erating nerve fibers, spinal ganglion cells, in areas of
blood glucose levels; adherence to antidiabetic medica-
demyelination and through adjacent intact nerve fibers.
tion is associated with reduced diabetic peripheral
Abnormal impulse generation is a general characteristic
neuropathic pain.9
of neuropathic pain, explaining the efficacy of medica-
This review includes oral and topical medications for
tions that stabilize the membrane potential, including
neuropathic pain conditions. While intrathecal and
anti-epileptic drugs (AEDs) and tricyclic antidepressants
epidural pharmacological interventions are used in
(TCAs). A key role of glia in the initiation and
neuropathic pain, these techniques have been recently
maintenance of spinal neuropathic pain mechanisms
reviewed elsewhere.10
has until recently been underappreciated and cannot be
overemphasized.13 This pivotal process has recently
been extensively reviewed by Vallejo et al.14

Table 1. Neuropathic Pain CLINICAL PRACTICE

Causes of peripheral neuropathic pain
Diabetic polyneuropathy
In most cases, the diagnosis can be established by a
Alcoholic polyneuropathy combination of medical history and neurological exam-
HIV-related polyneuropathy
Chemotherapy-induced polyneuropathy
ination. Different questionnaires intended to distinguish
Polyneuropathy as a result of a systemic disease (polyarteritis nodosa, neuropathic pain from nociceptive pain, such as the
€ gren syndrome, sarcoidosis, amyloidosis)
Sjo Leeds Assessment of Neuropathic Pain Symptoms and
Idiopathic thin fiber neuropathy
 syndrome, CMV infection,
Polyradiculitis (resulting from Guillain-Barre Signs (LANSS),15 the Neuropathic Pain Questionnaire,16
Borrelia Burgdorferi infection) and Douleur Neuropathique4 (DN4),17 may be used as
Lumbar and cervical radicular syndrome caused by compression (benign/
malignant) screening instruments, but should not be relied upon
Brachial plexus/lumbosacral neuropathy (idiopathic/familial/caused by solely to establish a diagnosis of neuropathic pain.18
malignant compression/caused by radiation)
Post herpetic neuralgia
Some of these tools, such as the PainDETECT Question-
Trigeminal neuralgia naire, have also been adapted for languages other than
Traumatic neuropathy, iatrogenic neuropathy and compression
neuropathy
English.19 The sensitivity, specificity, and predictive
Dietary insufficiencies values of the different scales are indicated in Table 2.
Heavy metal exposure Apart from the usually constant spontaneous pain,
Causes of central neuropathic pain
Spinal cord injury clinical neuropathic pain is characterized by altered
Multiple Sclerosis sensitivity to sensory stimuli that may give rise to bouts
Cerebrovascular Accident
Parkinson’s disease* of evoked pain. This altered sensitivity may be classified
Tumor as hyperalgesia (increased pain from a stimulus that
Syrinx
normally provokes pain), hypoalgesia (diminished pain
*Parkinson’s disease is not a disease of the somatosensory system. The assumption is in response to a normally painful stimulus), hypoesthe-
that pain with Parkinson’s disease is caused by a dopamine deficiency in the pain
suppression center in the brain stem. Ford B. Pain in Parkinson’s disease. Clin Neurosci. sia (decreased sensitivity to stimulation), and allodynia
1998;5:63–72.
 Neuropathic Pain  285

Table 2. Validity and Reliability of the Different Neuropathic Pain Scales

Sensitivity Specificity Predictive

Scale Description Scoring (%) (%) Value (%)

LANSS15 7-item scale: 5 questions (unpleasant skin Maximum score: 24 85 80 82

sensations, appearance, increased sensitivity to Neuropathic: > 12
touch, electric-shock, or hot/burning sensations), Nociceptive: < 12
2 questions (sensory testing for allodynia and
altered pinprick threshold)
NPQ (short-form)16 3-items on a 0–100 mm scale (numbness, pain, Neuropathic: At or above 0 64.5 78.6 73
increased pain from touch) Non-neuropathic: Below 0
DN417 4 Questions (characteristics of pain, symptoms, Maximum: 10 82.9 89.9 86
presence of hypesthesia, effect of brushing) Neuropathic pain:
4 or higher

LANSS, Leeds Assessment of Neuropathic Pain Symptoms and Signs; NPQ, Neuropathic Pain Questionnaire; DN4, Douleur Neuropathique 4.

(pain due to a stimulus that does not normally provoke painful neuropathy in patients with Sj€ ogren syndrome.
pain). An example is painful diabetic neuropathy, in Secondly, the distribution of the pain may help to
which there may be bouts of shooting pain evoked by identify the underlying cause. Pain in the feet and hands
touch, superimposed on a constant spontaneous burning usually corresponds to polyneuropathy, pain along a
pain. Another characteristic of neuropathic pain is that specific dermatome implies a spinal nerve root lesion,
the pain is not limited to the region of the nerve lesion; while unilateral pain usually corresponds to a disease in
pain and/or change in sensitivity can occur in the the contralateral hemisphere of the brain.
surrounding area (secondary hyperalgesia). An example Apart from the medical history, the sensory exami-
is pain after a herpes zoster infection of Th7, which may nation as part of the whole neurological examination is
also be felt in surrounding areas such as in the Th6 and very important to establish a reliable diagnosis of
Th8 dermatome. One should be aware that this neuropathic pain. One should realize, however, that
secondary hyperalgesia is not the same as referred pain. this sensory examination is subjective; the examiner is
Referred pain is caused by convergence of (stimulated) almost completely dependent on the cooperation and
visceral primary afferent nerve fibers with (unstimu- reliability of the patient. Because most patients with
lated) dermal nerve fibers on secondary projection pain indicate sensory alterations during the neurological
neurons in the spinal cord or the brain stem.20 Conse- examination, one again (as in taking the medical history)
quently, referred pain may be distant and discontinuous should search for patterns in sensory disturbances. For
from the primary pain site. This is why patients with example, altered sensation on the anterior or lateral side
carpal tunnel syndrome often have pain not only in the of the right leg in a patient with back pain usually does
fingers but also in the forearm, upper arm, and even not imply neuropathic pain. On the other hand, tingling
occasionally in the chest. However, referred pain is not in the feet, reduced vibration perception, hot and cold
neuropathic pain, as there is no nerve lesion involved. sensory discrimination, decreased sense of movement
Although neuropathic pain may be associated with and position in the toes in a patient with diabetes
verbal descriptors like burning, shooting, electric, etc., indicate polyneuropathy. The testing of muscle strength,
pain and complaints of altered sensitivity to sensory skill, coordination, and reflexes additionally provides
stimuli and extension of the painful area are common in important information. If foot drop and absence of
neuropathic pain syndromes, this is not sufficient to ankle reflexes are found in the patient mentioned above,
establish a diagnosis of neuropathic pain.9 As an then the diagnosis of polyneuropathy is further sup-
example, a patient with tingling pain in the feet can ported. Polyneuropathy is characterized by distal atro-
suffer from ischemic pain, pain resulting from venous phy, distal muscle weakness, a stocking-glove pattern of
insufficiency, restless legs syndrome, and neuropathic sensory disturbances, and hyporeflexia.
pain. Therefore, in addition one should specifically ask
the patient about medical conditions associated with
DIFFERENTIAL DIAGNOSIS AND ADDITIONAL
neuropathy and neuropathic pain. If, for example, the
TESTING
above patient would be diagnosed with Sj€ ogren syn-
drome, then it would be very likely that the pain is The majority of patients with neuropathic pain can be
neuropathic in nature in view of the high incidence of diagnosed based on medical history and neurological
286  JONGEN ET AL.

examination alone. A diagnosis of neuropathic pain can method as it is also highly dependent on cooperation of
be rejected, and no additional testing needs to be the patient.
performed if there is absolutely no indication for neuro- Computerized tomography (CT) and magnetic res-
pathic pain based on the medical history and neurolog- onance imaging (MRI) are important diagnostic tests
ical examination. Patients eligible for additional testing in the diagnosis of central neuropathic pain. The
have a medical history that is suspicious for neuropathy intention of these tests is to identify a lesion of the
but show no objective findings on neurological exami- somatosensory system to substantiate the diagnosis of
nation. An example is a patient with nocturnal tingling in central neuropathic pain. In some cases, when central
the fingers and a normal neurological examination, neuropathic pain is suspected, psychogenic pain can-
indicative of carpal tunnel syndrome. Another group in not be completely ruled out, a CT/MRI may help
which additional testing may be considered are patients establish correct diagnosis. Functional MRI, positron
with a medical history and physical examination findings emission tomography, somatosensory evoked poten-
suggestive of polyneuropathy. In this case, EMG-NCV tials (SSEP), magneto-evoked potentials (MEP), and
may help to identify the underlying cause of polyneur- laser-evoked potentials may provide additional infor-
opathy, but is not necessary to confirm the diagnosis of mation in central neuropathic pain. With the exception
neuropathic pain. of SSEP and MEP, these techniques are not readily
A major disadvantage of EMG is its inability to assess available in most hospitals and are used mostly for
Ao fibers and C fibers, the nerve fibers that are mostly research purposes. The diagnosis of neuropathic pain
affected in neuropathic pain. Quantitative sensory is summarized in Figure 1.1
testing (QST), microneurography, or measurement of
the intra-epidermal nerve fiber density in epidermal
GENERAL METHOD OF TREATMENT
biopsies may provide additional information. These
OF NEUROPATHIC PAIN
techniques, however, are not available in most hospitals
and while often reserved only for research purposes, The treatment of painful neuropathies is twofold21,22:
clinically suitable diagnostic protocols and instruments  The primary treatment is focused on the treatment
(eg, Q-Sense; Medoc Ltd, Ramat Yishai, Israel) are of the underlying disease processes and should be
being developed. Also, QST is not an entirely objective started as quickly as possible. This approach can

Figure 1. Diagnosis of neuropathic pain. From: Treede et al.1 (With the publisher’s permission).
 Neuropathic Pain  287

lead to a clear reduction in pain. Early treatment GUIDELINES CONCERNING THE TREATMENT
of neuropathic pain can prevent the development OF NEUROPATHIC PAIN
of chronic treatment-resistant neuropathic pain
Guidelines on the pharmacological treatment of neuro-
syndromes.
pathic pain have been proposed by several groups in
 Parallel to and simultaneously with the causal
recent years. These guidelines were based on available
treatment, a symptomatic treatment should be
scientific evidence (and its consistency), degree of
started based on the patient’s symptoms. Based on
efficacy, safety, and clinical experience with the indi-
current scientific data, differences in symptom-
vidual drugs. The available guidelines for the treatment
atology should be interpreted as expressions of
of certain forms of painful neuropathy have been
distinct pathophysiological mechanisms in the
adjusted by different organizations in various countries
somatosensory nervous system. Pharmacologic
to accommodate drug availability.27–30 There are few
treatment that focuses on specific sensory symp-
differences among these various guidelines although
toms, while taking into consideration the rela-
local treatment practices were incorporated into these
tionship between pathophysiological mechanisms
guidelines. Treatment guidelines for neuropathic pain
and symptoms, should result in a more efficient
recommended by the different groups are in Table 4.
treatment (signs and symptoms based approach).
A well-respected international guideline has been
Causes of neuropathic pain syndromes could lead
proposed by NeuPSIG (Special Interest Group on
to specific pharmacological therapeutic
Neuropathic Pain of the IASP).31 In their guideline,
approaches tailored to the underlying mecha-
certain antidepressants (including TCAs and serotonin-
nism(s) present in the individual patient (mecha-
norepinephrine reuptake inhibitors [SNRIs]), certain
nism-based approach to neuropathic pain as
AEDs (more specifically those acting on a2-d subunit of
shown in Table 3). Although still somewhat
the Ca2+ channels), and topical lidocaine are proposed
preliminary, a mechanism-based treatment
as potential first-line treatment options. Opioids and
approach may prove to be successful in effective
tramadol are proposed as general second-line treatment,
treatment of neuropathic pain, but requires more
although these analgesics could also be first-line treat-
detailed insights into the persistence of cellular
ment in some cases. Other drugs belong to third-line
and molecular pain mechanisms, which renders
treatment although they can be used as second-line
neuropathic pain unremitting.23–26
treatment in some cases. These other drugs include some

Table 3. Pharmacological Treatment of Neuropathic Pain Based on the Pathophysiological Mechanism

Symptom Pathophysiological Mechanism Most Suitable Medicine

Paroxysmal shooting or Ectopic activity in nociceptive unmyelinated C fibers Anticonvulsants

stabbing pain Anti-arrhythmics
Tricyclic antidepressants
Spontaneous (continuous) Sensitization of peripheral receptors, ectopic discharges in C fibers and Topical anesthetic drugs
burning pain disconnection of descending pain-inhibiting pathways IV lidocaine or infiltration
Tricyclic antidepressants
Anticonvulsants
Dysesthesias Ectopic discharges in thick myelinated (A-ß) nerve fibers Drugs with inhibiting influence
on sodium channels
Anticonvulsants
Anti-arrhythmics
Tricyclic antidepressants
Paresthesias Spontaneous, ectopic discharges in different types of nerve fibers, Membrane-stabilizing drugs
going from A-ß fibers to the thin myelinated A-d fibers, and in the Anticonvulsants
unmyelinated C fibers Anti-arrhythmics
Tricyclic antidepressants
Allodynia Complex combination of different mechanisms, such as central Anticonvulsants
reorganization (with the implementation of ectopic impulses) of A-ß Baclofen
fibers, central sensitization of A-ß fibers, loss of descending inhibiting Opioids
control Clonidine
Tricyclic antidepressants
NMDA antagonists
Local anesthetics
288  JONGEN ET AL.

Table 4. Recommended Treatments for Neuropathic Pain Syndromes by the Canadian Pain Society, European
Federation of Neurological Sciences (EFNS), and the International Association for the Study of Pain (IASP) Neuropathic
Pain Special Interest Group (NeuroPSIG)

Group First-Line Treatment Second-Line Treatment Third-Line Treatment

Canadian Pain TCAs SNRIs Tramadol

Society, CPS29 Anticonvulsants Topical lidocaine Opioids

EFNS27 SNRI Tramadol

Pregabalin Opioids
TCAs

IASP NeuroPSIG31 SNRIs, TCAs Tramadol Antidepressants (bupropion, citalopram, paroxetine)

Gabapentin, Pregabalin Opioids Anticonvulsants (carbamazepine, lamotrigine, oxcarbazepine,
Topical lidocaine topiramate, valproic acid)
Topical low-concentration capsaicin
Dextromethorphan
Memantine
Mexiletine

SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressants.

antidepressants (bupropion, citalopram, paroxetine) The need for combination therapy may have its basis
and AEDs (carbamazepine, lamotrigine, oxcarbazepine, in the underlying pathophysiology. There is preclinical
topiramate, valproic acid), mexiletine, NMDA receptor evidence of a phenotypic shift away from predominant
antagonists including ketamine, and topical low-con- opioid sensitive pathways toward noradrenergic sensi-
centration capsaicin. The absence of a “gold standard” tive pathways in the genesis of neuropathic pain.34 This
in the treatment of neuropathic pain that is effective in may explain why opioids, while appearing to be
all patients should be taken into account.32 relatively less effective clinically in neuropathic pain
Various guidelines mention polypharmacological states, may become effective when used in combination
management of neuropathic pain syndromes. A recent with other agents such as gabapentin or pregabalin.33
Cochrane review33 provides a rationale for the use of This improved efficacy with complementary agents,
such combination therapy. Although this review has having differing mechanisms of action, could be due to
included many reports on combination therapy for the additive effects or even synergistic effects made
neuropathic pain in general, the number of studies for possible by interaction among multiple pathways.
any specific combinations, as well as the size and study Tapentadol, an agent having a dual mode of action
duration of the individual studies, presents significant with both opioid agonist and noradrenergic reuptake
methodological limitations. Taken together with inhibitory properties, has been suggested to exhibit such
increased drop-out rates from additional side effects synergism35 and has been effective in the treatment of
encountered with combination therapy, the authors some neuropathic pain states.36,37
were not able to draw any firm conclusions nor were The pharmacological treatment of cancer-related
they able to compare various combinations with one neuropathic pain has also been recently reviewed.38,39
another.33 Moreover, studies examining combinations While there has been some evidence for prediction of
of agents used topically in neuropathic pain have not neuropathic pain following chemotherapy based upon
consistently demonstrated clear benefit over topical patient characteristics,40 it is usually difficult to deter-
monotherapy (Table 5). mine which patients will develop neuropathic pain and

Table 5. Efficacy of Drug Combinations

Study Drug Condition Nature of Study Efficacy

Gilron et al. 62
Gabapentin + morphine PHN, DPN P, R, C Positive
Gilron et al.56 Gabapentin + nortriptyline PHN, DPN P, R, C Positive
Baron et al.87 Gabapentin + lidocaine plaster PHN, DPN P, R, C Positive
Hanna et al.63 Gabapentin + oxycodone DPN P, R, C Positive
Zin et al.68 Oxycodone + pregabalin PHN, DPN P, R, C No difference
Khoromi et al.54 Morphine + nortriptyline Lumbosacral radiculitis P, R, C No difference
Mercadante et al.55 Morphine + amitriptyline Neuropathic cancer pain P, R, C, Crossover No difference

C, controlled; DPN, diabetic painful neuropathy; P, prospective; PHN, postherpetic neuralgia; R, randomized.
 Neuropathic Pain  289

which medications might be most helpful in a particular In moderately severe pain syndromes, paracetamol
patient. The final choice of pharmacological treatment (acetaminophen; a centrally acting analgesic), tramadol,
should be based on the underlying pathophysiological tilidine (preferably in a sustained- or extended-release
mechanisms, immediate and potentially long-term form for more stable plasma levels and less adrenergic
adverse effects, cost of the proposed treatment, presence stimulation), nefopam, or buprenorphine43 can be used.
of comorbidity and concomitant medications. Based on A consensus statement from an international panel of
these elements, the physician should establish an experts suggested that if opioids are used for severe
individually tailored treatment plan. Until more specific neuropathic pain in the elderly, buprenorphine, a partial
pathophysiological treatments become available, this mu-opioid agonist with differing effects on other opioid
will regrettably be based on a trial-and-error approach. receptor types (kappa antagonist, delta agonist, ORL-1
Physicians should substantiate their treatment of choice partial agonist), offers some advantages.44 There is
based on available scientific evidence and mode of limited evidence to suggest that agents such as buprenor-
action of the treatment being considered. phine and tapentadol have reduced propensity to induce
tolerance compared with pure mu-opioid agonists.45
The aforementioned analgesics can be combined with
PHARMACOLOGICAL TREATMENT OPTIONS NSAIDs. Although animal models have shown efficacy
of NSAIDs in neuropathic pain,46,47 clinical studies on
Analgesics and Nonsteroidal Anti-Inflammatory Drugs
NSAIDs or COX-2 inhibitors either showed some
Nonopioid analgesics, opioid analgesics, and nonsteroi- efficacy,48,49 no efficacy,50 or equivocal efficacy.51 The
dal anti-inflammatory drugs (NSAIDs) can be of some lack of clear-cut clinical evidence on the efficacy of
use in the treatment of various types of neuropathic NSAIDs in neuropathic pain calls for randomized
pain, such as postherpetic neuralgia (PHN), diabetic studies.
polyneuropathy, and post-traumatic peripheral neurop- If inadequate analgesic effect from Class II analgesics,
athies, especially in the acute phase of these conditions. one may consider a transition to a maintenance level
These medications are, as previously mentioned, inad- treatment with opioids (Class III analgesics), although
equate as monotherapy in most patients, and a poly- opioids are only recommended as second-line medica-
pharmacological approach is necessary. In general, tions for the treatment of chronic neuropathic pain, as a
neuropathic pain syndromes are still described as being result of unknown long-term side effects, tolerance, and
“opioid resistant”, although this notion is also subject to potential opioid-induced hyperalgesia and misuse.31
much scientific debate. Recent data indeed indicate the There is currently limited evidence to select a certain
necessity for higher doses of opioids (in comparison with opioid over another based upon efficacy. However,
the doses needed for the treatment of nociceptive pain there may be significant differences in the incidence of
syndromes) to achieve a more effective analgesia. adverse effects among various opioid compounds.
Moreover, the efficacy of opioid analgesics varies As patients tend not to accommodate to constipation
strongly from one individual to another, which makes over time, as they do for most other opioid-induced
dose adjustments tailored to individual patients abso- adverse effects, drug selection for long-term opioid use
lutely necessary. Although a single gene codes for the may have pharmaco-economic implications based on
mu-opioid receptor, splice variants contribute to the differences in adverse effect profiles between opioids.37
clinical variability in response and the incomplete cross-
tolerance observed, as different agents affect the recep-
Antidepressants
tors in subtly different ways.41 This allows for potential
synergy when 2 different opioid agents are used The TCAs can be used for the treatment of neuropathic
concurrently, partly explaining the apparent synergy pain. The agents that are most commonly used in clinical
when methadone is administered along with mor- practice are amitriptyline and nortriptyline, although
phine.42 Alternatively, opioid analgesics can exhibit also imipramine, clomipramine, desipramine, maproti-
other analgesic activities in addition to their action as line belong to this group of agents and have been studied
mu-opioid agonists. Notable examples include metha- in neuropathic pain syndromes.52 A favorable effect
done, which exhibits NMDA antagonism, and, as from TCAs for diabetic neuropathic pain (DNP) and for
previously mentioned, tapentadol, with noradrenergic PHN has been demonstrated in several randomized,
reuptake inhibiting activity. placebo-controlled studies. The analgesic effect is not
290  JONGEN ET AL.

dependent on their antidepressant effect. The analgesic receptor effects and potentially fewer adverse effects
effect occurs sooner (within 1 to 7 days), and the dose is because of fewer receptor interactions.59
lower than for the treatment of depression (the mean
effective daily dosage of amitriptyline for neuropathic
Anti-Epileptics
pain being only 50 mg). The treatment is started with a
low dose that can be increased if necessary. Undesirable The use of some AEDs in the treatment of certain
side effects, such as sedation, anticholinergic effects, and neuropathic pains has been scientifically endorsed.
orthostatic hypotension, frequently occur with TCAs, Carbamazepine and phenytoin have proven to be
particularly in the elderly. These have even been effective for the treatment of DNP.52 The efficacy of
reported with topical amitriptyline when used in high carbamazepine has also been demonstrated with tri-
doses.53 The addition of nortriptyline54 or amitripty- geminal neuralgia, an indication for which it still
line55 to morphine for lumbar radicular and neuropathic remains indicated as a first-line treatment.60 There are
cancer pain has not been shown to provide an additional not enough studies on the efficacy of phenytoin for
benefit over the individual agents. The absence of trigeminal neuralgia or about the efficacy of either
efficacy of the combination of nortriptyline and mor- carbamazepine or phenytoin in monotherapy for PHN.
phine, or the individual drugs, in lumbar radiculopathy There are no studies that compare these AEDs with
may reflect resistance of the pain syndrome to pharma- TCAs. The most common adverse effects of carbamaz-
cologic therapy.54 Nortriptyline in combination with epine and phenytoin are mental, motor and visual
gabapentin, however, did provide significant benefit impairments, headache, gastrointestinal problems; and
over individual agents in subjects with DNP and PHN.56 more rarely, epidermal reaction, and hematological
More studies are needed to determine which neuropath- reactions. For these reasons, the newer agents are more
ic pain syndromes show added efficacy with combina- often used clinically.
tions of drugs. The efficacy of gabapentin for PHN and for DNP has
The selective serotonin reuptake inhibitors have been been repeatedly demonstrated. Gabapentin seems to be
studied in a few neuropathic pain trials, which have at least as effective as amitriptyline in patients with
demonstrated only a weak analgesic effect. Therefore, diabetic neuropathy. The use of gabapentin in a variety
their clinical relevance for the treatment of neuropathic of neuropathic pain conditions was recently reviewed.61
pain is questionable.57 SNRIs have demonstrated greater Overall, the efficacy of gabapentin (50% pain relief
efficacy in the treatment of neuropathic pain. Duloxetine compared to baseline) in PHN, DNP, complex regional
belongs to this category of drugs,58 and, as of 2006, there pain syndrome type I (CRPS-1), nerve injury pain, small
were 6 studies supporting the analgesic effect of duloxe- fiber sensory neuropathy, phantom pain, and mixed
tine in diabetic polyneuropathy (n = 3) and fibromyalgia neuropathic pain was reported to be superior to placebo
(n = 3). For both of these pain syndromes, a similar (Risk ratio: RR 1.7, 95% CI: 1.46 to 1.99; NNT: 6.8,
efficacy was shown (number needed to treat; NNT: 6). 95% CI: 5.4 to 9.2) at the expense of relatively frequent,
These studies demonstrated a significantly higher num- but most often tolerable, adverse effects. These adverse
ber of patients with adverse effects (number needed to effects include fatigue, dizziness, confusion, ataxia,
harm; NNH: 15), including nausea, somnolence, con- headache, nausea, and peripheral edema.
stipation and reduced appetite, compared with placebo. Gabapentin, when used in combination with mor-
Duloxetine is FDA approved for the treatment of phine to treat neuropathic pain, also has an opioid-
diabetic polyneuropathy and fibromyalgia. A more sparing effect. A meta-analysis of patients with neu-
recent survey on duloxetine use included 12 studies on ropathic pain receiving either the previously mentioned
DNP and 9 studies on fibromyalgia. These studies combination of gabapentin and morphine62 or gaba-
confirmed a positive effect in some patients and empha- pentin and oxycodone63 marginally supported the use
sized the need to adhere to prescribing guidelines to of the combination (RR: 1.3, 95% CI: 1.04 to 1.61;
minimize adverse effects.36 Venlafaxine is another SNRI NNT: 9.5, 95% CI: 5.0 to 86), again associated with
that has been shown effective in painful polyneuropathy, increased adverse effects (RR: 2.8, 95% CI: 1.5 to 5.2;
although this agent (at a low dose) failed to demonstrate number needed to treat to harm: 10, 95% CI: 6.5 to
greater efficacy than placebo in postmastectomy pain.52 25).33
The SNRIs have added salutary properties over TCAs Pregabalin has been introduced more recently; it is a
including the absence of cholinergic and histamine molecular compound with a comparable mode of action
 Neuropathic Pain  291

as gabapentin. There are an increasing number of approved for use in PHN. Its off-label use in other
clinical studies with pregabalin that provides supportive neuropathic conditions has been recommended.3,31,76
evidence for the treatment of DNP, PHN, and other
neuropathic pain conditions.64,65 The suggestion that
NMDA Antagonists
the overall cost of care may be reduced in gabapentin-
refractory neuropathic pain by switching to pregabalin The NMDA receptors play a crucial role in the devel-
has been made, but further supporting studies are opment of central sensitization, as well as in the
needed to confirm this contention.66 The advantages of appearance of tolerance to classical analgesics (includ-
pregabalin are the twice-daily administration schedule, ing opioids). NMDA antagonists are considered to be an
a narrower dosage range (between 150 and 600 mg/ important therapeutic option in the treatment of neuro-
day), fewer potential adverse effects, and a more rapid pathic pain (as well as in the prevention of the
therapeutic effect.67 The combination of pregabalin with development of tolerance with regard to analgesics).
oxycodone did not clearly show benefit compared with Currently, the clinically available (oral) NMDA antag-
pregabalin alone in a randomized controlled trial (RCT) onists demonstrate limited potential (including dextro-
for PHN or DNP.68 The placebo response has recently methorphan, amantadine, memantine). Occasional
been shown to be significantly influenced by the type of reports have demonstrated the potential use of dextro-
condition under study, which may have particularly methorphan in the treatment of therapy-resistant
significant implications for RCTs involving neuropathic neuropathic pain syndromes. However, there are cur-
pain.69 This contributes to the difficulty in interpreting rently no confirmatory RCTs. The clinical use of the
the results from traditional RCTs into clinical practice. NMDA antagonists is to a significant degree negatively
A novel research design, an enriched-enrollment ran- influenced by the occurrence of central neurological
domized withdrawal protocol, recently confirmed the adverse effects, such as hallucinations and agitation.
clinically relevant effectiveness and dose range of This is certainly the case with ketamine, which has been
pregabalin in both PHN and DNP.70 Finally, it should available for decades, but its large-scale use in clinical
also be noted that pregabalin, in addition to its analgesic practice has been curtailed due to adverse effects.
effect, has also demonstrated an anxiolytic effect.71,72 Currently, ketamine is mainly used intravenously as an
Currently, evidence for the suitability of other antineuropathic treatment when more traditional treat-
agents such as lamotrigine and topiramate for neuro- ments fail.77 Its topical use, alone or in combination
pathic pain is limited. However, another drug that is with other agents especially amitriptyline, is increasing.
currently approved for seizures, but still pending FDA Topical ketamine has also been reported to be effective
approval for diabetic painful neuropathy, is lacosa- in chemotherapy-induced neuropathic pain (ketamine,
mide. Lacosamide has a dual mode of action resulting amitriptyline and baclofen)78 and radiation-induced
in a delayed inactivation of the voltage-dependent Na+ neuropathic pain (ketamine, amitriptyline, lidocaine).79
channels.73 The efficacy of lacosamide has thus far Although case reports of efficacy of oral ketamine have
been mainly investigated in diabetic polyneuropathy, been reported,80 its widespread chronic use is not
with a favorable efficacy in both the short term and practical due to the instability of the oral solution
long term.74 resulting in a limited shelf-life. The oral preparation,
however, can be ordered from compounding companies
in some jurisdictions.
Membrane Stabilizers
Anti-arrhythmics such as mexiletine do not demonstrate
Other Agents and Future Directions
any local anesthetic effect, but despite a lack of
convincing evidence, continue to be used, albeit occa- Various other topical analgesics are available. The
sionally, in the treatment of neuropathic pain. Adverse generally low systemic absorption of topical analgesics
effects are frequent and include nausea, vomiting, reduces the risk for adverse effects and interactions with
abdominal pain, trembling, dizziness, and headache. concomitant medication. The high dose capsaicin patch
Intravenously administered lidocaine may provide some (8%) has been shown to be effective in the treatment of
pain relief in some neuropathic pain states,75 but DNP, PHN, and HIV neuropathy.81–84 It offers an
evidence is conflicting and it cannot be administered advantage over lidocaine patches in that it needs to be
orally. Topical lidocaine (5% patch) is FDA and EMA applied only once every 3 months. The cost and the pain
292  JONGEN ET AL.

TREATMENT ALGORITHM
Finnerup et al.28 propose the algorithm illustrated in
Figure 2 for the pharmacological treatment of neuro-
pathic pain.

SUMMARY
Neuropathic pain is a direct result of a lesion or disease
of the somatosensory system. This condition may be
localized in the central nervous system as well as the
peripheral nervous system.
In most cases, the diagnosis can be established by the
combination of history-taking and neurological exam-
ination.
Figure 2. Treatment algorithm. Proposed algorithm for the The treatment of neuropathic pain focuses on 2
treatment of peripheral neuropathic pain. TCA, tricyclic antide- levels: the underlying medical condition and the somato-
pressants; SNRI, serotonin noradrenaline reuptake inhibitors. sensory symptoms. Specific pharmacological treatment
*Pain relieving effect of topical lidocaine has been shown in
patients with allodynia. From Finnerup NB, Otto M, McQuay HJ, should focus on the underlying pathophysiological
Jensen TS, Sindrup SH. Algorithm for neuropathic pain treat- mechanisms as much as possible. The physician should
ment: an evidence based proposal. Painâ 2005 December 118(3); select a specific (poly) pharmacological treatment plan
289–305.
based on the individual patient’s situation.

associated with its use, even after a local anesthetic ACKNOWLEDGEMENTS

cream pre-application, is a serious drawback. Topical
This review was initially based on practice guidelines
clonidine (patch) was recently reported to be effective in
written by Dutch and Flemish (Belgian) experts that
DNP patients with intact (possibly sensitized) nocicep-
were assembled in a handbook for the Dutch-speaking
tors.85 Topical agents are available in gel, ointment, or
pain physicians. After translation, the manuscript was
cream form. A combination of amitriptyline and keta-
updated and edited in cooperation with U.S./interna-
mine has more versatility, as it can easily be applied to
tional pain medicine specialists.
the hands, feet, or digits, which are frequent sites of
The authors thank Nicole Van den Hecke for
peripheral neuropathic pain.
coordination and suggestions regarding the manuscript.
Other drugs currently in use or under late-stage
development involve cannabinoids,86 NMDA antago-
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