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Research Signpost 37/661 (2), Fort P.O., Trivandrum-695 023, Kerala, India Mechanisms of Pain in Peripheral Neuropathy, 2009: 295-375 ISBN: 978-81-308-0358-6 Editor: Maxim Dobretsov and Jun-Ming Zhang 12 Pharmacological and
interventional treatments for
neuropathic pain
Bryan S. Williams1 and Paul J. Christo1,2
1Department of Anesthesiology and Critical Care Medicine 2Division of Pain Medicine, The Johns Hopkins University School of Medicine, 550 N. Broadway, Suite 301, Baltimore, Maryland 21205, USA Abstract
Neuropathic pain originates from a lesion within
the central or peripheral nervous system. The signs of
neuropathic pain include heat hyperalgesia, mechano-
hyperalgesia, and mechano- and cold allodynia.
Traditionally, neuropathic pain responds poorly to
conventional analgesics. This chapter will provide
recommendations for medical and interventional
management of neuropathic pain conditions based
on the best scientific evidence in the literature.
Anticonvulsants (e.g., gabapentin and pregabalin),
antidepressants (e.g., amitritpyline and duloxetine),
and topical lidocaine have been the most consistent
Correspondence/Reprint request: Dr. Paul J. Christo, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 550 N. Broadway, Suite 301, Baltimore Maryland 21205, USA. E-mail: [email protected] Bryan S. Williams & Paul J. Christo in demonstrating effectiveness through randomized control trials. Certain
circumstances may require the use of opioids as a first-line treatment for
specific neuropathic pain states. Interventional strategies such as neural
blockade, implantable drug delivery systems, and spinal cord stimulation can
be beneficial for alleviating painful neuropathic conditions that respond less
favorably to medical therapies, or as a method of augmenting current
medical therapies. A rational approach for the treatment of specific
neuropathic conditions is presented in the form of tables that consider first
line, second line, and other therapies.

1. Introduction

Neuropathic pain (NP) is not a disease per se; rather, it is a manifestation of multiple and varied disorders that display both peripheral and central sensitization mechanisms[1] which affect the somatosensory components of the nervous system[2]. Animal and human models of neuropathic pain have shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. The change, known as neuroplasticity causes morphological & functional adaptation to external stimuli or insults and plays a crucial role in the onset and maintenance of pain symptoms[3]. Injured peripheral nerve fibers give rise to an intense and prolonged input to the central nervous system of ectopic activity and in some may induce secondary changes to the excitability of dorsal horn neurons. At the cellular level, formation of new channels, up and down regulation of certain receptors, and altered local or descending inhibition represent some of the biological mechanisms that can lead to a hyperexcitable state, known as chronic pain[4]. Randomized placebo-controlled trials investigating the treatment of neuropathic pain have increased recently, but the synthesis of information gained from these trials still lags clinical application, with less than half of patients achieving significant benefit with any pharmacological drug [5-7]. By definition, neuropathic pain originates from a lesion within the nervous system. In fact, there are many pathologic conditions that can produce a lesion in the nervous system from which neuropathic pain may originate. Examples include autoimmune disease (e.g., multiple sclerosis), metabolic diseases (e.g., diabetic neuropathy), infection (e.g., shingles and the sequelae, postherpetic neuralgia), vascular disease (e.g., stroke), trauma, and cancer[1] (Table 1). Recently, strategies aimed at selecting treatments by targeting the putative mechanisms of pain (mechanism-based strategies) have been proposed[7-9]. The signs of neuropathic pain (heat hyperalgesia, mechano-hyperalgesia, mechano- and cold allodynia) may have different pathophysiologic Treatments of neuropathic pain Table 1. Types of Neuropathic Pain.
Peripheral Neuropathic Pain Painful Polyneuropathy/Diabetic Peripheral Neuropathy Radiculopathy Trigeminal Neuropathy Post-Herpetic Neuralgia Post-Surgical/Phantom Limb Chemotherapy-induced polyneuropathy HIV sensory neuropathy Iatrogenic neuralgias (e.g., postmastectomy pain or post-thoracotomy pain) Complex Regional Pain Syndrome Central Neuropathic Pain Post-stroke Pain Multiple Sclerosis-related pain Compressive myelopathy from spinal stenosis HIV myelopathy mechanisms. Evidence from animal models indicate that distinct signs of neuropathic pain respond differently to various drugs[10-14]. For instance, in a rat model of mononeuropathy produced by a chronic constrictive injury to the sciatic nerve, the animals exhibit abnormal pain sensitivities to non-noxious cold and heat stimuli (e.g., allodynia) and to noxious thermal stimuli (e.g, hyperalgesia). These animals were treated with morphine and other selective opioid agonists at doses known to produce potent antinociceptive effects on mechano-allodynia. The opioids reversed heat hyperalgesia but failed to alleviate thermal allodynia[11, 13]. Another study demonstrated that dextromethorphan, an N-methyl-D-aspartic acid (NMDA) antagonist produced the opposite effect in the experimental trauma model; that is, dextromethorphan blocked heat hyperalgesia and had no effect on mechano-allodynia[10, 11]. Treatment with the synthetic ω-conotoxin (e.g., cone snail polypeptide) ziconotide was able to alleviate heat hyperalgesia but not mechano-hyperalgesia in rat models of neuropathic pain[11, 14]. Additionally, NMDA-receptor blockers such as dextromethorphan are usually effective in models of post-traumatic painful peripheral neuropathy, but fail to relieve the mechanical and cold hypersensitivity evoked in rats by the chemotherapeutic agent paclitaxel[11, 12]. Since patients report symptoms and not mechanisms and clinicians uncover signs and not mechanisms, researchers could focus on how symptoms and signs of neuropathic pain reflect mechanisms[4]. Practitioners treat signs and symptoms in the attempt to control the mechanism propagating the symptoms. Difficulty arises when critically assessing the source of neuropathic pain since at least four fairly broad etiologic groups Bryan S. Williams & Paul J. Christo should be considered when a treatment decision is made: peripheral neuropathic pain (PNP), complex regional pain syndrome (CRPS), trigeminal neuralgia (TN), and central neuropathic pain (CNP)[15]. Neuropathic pain seems to respond poorly to conventional analgesics which adds to the challenge of treating patients due to the heterogeneity of etiologies, symptoms, and underlying mechanisms[15]. Finally, clinicians are confronted with an array of medications for the treatment of neuropathic pain that are commonly classified by their original therapeutic category and not by their effectiveness in treating a particular pain condition[15]. For instance, tricyclic antidepressants and antiepileptics are generally approved for depression and epilepsy respectively, rather than for the alleviation of neuropathic pain. In addition to controlling pain, it is important to recognize and treat comorbidities, such as anxiety and depression. It is also important to recognize secondary treatment goals, such as improving sleep, advancing function, and enhancing overall quality of life. Treatment goals must be realistic and clinicians should validate a patient's pain in order to gain trust. Common treatment goals for the patient and clinician alike center on mitigating symptoms, reducing pain duration, decreasing pain severity, improving quality of life, and reducing psychological distress[16]. Setting reasonable expectations is equally important. For example, a patient should view pain attenuation as the primary goal and clinicians should realize that a 30% reduction in pain intensity can be considered a clinically relevant response[17] given that complete pain cessation is rarely possible. When selecting among treatments for patients with neuropathic pain, clinicians should consider the efficacy data of various options. Most randomized controlled trials (RCT) examining the treatment options for neuropathic pain have included patients with postherpetic neuralgia (PHN), as well as painful polyneuropathies (PPN) & peripheral neuropathies (PN) that are a result of diabetes[7]. The extent to which the results of RCTs for one type of NP can apply to other types of NP is unknown. However, clinicians often extrapolate the data on effectiveness from one particular NP condition to another based on a broad spectrum of analgesic activity of a specific intervention. The ability to use medications for the treatment of neuropathic pain conditions requires an understanding of the pathophysiological manifestations of the pain state rather than the etiology. Ideally, treatment interventions should target pain mechanisms and efficacy data should be extrapolated from more comprehensively studied pain states to less investigated pain conditions. Until clinicians use mechanism-based treatments for the control of neuropathic pain, symptom manifestation will continue to direct analgesic interventions. To date, no medication has shown long-term efficacy and tolerability for all neuropathic pain conditions. Therefore, this chapter will focus on Treatments of neuropathic pain medications and interventions that consistently show efficacy in neuropathic pain states with mention of alternative medications. Although a number of drugs are commonly used to treat neuropathic pain, the only drugs presently approved by the Food and Drug Administration (FDA) include carbamazepine for the treatment of trigeminal and glossopharyngeal neuralgias, gabapentin for the treatment of postherpetic neuralgia, duloxetine for the treatment of painful diabetic neuropathy, topical lidocaine for control of post-herpetic neuralgia (PHN) and pregabalin for control of postherpetic neuralgia and painful diabetic peripheral neuropathy[18] (Table 2.). Moreover, certain interventional and pharmacological treatments that show promise in treating NP will be discussed. Any listing of medications for treating neuropathic pain should serve as a guide based on the available data. No medication has been shown efficacious in treating all neuropathic pain states. A useful method of assessing the efficacy of medications, the "number needed to treat" (NNT) evaluates the efficacy of active treatment compared to placebo. Clinically, the NNT measures how many patients need to receive a certain treatment in order for one patient to derive a clear benefit. In pain studies, this translates into the number of patients needed to treat with a certain drug in order for one patient to achieve at least a 50% decrease in pain intensity. This value is calculated by 1/([goal achieved active group/total active]-[goal achieved placebo group/total placebo]), and the 95% confidence interval (CI) of NNT can be obtained by taking the reciprocal value of the 95% CI for the absolute risk reduction. The NNT can only be calculated from placebo-controlled trials, since a correction for "placebo responders" is included in the formula for NNT"[19]. The NNT is used in formulating treatment recommendations. That is, either the study provides the NNT or it can be calculated from available data. Therapeutic options for each pain condition are derived from evidence-based research, improvement in quality of life, the risk of adverse effects and clinical experience. Table 8 lists recommended medications for the treatment of neuropathic pain. Table 2. FDA Approved Medications for Neuropathic Pain.
Medication Indication
Topical lidocaine FDA – Food and Drug Administration; DPN – Diabetic Peripheral Neuropathy; PHN –
Post-Herpetic Neuralgia
Bryan S. Williams & Paul J. Christo 2. Peripheral neuropathic pain

Peripheral neuropathy pain (PNP) or painful polyneuropathy are terms used to describe pain due to peripheral nerve injury and includes diabetic
peripheral neuropathy (DPN), non-diabetic peripheral neuropathy, human-
immunodeficiency virus (HIV) neuropathy, and chemotherapy-induced
peripheral neuropathy (e.g., cisplatin, vincristine, paclitaxel). Diabetic and
non-diabetic peripheral neuropathy are similar in symptomatology and
treatment response although HIV- and chemotherapy-induced neuropathies
may differ in both symptom presentation and treatments[7].

Painful polyneuropathy & diabetic peripheral neuropathy
Painful diabetic peripheral neuropathy (DPN) reflects long-standing
peripheral neuropathic disease that occurs in one of six diabetic patients[20, 21].
An acutely detected abnormality in DPN is a disturbance of nerve
electrophysiology[22]. Clinically, patients may present with loss of light touch and
pressure sensation, a decrease in vibration detection threshold (VDT), decreased
motor strength, and areflexia; however, pain is the most distressing symptom of
DPN and the primary reason for patients to seek medical advice[23, 24]. Chronic
diabetic peripheral neuropathy can cause symptoms that last for years and
severely impair quality of life[21, 25]. Despite its many etiologies, neuropathic
pain is usually spontaneous, continuous, burning, paroxysmal, and evoked by
various mechanical or thermal stimuli[21, 23]. Treatment of DPN rests on a
two-pronged approach: modification of the underlying disease and control of
pain symptoms[26]. Currently, the only treatment that addresses the cause of
painful diabetic neuropathy requires improved control of blood glucose levels. A
combination of pharmacologic or nonpharmacologic therapy should be employed
to control the symptoms of painful diabetic peripheral neuropathy[27]. Prevention
of peripheral neuropathy centers on improved glycemic control, which may
reduce the risk of developing diabetic neuropathy in patients with insulin-
dependent diabetes by as much as 62%[28]. Symptomatology and treatment
options for diabetic and non-diabetic peripheral neuropathy are similar. HIV- and
chemotherapy-induced neuropathy do display different symptoms and respond
differently to treatment[7]. Therefore, treatment choices for painful
polyneuropathy and diabetic peripheral neuropathy will be discussed together,
and separate options for HIV and chemotherapy-induced neuropathy will follow.
A. Antidepressants
1. Tricyclic antidepressants (TCA)
Tricyclic antidepressants (TCA) have an analgesic effect that is
demonstrated to be independent of their antidepressant effect[5]. The
Treatments of neuropathic pain pharmacological actions of tricyclic antidepressants can be linked to their effect as a calcium channel antagonist, sodium channel antagonist, presynaptic reuptake inhibition of the monamines such as serotonin and norepinephrine, and NMDA receptor antagonist effect[29, 30]. More specifically, the analgesic effect is believed to occur primarily through reuptake inhibition of norepinephrine rather than serotonin at spinal dorsal horn synapses, with secondary activity at the sodium channels[31, 32]. The tricyclic antidepressants have no effect on dopamine reuptake, but may have some indirect dopaminergic action by means of their adrenergic effect and desensitization of dopamine D2 receptors[29]. Within the class of tricyclic antidepressants, variation exists between the inhibition of norepinephrine and serotonin. The tertiary amine agents (e.g., amitriptyline & imipramine) demonstrate a balance in their ability to inhibit norepinephrine and serotonin, while the secondary amines (e.g., nortriptyline & desipramine) favor the inhibition of norepinephrine. The secondary amines appear to be as effective as the tertiary agents in treating neuropathic pain and produce markedly fewer side effects[33, 34]. Currently no TCA carries a US Food and Drug Administration (FDA) indication for DPN, despite many studies showing efficacy in treating painful
polyneuropathy. Sindrup & Jensen reviewed RCTs of antidepressants for the
treatment of neuropathic pain and found that the number needed to treat for
DPN was 2.4[35]. Max et al., in a randomized, double-blind, crossover study in
patients with painful diabetic neuropathy compared amitriptyline to desipramine, a
relatively selective blocker of norepinephrine reuptake. They concluded that
desipramine (e.g., secondary amine) was as effective as amitriptyline (e.g., tertiary
amine) in relieving pain caused by diabetic neuropathy[36]. The NNT for TCAs
and peripheral neuropathic pain, excluding HIV neuropathy is 2.3 (2.1–2.7)
with no major difference across the different disease entities. For tricyclic
antidepressants with balanced reuptake inhibition of norepinephrine and
serotonin (e.g., amitriptyline & imipramine), the NNT is 2.2 (1.9–2.6) and for
the relatively noradrenergic tricyclic antidepressants (e.g., nortriptyline &
desipramine) the NNT is 2.5 (2.1–3.3)[29]. In a report published by the Cochrane
Collaborative meta-analysis of studies examining antidepressants for the
treatment of DPN, the NNT was 1.29. The Cochrane Collaborative NNT was
consistent over several other studies and lends support for the effectiveness of
TCA's in the treatment of diabetic peripheral neuropathy[37].

2. Serotonin-norepinephrine reuptake inhibitors (SNRI)

Serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine & venlafaxine) inhibit the reuptake of both serotonin and norepinephrine and Bryan S. Williams & Paul J. Christo are often referred to as a dual inhibitors[38] or "selective" serotonin-
norepinephrine reuptake inhibitors. For example, duloxetine is a potent,
balanced inhibitor of serotonin and norepinephrine reuptake[39]. Venlafaxine
inhibits serotonin reuptake at lower dosages and inhibits both serotonin and
norepinephrine reuptake at higher dosages[29, 40]. Venlafaxine produces no
postsynaptic effects. It does however block sodium channels in a different
manner from that of tricyclic antidepressants[41]. Moreover, venlafaxine is
structurally related to the centrally acting and synthetic analgesic, tramadol
which has a mechanism of action analogous to that of the TCAs[42].
Venlafaxine's lack of anticholinergic side effects results in a distinct
advantage over traditional TCAs[43-45].
a. Duloxetine
Duloxetine
approved by the US Food and Drug Administration for painful diabetic neuropathy[46, 47]. Goldstein et al. examined the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine for the management of diabetic peripheral neuropathic pain. They found that duloxetine 60 mg and 120 mg per day compared to placebo significantly reduced pain severity beginning at week 1 and continued throughout the study. A 50% reduction in the 24 hour average pain score was achieved by 26% in the placebo group, 41% in the duloxetine 20 mg per day group, 49% in the 60 mg per day group, and 52% in the 120 mg per day group. The number of patients achieving a 50% reduction in the 24 hour average pain score was significantly greater for all three active treatment groups when compared to placebo (p <0.05)[46]. No significant difference was found between the 60 mg per day group and the 120 mg per day group. Similar results were replicated by Raskin et al. who demonstrated that the efficacy of duloxetine for DPN was significantly better than placebo in reducing Brief Pain Inventory (BPI) pain severity scores. Further, duloxetine treatment groups were superior to placebo on Clinical Global Impressions (CGI) Severity and Patient's Global Impression Improvement scores. Patients also demonstrated an improvement in the sensory component of the Short-Form McGill Pain Questionnaire [48]. Although these two studies show efficacy in treating DPN, the NNT for duloxetine is greater than that for other pain pharmacotherapies. That is, the NNT is 2.7 for anticonvulsants, 3.4 for antidepressants, 2.6 for tricyclic antidepressants, and 5 for duloxetine. However, duloxetine's more favorable side effect profile may confer an advantage in treating certain diabetic patients with pre-existing comorbidities[49] such as cardiac conduction abnormalities, a relative contraindication to prescribing TCAs. Treatments of neuropathic pain b. Venlafaxine
Venlafaxine exhibits serotonin and weak norepinephrine reuptake inhibition, but with increasing doses norepinephrine reuptake inhibition increases[29].
Currently, venlafaxine does not have an FDA indication for the treatment of
diabetic peripheral neuropathy; rather, it is approved for major depressive
disorder. However, venlafaxine has been investigated for the treatment of
diabetic peripheral neuropathy. In a multicenter, double-blind, randomized,
placebo-controlled study including 244 patients, venlafaxine was evaluated for
its efficacy in treating diabetic peripheral neuropathy. In this study, venlafaxine
was shown to be significantly more effective than placebo (p < 0.001) with an
NNT of 4.5 (venlafaxine ER 150–225 mg per day)[50] according to the primary
measures of efficacy; namely the Visual Analog Pain Intensity (VAS-PI) and
Visual Analog Pain Relief (VAS-PR) scales. In a comparison study of drug
efficacy for the treatment of polyneuropathy, Sindrup et al. reported that
venlafaxine relieved pain equally as well as imipramine. Pain summation was
used as the primary efficacy measure and showed no statistical difference
between venlafaxine and imipramine. The calculated NNT for venlafaxine was
5.2 (95% CI 2.7 to 5.9) compared to 2.7 (95% CI 1.8 to 5.5) for imipramine[43].
In a review of antidepressants for the treatment of neuropathic pain, Sindrup et
al. report an NNT for venlafaxine in painful polyneuropathy of 5.5 (3.4–
13.5)[29]. These results support the use of venlafaxine for the treatment of
peripheral neuropathy and in particular, diabetic peripheral neuropathy.
3. Selective serotonin reuptake inhibitors (SSRI)
Selective serotonin reuptake inhibitors differ from the tricyclic
antidepressants in that SNRI's selectively inhibit serotonin rather than
norepinephrine. The SSRI medication class (e.g., citalopram, escitalopram oxalate,
fluoxetine, paroxetine, sertaline) have shown efficacy in the treatment of
neuropathic pain in small studies. For instance, paroxetine was shown to have
a NNT of 2.9 compared to placebo in a small crossover study investigating the
treatment of diabetic neuropathy symptoms[51]. In other studies of patients with
DPN, paroxetine and citalopram were associated with statistically significant
greater pain relief than placebo, whereas fluoxetine was found to be no more
effective than placebo[5]. Conversely, a small trial investigating pain treatment
in diabetic neuropathy revealed that SSRIs may not offer greater effectiveness
than placebo given that fluoxetine's NNT was 15.3[36]. Moreover, pooled data
from three trials (e.g., 162 patient episodes) studying citalopram, fluoxetine,
and paroxetine only demonstrated a relative benefit of 1.3 (1.0–1.8), indicating no
significant difference in pain relief compared with placebo[52].
The reduced effectiveness of SSRIs compared to TCAs appears to be directly related to the specific mechanism by which they exert their effects. Bryan S. Williams & Paul J. Christo Unlike TCAs, SSRIs selectively block the reuptake of 5-HT alone[45]. The
higher NNT is comparable to other studies that examine the efficacy of
SSRI's and provides little support for their use as a first or second-line
medication in the treatment DPN (Table 4)[7, 40, 43, 50, 53].

B. Antiepileptic medications
1. Gabapentin

The gabapentinoid group of drugs, gabapentin and pregabalin appear to offer the most evidence-based data for the treatment of DPN[54]. The analgesic
mechanism of action for gabapentin remains unknown, although possible
mechanisms include the modulation of voltage-gated calcium channels.
Initially developed to mimic the neurotransmitter γ-aminobutyric acid
(GABA), but is not believed to act at the GABA receptor. Gabapentin blocks
the tonic phase of nociception induced by formalin and carrageenan, and it
exerts a potent inhibitory effect in several animal modes of neuropathic pain
such as mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia,
and thermo-allodynia[3, 55]. Gabapentin is FDA approved for the treatment of
postherpetic neuralgia, and has shown efficacy for the treatment of other
neuropathic pain conditions[56, 57]. For instance, a randomized, double-blind,
placebo-controlled trial demonstrated the effectiveness of gabapentin in treating
diabetic peripheral neuropathy based on a significant reduction in daily pain
severity measured on an 11-point Likert scale[56]. The initial mean pain score
was reduced from 6.4 to 3.9 at the conclusion of the study with a NNT of 3.7.
To investigate the effects of gabapentin and venlafaxine on painful diabetic
neuropathy, Simpson performed a randomized double-blind serial comparison
study in three arms: 1gabapentin versus placebo, 2gabapentin and venlafaxine
versus gabapentin, and an 3uncontrolled arm for patients who did not improve
on gabapentin monotherapy and who subsequently received venlafaxine in
addition to gabapentin. The primary efficacy parameter was pain severity
rating based on an 11-point Likert scale. The gabapentin-treated patients
showed statistically significant improvement in pain reduction based on initial
mean pain scores that decreased to 4.0 from an initial rating of 6.4 (p < 0.01).
Among the placebo group, there was a decrement in pain scores from a 6.5 to
6.0, which was not statistically significant [58]. A systematic review of
gabapentin for neuropathic pain further demonstrates the efficacy of gabapentin
for the treatment of peripheral neuropathy and other neuropathic pain states[59].

2. Pregabalin

Similar to gabapentin, pregabalin is a GABA analog without proven agonistic effect on GABA receptors. Pregabalin also modifies voltage-gated calcium channels in a similar manner to gabapentin. Potent binding at this Treatments of neuropathic pain site reduces calcium influx at nerve terminals and therefore, reduces the release of several neurotransmitters including glutamate, norepinephrine, and substance P [60, 61]. Pregabalin is FDA approved for the treatment diabetic peripheral neuropathy and has shown efficacy in several trials[61-63]. For example, Lesser et al. evaluated dose response to pregabalin and painful diabetic neuropathy in a multicenter double-blind, placebo-controlled trial. The primary efficacy measure of pain relief focused on patient recordings of daily pain in a daily diary, and pain rating was based on an 11-point Likert scale. The study determined that endpoint mean pain scores were significantly improved with pregabalin 300 mg per day and 600 mg per day compared to placebo when using ≥ 50% reduction in pain as a marker for response. The 300 mg per day (37/81, 46%) and 600 mg per day pregabalin groups (39/81 patients, 48%) both showed a significant response compared to placebo (17/97, 18%). The NNT for a ≥ 50% reduction in pain was calculated to be 3.52 for the 300 mg per day group and 3.26 for the 600 mg per day group. If a smaller 30% reduction in pain response rates was considered, similar NNT results were reported for the 300 mg per day (50/81, 62%) and 600 mg per day (53/81, 65%) groups. For instance, there was an NNT of 3.48 for the 300 mg per day group, and 3.08 for the 600-mg per day group[62]. Other studies provide comparable results of efficacy for pregabalin in relieving diabetic neuropathic pain[61, 63]. In another multicenter double-blind, placebo-controlled trial, pregabalin provided a statistically significant decrease in mean pain score at endpoint at a dose of 300 mg per day (baseline, 6.5; endpoint, 4.0) compared with placebo (baseline, 6.1; endpoint, 5.3; (p = 0.0001)[61]. Furthermore, pregabalin-treated patients attained significant improvements in secondary variables such as mean sleep interference scores, and the total SF-MPQ score compared with the placebo-treated group[61]. Treatment with pregabalin was not associated with serious adverse effects such as orthostatic hypotension, falls, cognitive changes, tachycardia, urinary hesitation and other risks more commonly seen in older patients, TCA associated cardiac arrhythmias, or nonsteroidal anti-inflammatory drug induced gastropathy[62, 64]. Pregabalin was generally well tolerated in clinical trials, and most treatment-related adverse effects were dose dependent. Adverse effects typically related to the central nervous system. Clinical trials reveal that the rate of adverse effects vary by pregabalin dosage and dosing regimen and generally include dizziness, somnolence, weight gain, peripheral edema and diplopia [65]. In a review of randomized controlled trials of antidepressants and anticonvulsants for the treatment of pain associated with diabetic and post-herpetic neuropathies, one third of patients achieved at least 50% pain relief with either category of drug[66]. Bryan S. Williams & Paul J. Christo 3. Carbamazepine (Tegretol)

Carbamazepine is an iminostilbene derivative that is chemically related to the tricyclic antidepressants. The effect of carbamazepine on pain
suppression is probably mediated via central and peripheral mechanisms.
Carbamazepine, the first anticonvulsant studied in clinical trials for TN may
alleviate pain by decreasing conductance of Na+ channels and inhibiting
ectopic neural discharges[3]. There are multiple studies investigating the
efficacy of carbamazepine for the treatment of trigeminal neuralgia, but few
quality studies have examined the usefulness of carbamazepine for the
treatment of DPN. Yet, carbamazepine was one of the first antiepileptic drugs
used for the treatment of painful diabetic neuropathy[67]. For example, a 1969
double-blind, placebo-controlled crossover study demonstrated pain relief in
28 of 30 participants with peripheral diabetic neuropathy[68]. Another 2-week,
crossover study of 40 patients with painful diabetic neuropathy showed a
significantly greater reduction in pain with carbamazepine than with placebo
on days 10 and 14[67, 69]. Despite the smaller sample size of these trials and a
weaker evidence base for the use of carbamazepine in DPN, the NNT is
strongly suggestive of efficacy (e.g., for every 2.5 patients with neuropathic
pain treated with carbamazepine, at least one will achieve moderate pain
relief or greater)[70]. Safety concerns (e.g., skin rash, hyponatremia, decreased
bone density, and hematopoetic issues) may limit the use of carbamazepine in
the older population[7, 71]. Table 4 profiles medications used for the treatment
of NP. There is supportive evidence for the use of carbamazepine in the
treatment of DPN, but due to a weaker evidence base and significant adverse
effect profile, it ranks as a second-line medication[5, 7, 70].

4. Oxcarbazepine (Trileptal)
Oxcarbazepine is keto-analogue of carbamazepine. The therapeutic
window for the treatment of pain conditions with this drug has yet to be
established[67, 72]. In a multicenter, placebo-controlled trial, the efficacy of
oxcarbazepine in patients with diabetic peripheral neuropathy was evaluated
using VAS scores as a primary efficacy variable[73]. In this study, Dogra et al.
concluded that a significantly greater proportion of oxcarbazepine-treated
patients experienced a >50% reduction from baseline VAS pain scores at
study conclusion compared with placebo (35.2% vs. 18.4%, respectively;
p = 0.0156), with a calculated NNT of 6.0. When utilizing global assessment
of therapeutic effect (GATE) as a secondary efficacy variable, the NNT was
3.9[73]. In another oxcarbazepine study by Grosskopf, there were no
significant differences in primary or secondary efficacy outcomes between
patients treated with oxcarbazepine (1200 mg per day) and those taking
Treatments of neuropathic pain placebo[74]. In effect, the Dogra study shows a significant difference in pain
relief comparing oxcarbazepine at 1800 mg per day to placebo, while the
Grosskopf study showed no significant difference in pain relief. In yet
another study examining dose ranging of oxcarbazepine for the treatment of
DPN, no significant difference between the oxcarbazepine-treated groups
and placebo groups was established[75]. The results of this study show a
NNT of 7.9 at 1200 mg per day and 8.3 at 1800 mg per day when comparing
global assessment of therapeutic effect. The lack of consistent efficacy data
and a higher NNT supports the use of oxcarbazepine as a second tier
medication for DPN[7, 40].

5. Phenytoin (Dilantin)

Phenytoin was one of the first non-sedating, sodium channel antagonists developed for treating epilepsy. Other mechanisms of action include the
blockade of L-type mediated Ca2+ currents, inhibition of NMDA receptors,
depression of basal intra-neuronal levels of cyclic guanosine monophosphate
and an increase in concentration of neuronal GABA[54]. Two studies
conducted on phenytoin and DPN yield opposite results[76, 77]. The difference
may be due to the variation in study design including sample size, length of
follow-up, and most importantly lack of statistical power to detect differences
between the placebo and phenytoin[3, 76, 77]. For instance, Saudek et al.
investigated the treatment of diabetic symmetrical polyneuropathy and
concluded that phenytoin has no role in the treatment of this symptom entity
given no significant symptomatic improvement among those patients in the
phenytoin arm of the study[77]. However, Chadda et al. explored the effects of
diphenlhydantoin sodium in diabetic neuropathy and reported improvements
in pain[76]. Furthermore, evidence of phentyoin's efficacy for the treatment of
diabetic sensorimotor neuropathy would need to be considerable in order to
justify the clear risk of adverse effects (e.g., Stevens-Johnson syndrome,
hyperglygemia, gingival hyperplasia, liver toxicity, nerphrotoxicty) and drug
interactions (e.g., impairs coumadin efficacy) associated with this
medication[78, 79].
6. Sodium valproate (Valproic acid)

Sodium valproate potentiates the inhibitory transmitter γ-aminobutyric acid (GABA), and thereby increases GABA levels. Moreover, sodium valproate blocks T-calcium channels, increases neuronal potassium conductance, and prevents the degradation and uptake of GABA[54]. Kochar et al. examined the utility of sodium valproate for the treatment of DPN. They found a statistically significant reduction in pain scores utilizing the Bryan S. Williams & Paul J. Christo short-form McGill pain questionnaire (SF-MPQ), visual analogue scale
(VAS), and present pain intensity (PPI) among patients treated with sodium
valproate compared to placebo[80]. In an earlier study by Kochar et al.,
sodium valproate was investigated for its efficacy in treating DPN and was
proved beneficial compared to placebo (p < 0.05) at study conclusion [81].
However, a randomized, double-blind, placebo-controlled cross-over trial
found no significant difference between valproic acid and placebo in the
assessment of total pain among DPN patients[82]. Other studies confirm
valproic acid's poor efficacy compared to placebo for the reduction in overall
pain or improvement in quality of life[83].
7. Lamotrigine (Lamictal)
Lamotrigine
by voltage and frequency-dependent blockade of sodium channels. Other important actions include the blockade of
Ca2+ currents, altering presynaptic release of glutamate and aspartate, as well as
an increase in brain GABA concentrations[54]. A randomized placebo-
controlled study of lamotrigine for the treatment of DPN found that lamotrigine
attenuated painful diabetic neuropathy at a daily dosage of 200 to 400 mg, and
had a significantly superior analgesic effect compared with placebo[84]. Vinik et
al. investigated the efficacy of lamotrigine at 200 mg, 300 mg and 400 mg
doses in two replicate randomized, double-blind, placebo-controlled studies. In
one of the studies, lamotrigine was found to be efficacious in treating diabetic
neuropathy, but the result was not replicated in the parallel study. Further, no
difference between lamotrigine and placebo was found when measured by the
McGill Pain Questionnaire, Pain Disability Index, and Beck Depression
Inventory. Another study by Silver et al. reported no significant difference in
primary outcome measures when examining the efficacy of lamotrigine
compared with placebo[85]. The outcome variability between these studies
demonstrates marginal improvement in pain scores which do not support the
initial primary use of lamotrigine for the treatment of DPN[86]. Lamotrigine
requires careful titration to avoid the potentially devastating adverse effect of
a cutaneous hypersensitivity reaction (e.g., Steven's Johnson Syndrome),
which may limit its use as a primary agent for DPN treatment.
8. Topiramate (Topomax)

Topiramate blocks activity-dependent voltage-gated sodium channels, enhances the action of GABA, inhibits L-type voltage-gated calcium channels, acts presynaptically to reduce the release of glutamate, and post-synaptically blocks kainite/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) excitatory amino acid receptors[54]. Raskin et al. investigated Treatments of neuropathic pain topiramate's efficacy in treating DPN in a multicenter, randomized, double-
blind trial. The study included 323 subjects with DPN and utilized pain visual
analog scoring (VAS) as the primary measure of efficacy. Using a 100 mm
scale, the authors found mean score decreases from 68.0 mm at baseline to
46.2 mm among the topiramate group and decreases from 69.1 to 54.0 mm in
the placebo group (p = 0.038) [87]. In contrast, a multicenter, randomized,
double-blind trial examining pain reduction as the primary efficacy variable
included 1269 subjects with DPN. The investigators reported no statistically
significant difference in pain reduction between topiramate and placebo. There
were three arms to the study: 100 mg per day, 200 mg per day, and 400 mg per
day. Examining VAS scores as the primary measure of efficacy, mean pain
scores decreased from 60.1 mm at baseline to 36.1 mm (p < 0.043) in the
topiramate group 1 at 100 mg per day, and decreased from 60.4 mm to 44.7
mm in group 3 (i.e., no group 2). At 200 mg per day, mean pain decreased
from 55.8 mm to 38.3 mm, 58 mm to 37.8 mm, and 59.3 mm to 44.7 mm in the
three treatment groups (1, 2, and 3), respectively. In the 400 mg per day arm,
mean VAS pain scores decreased from 56.3 mm at baseline to 39.7 mm at
conclusion, and from 57.8 mm to 39.3 mm for groups 1 and 2 (no group 3).
The placebo mean VAS scores in the three groups decreased from 57.7 mm at
baseline to 43.1 mm, 57.5 mm to 41.6 mm, and 55.3 mm to 37.8 mm at study
conclusion. Only topiramate at 100 mg per day reached statistical significance
(p = 0.05) compared to placebo for the treatment of diabetic polyneuropathy[88].
Given mixed outcome data, the use of topiramate may be considered a second
line agent for treatment of DPN.
C. Other medications
1. Lidocaine 5% patch (Lignocaine)

Lidocaine 5% patch produces a local effect by antagonizing sodium channels, and causing a reduction in spontaneous ectopic nerve discharge[89]. Topically administered pain medications provide a number of advantages over first-line agents for neuropathic pain, such as tricyclic antidepressants, anticonvulsants, and opioids[90, 91]. The most important of these advantages includes the avoidance of clinically significant systemic drug concentrations, which may reduce the risk of systemic adverse effects and the potential for drug–drug interactions[92]. This may be particularly important in older patients since nausea, constipation, urinary difficulties, sedation and dizziness are possible adverse effects in patients using TCA's, antiepileptic drugs (AED) and opioids and may lead to medication discontinuation[93]. Argoff et al. studied the effectiveness of the lidocaine patch 5% on pain qualities associated with postherpetic neuralgia (PHN), painful diabetic neuropathy Bryan S. Williams & Paul J. Christo (DPN/PDN), and low-back pain (LBP)[94]. This open-label, non-randomized,
prospective trial utilized the neuropathic pain scale (NPS) as the primary
efficacy measure and showed significant improvement in several NPS
measures (p < 0.001) among patients with DPN. Further, Barbano et al.
evaluated the effectiveness, tolerability, and impact on quality of life of the 5%
lidocaine patch in painful diabetic polyneuropathy. Patients with and without
allodynia were included and significant improvement was demonstrated in
mean daily pain diary ratings from baseline SF-MPQ sensory, affective, and
visual analog scores, as well as Brief Pain Inventory (BPI) pain relief scores[95].
2. Mexiletine

Mexiletine is an oral, local anesthetic-type antiarrhythmic agent which is similar to lidocaine. Mexiletine is a class Ib antiarrhythmic[38]. Blockade
of sodium channels by mexiletine is frequency-dependent, having a greater
effect on rapidly firing channels. The mechanism of action of mexiletine in
painful diabetic neuropathy at the site or sites of action is unknown[96].
Mexiletine has shown promise in decreasing VAS pain scores in several
small, high quality studies. Further, mexiletine has shown promise in
reducing VAS pain scores, dysesthesia and paraesthesia[96, 97] and in select
patients with stabbing or burning pain, heat sensations, or formication[98].
Adverse effects of mexiletine have been associated with agranulocytosis,
hepatotoxicity, and toxic epidermal necrosis. It is absolutely contraindicated
in patients with second- and third-degree atrioventricular block unless an
artificial pacemaker is placed. Patients on mexiletine therapy should be
monitored with complete blood count and platelet measurement,
electrocardiogram, and liver enzyme tests[99]. These adverse effects may
limit its use in selective patients who have failed first-line treatments for
diabetic neuropathy.
3. Capsaicin

Capsaicin, the active component of hot chili pepper selectively stimulates unmyelinated C fiber afferent neurons and causes the release of substance P and subsequently depletes and prevents the reaccumulation of substance P. Moreover, capsaicin produces complete or nearly complete denervation of the epidermis[100]. Repeated application of capsaicin reversibly depletes stores of substance P, and possibly other neurotransmitters from sensory nerve endings[101]. In a 12-week double-blind, placebo-controlled randomized study, Low et al. investigated the efficacy of the capsaicin cream (0.075%) vs. inactive placebo cream for the treatment of chronic distal painful polyneuropathy. The group found no statistical difference in pain reduction measured by VAS, allodynia or activities of daily living [102]. In an 8-week Treatments of neuropathic pain multicenter, double-blind, vehicle-controlled trial, 0.075% topical capsaicin
was investigated for is efficacy in treating peripheral neuropathy associated
with diabetes[103]. The investigators showed a statistically significant
improvement compared placebo in physician's global evaluation scale
(69.5% vs. 53.4%), pain intensity (38.1% vs. 27.4%) and pain relief (58.4%
vs. 45.3%) among diabetic patients[103]. Biesbroeck et al. conducted an 8-
week double-blind, multicenter, parallel study to compare the efficacy of
topical capsaicin and oral amitriptyline in patients with painful diabetic
neuropathy. They concluded that topical capsaicin and oral amitriptyline
produced equal and statistically significant improvement in VAS pain and
physician's global evaluation scale[104]. Other RCTs have been inconsistent
with respect to capsaicin's effectiveness for the treatment of peripheral
neuropathy[105]. Capsaicin can be difficult for patients to apply, must be
applied multiple times a day to the entire painful area, and often causes
painful cutaneous sensations during the initial weeks of application that
may reduce patient compliance. However, capsaicin may be a reasonable
alternative for patients with contraindications or intolerances to oral agents.

4. Tramadol
Tramadol
μ-opioid receptor agonist and affects descending inhibitory pathways that modulate nociception, possibly by inhibiting presynaptic monoamine uptake and stimulating serotonin release. Theoretically, these properties may confer an advantage compared to opioids for the treatment of neuropathic pain[54]. For example, Sindrup et al. studied tramadol in a randomized, double-blind, placebo-controlled cross-over study and found better pain relief and allodynia reduction[106]. Patients rated their pain (median 4 vs. 6, p < 0.001), paraesthesias (median 4 vs. 6, p < 0.001), and touch-evoked pain (median 3 vs. 5, p < 0.001) as lower with tramadol than with placebo on a 0-10 point numeric scale. Their ratings of allodynia were decreased as well (0 vs. 4, p < 0.012). The NNT to obtain one patient with ≥ 50% pain relief was 4.3 (95%, CI 2.4-20), indicating statistically significant pain reduction in this study. Similar evidence for tramadol's effectiveness derives from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study[107]. Tramadol versus placebo was investigated using patient ratings on pain intensity as the primary efficacy measure (e.g., 5-point Likert scale). The group found that tramadol produced significantly (p < 0.001) greater pain relief compared to placebo with a NNT of 3.1. Finally, in a meta-analysis analyzing the effectiveness of tramadol in providing ≥ 50% pain relief, tramadol was found effective at relieving peripheral neuropathic pain, with a NNT of 3.8 (95% confidence interval 2.8 Bryan S. Williams & Paul J. Christo to 6.3)[108]. Hence, evidence suggests that tramadol may provide effective
pain relief in peripheral neuropathic pain.
D. Opioids

Opioid agonists such as codeine, morphine, oxycodone, and fentanyl mimic the activity of enkephalins and endorphins at the central descending pathways of the pain-processing loop[45]. Endorphins and enkephalins are endogenous opioids that are released from the periaqueductal gray matter and nucleus raphe magnus, respectively and travel within the central nervous system (CNS) descending pain-control systems[109]. The use and efficacy of opioids for the treatment of chronic pain is controversial; however, a growing body of clinical evidence supports their use in treating neuropathic pain. Opioid-induced adverse effects such as constipation, nausea, sedation, and the potential for addiction continue to limit their use among health care practitioners. Furthermore there is evolving data that suggest immunologic and endocrine effects of long-term opioid therapy as well as the hypothesized production of opioid-induced hyperalgesia with prolonged use [110]. A meta-analysis of 22 articles (e.g., 14 investigating short-term [< 24 hrs] opioid use and 8 studying intermediate [8-56 days] opioid use) revealed contradictory results when analyzing opioids for the treatment of neuropathic pain[111]. In the intermediate analysis, all eight trials reported that opioids were efficacious in reducing spontaneous neuropathic pain by demonstrating either superiority over placebo or a dose-dependent analgesic response. Short-term studies provided only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Those studies suitable for pooled analysis did show overall mean pain intensity 14 points lower in the opioid-treated patients than in those treated with placebo (95% CI, −18 to −10; p < 0.001)[111]. Though substantial clinical evidence is lacking for the specific use of opioids for the treatment of DPN, a multicenter, randomized, double-blind, placebo-controlled trial by Gimbel et al. examined the efficacy and safety of controlled-release (CR) oxycodone in 159 patients[112]. They found that oxycodone provided statistically significant reductions in average daily pain intensity at study end (e.g., 42 days); that is, the oxycodone group demonstrated an average daily pain intensity of 4.1 ± 0.3 compared to 5.3 ± 0.3 (p = 0.002) for the placebo groups. Another confirmatory study by Watson et al. examined oxycodone in a randomized, double-blind, crossover comparison study of the efficacy, safety and clinical effectiveness of controlled-release (CR) oxycodone compared to benztropine, an active placebo. They included pain intensity scores on a 100 mm visual analogue scale and pain relief scores as primary efficacy measures. Secondary efficacy measures incorporated the Pain Disability Index (PDI), Treatments of neuropathic pain health-related status outcome measure, SF-36, and pain and sleep questionnaire. At study completion, pain intensity outcomes showed significantly better pain intensity VAS scores (26.3 ± 24.7 vs. 46.7 ± 26.9, p = 0.0001) and significantly better pain relief scores (1.8 ± 1.4 vs. 2.7 ± 1.2, p = 0.0006) than placebo. When examining secondary measures, health-related quality of life domains were significantly better during the controlled-release oxycodone treatment period than placebo treatment for the Physical Functioning (p = 0.0029), Pain Index (p = 0.0001), Vitality (p = 0.0005), Social Functioning (p = 0.0369) and Mental Health Index (p = 0.0317) domains of the SF-36. Both the Standardized Physical Component (p = 0.0002) and the Standardized Mental Component (p = 0.0338) were significantly better during the CR oxycodone treatment period than the placebo treatment period. The calculated NNT was 2.6 based on the number of patients with at least moderate pain relief [113]. A Cochrane Collaborative meta-analysis on opioid use for neuropathic pain concluded that opioids reduce neuropathic pain, but are treatment-duration dependent[114]. The analysis of short-term trials showed varying statistically significant results. Although all short-term studies showed positive results in attenuating neuropathic pain, 4 trials reported means and standard deviations for pain intensity, which permitted meta-analysis for pain intensity after active drug or placebo. The Cochrane group concluded that short-term opioid trials yielded mixed analgesic efficacy, but emphasize that the analysis was based on only four studies. In contrast, the intermediate-term analysis found that opioids were efficacious in reducing the pain associated with neuropathy[114]. Rowbotham et al. studied high-strength and low-strength opioids for patients with refractory, chronic peripheral and central neuropathic pain[115]. Primary outcome variables include daily VAS scores. They found significantly greater pain reduction at eight weeks in the high-strength group (65.4 ± 18.2 mm to 42.1 ± 26.5 mm) than in the low-strength group (69.3 ± 17.0 mm to 53.4 ± 24.7 mm, p = 0.02)[115]. The investigators concluded that high dose opioids reduce neuropathic pain, but this decrement is accompanied by increasing side effects at higher doses. Finally, compelling but lower quality evidence from an open label trial of transdermal fentanyl for neuropathic pain conditions demonstrated a significant reduction in pain (-2.94 ± 0.27), meaningful percent pain relief (33.7 ± 14%), and a 37.4% increase in daytime activity[116]. The authors concluded that transdermal fentanyl provides significant reduction in neuropathic pain. Although opioids have shown efficacy for the treatment of several pain conditions including cancer pain, peripheral neuropathy, and post-herpetic neuralgia, they should be considered second-line medications when treating neuropathic pain. Table 3 provides a useful model for considering opioid use in neuropathic pain based on pain quality and adverse effects[40]. Bryan S. Williams & Paul J. Christo Table 3. Second and First Line Considerations for Opioids and Tramadol in Neuropathic
Pain.
Second Line Consideration
Side effect profile compared to other therapies Lack of long-term opioid therapy studies Risk of opioid induced hyperalgesia Risk of addiction First Line Consideration
Titration of a first-line medication to an efficacious dosage for prompt pain relief Episodic exacerbations of severe pain Acute Neuropathic pain Neuropathic cancer pain Eisenberg et al. acknowledge the value of opioids in their review of the efficacy and safety of opioids for the treatment of neuropathic pain[111]. They
further describe opioid-induced adverse effects in their analysis. For instance,
the most common adverse effects included nausea (NNH, 3.6; 95% CI, 2.9-
4.8), constipation (NNH, 4.6; 95% CI, 3.4-7.1), drowsiness (NNH, 5.3; 95%
CI, 3.7-8.3), vomiting (NNH, 6.2; 95% CI, 4.6-11.1), and dizziness (NNH,
6.7; 95% CI, 4.8-10.0). In a systematic review of opioid use for chronic non-
malignant pain, Moore & McQuay reported that approximately 50% of patients
may experience at least one adverse event (e.g., nausea, vomiting, constipation,
and drowsiness) and 20% of patients will discontinue opioid therapy due to
adverse events[117]. Morever, Højsted & Sjøgren's review of opioids for the
management of non-malignant neuropathic pain expresses concern over long-
term adverse effects of opioids, including physical dependence, tolerance,
addiction, immune suppression and opioid-induced hyperalgesia[118]. A
significant evidence base exists for the effectiveness of short-term opioid use;
however, the benefits and risks of long-term use remain inconclusive. As
investigators perform additional RCTs and longitudinal studies of increasing
duration, a more complete understanding of the value of opioids will be uncovered.
E. Dextromethorphan & levorphanol

Dextromethorphan (DM) is a dextrorotatory analogue of levorphanol, a noncompetitive antagonist of the NMDA-sensitive inotropic glutamate receptor[119-121]. It is also an agonist of the σ-1 receptor which suppresses the release of excitatory neurotransmitters, and may act on the N-type calcium channel[119-121]. Improvement in the function of NMDA receptor antagonists may improve the treatment of neuropathic pain. Investigators who research NMDA antagonists and other channel blockers theorize that relatively high doses of low-affinity, noncompetitive, channel blocking NMDA receptor Treatments of neuropathic pain antagonists such as dextromethorphan may offer a better therapeutic ratio
than dissociative, anesthetic-like blockers such as ketamine[122-124].
Randomized controlled clinical trials have demonstrated that acute, single-
dose administration of intraspinal and systemic NMDA glutamate receptor
antagonists in patients with chronic neuropathic pain reduces spontaneous
pain and hyperalgesia[121]. Furthermore, Sang et al. examined patients with
painful diabetic neuropathy (DN) and postherpetic neuralgia (PHN) in two
crossover trials[120]. The first trial examined the efficacy of dextromethorphan
vs. memantine vs. active placebo (e.g., lorazepam) and the second was a
dose–response trial. In the first study, dextromethorphan reduced pain
intensity by a mean of 33.4% from baseline in patients with DPN and
improved the efficacy variable of emotional dimension (e.g., QOL variable)
related to the disease and to pain. Responders from the first trial were
enrolled in the dose-response trial which showed that full-dose treatment with
dextromethorphan reduced pain significantly more than lorazepam
(34.8%, p = 0.027). A study by Thisted et al. examined the efficacy and
tolerability of concomitiant administration of dextromethorphan and
quinidine (DM/Q) for the treatment of DPN in an open-label, dose-escalation
study conducted at 5 clinical sites. They found that mean (SD) changes from
baseline in pain intensity rating scale (PIRS) scores were -1.8 (1.0) in the
DM120/Q120 mg per day group. Including all escalation intervals, the PIRS
change from baseline was -1.6 (0.9) (p < 0.001)[121]. The addition of
quinidine was hypothesized to contribute to the significant reduction in pain
by increasing the plasma concentration of dextromethorphan. Doses of
quinidine however were considerably lower than those used to treat
arrhythmias (e.g., 200-400 mg three times daily or four times daily is used to
suppress arrhythmias). The authors caution that these findings should be
considered merely suggestive of quinidine's benefit given that the study was
neither blinded nor placebo controlled.
F. Nonsteroidal anti-inflammatory drugs (NSAIDS)
Nonsteroidal
anti-inflammatory drugs (NSAID) are used to treat inflammation, pain, and fever. The analgesic effect of NSAIDs result from their ability to block prostaglandin synthesis by inhibiting the precursor enzyme, cyclooxygenase (COX)[45, 125, 126]. Generally, NSAIDs are effective in treating acute musculoskeletal pain and various other conditions such as arthritis, dysmenorrhea, and headaches[45, 126]. The efficacy of treating NP is questionable since multiple studies have yielded contradictory results. For example, ibuprofen and sulindac offered some pain relief for the treatment of diabetic neuropathy [127, 128]. Cohen et al. examined the efficacy of ibuprofen Bryan S. Williams & Paul J. Christo and sulindac for the treatment of DPN and found that compared to baseline, both drugs significantly reduced pain; however, long term use of NSAIDS may produce gastrointestinal and renal effects which limit their use[127]. Advancements in medicine have led to an increasing number of modalities for the treatment of pain, though prevention remains the best method for controlling diabetic pain. Strict blood glucose control with insulin can delay the onset of neuropathy in type 1 diabetes mellitus. For example, the diabetes control and complications trial demonstrated that strict insulin therapy decreased the incidence of neuropathy by 57-69%[129]. Although intensive therapy did not preclude the development of neuropathy, insulin therapy remained the best strategy for prevention and amelioration of diabetic peripheral neuropathy. Table 4 lists medications based on level of efficacy and provides an algorithm for the treatment of peripheral neuropathy. First line medications
offer the highest quality evidence, along with a more favorable side effect
profile. For instance, the algorithm begins with first line medications.
Clinicians may add or "cycle" through first-line medications, progress to
second-line medications, and then other medications for the treatment of
peripheral neuropathy. Monotherapy is recommended initially, though
combinations of first line, second line, or other medication categories may be
required to achieve meaningful analgesia.
Table 4. Algorithm for Treatment of Peripheral Polyneuropathy/Diabetic Peripheral
Neuropathy.
TCA ↔ Duloxetine ↔ Gabapentin ↔ Pregabalin Venlafaxine ↔ Lidocaine 5% Patch ↔ Lamotrigine ↔ Tramadol ↔ Carbamazepine ↔ Capsaicin ↔ Phenytoin ↔ Topiramate ↔ Opioids ↔ Mexiletine ↔ Oxcarbazepine ↔ Dextromethorphan 3. Human immunodeficiency virus (HIV) neuropathy

The etiology of human immunodeficiency virus (HIV) neuropathy or distal symmetrical polyneuropathy is unknown, but symptoms of polyneuropathy have been estimated to occur in > 35% of HIV+ patients[130-133]. As with diabetic neuropathy, optimizing pain therapies is essential for reducing pain. Tricyclic antidepressants and anticonvulsants have been investigated for their potential efficacy in treating HIV related neuropathy. For instance, amitriptyline and mexiletine were investigated in a randomized, double-blind Treatments of neuropathic pain trial of 145 patients with painful sensory neuropathy[133]. The primary
efficacy measure in the study was a change in mean pain intensity from
baseline. At study completion, the difference in mean pain intensities
between amitriptyline and placebo was only 0.035 units which did not reach
statistical significance. This finding was previously supported by an earlier
study by Shlay et al.[134]. A randomized, double-blind placebo-controlled
study by Hahn et al. examined the efficacy of gabapentin for the treatment of
HIV neuropathy[135]. Median pain scores were compared in the treatment and
placebo groups which showed that gabapentin reduced pain scores by 44.1%
(p < 0.05). The authors concluded that gabapentin was efficacious in treating
neuropathic pain related to HIV. In evaluating lamotrigine, Simpson et al.
found lamotrigine to be more effective than placebo for treating HIV related
neuropathy when comparing mean VAS scores in a randomized, double-blind
placebo controlled trial[136].
4. Chemotherapy-induced neuropathy

The mechanism by which chemotaxic agents cause neuropathy is unknown. The most neurotoxic agents include the vinca alkaloids (e.g., cisplatin
and its derivatives) as well as the taxanes[137]. These induced neuropathies are
often time sensitive and reversible and are drug, cumulative dose, and
duration dependent[138]. There are very few clinical trials assessing effective
drug treatment for chemotherapy-induced neuropathy. Hammack et al.
evaluated nortriptyline for the treatment of cis-diamminedichloroplatinum
(cisplatin)-induced neuropathy in a randomized, double-blind, placebo-
controlled trial. The group investigated the efficacy of nortriptyline and
utilized pain/paresthesias and change in the effect of pain on daily activities
as the primary efficacy measures. Results from the study indicated that
nortriptyline provided "modest improvement" in chemotherapy-related
neuropathy[139]. However, amitriptyline was recently examined for its efficacy
in the treatment of chemotherapy-induced neuropathy in a randomized double-
blind placebo control study[137]. The investigators used severity/intensity of
neuropathic pain, global improvement/quality of life, and sleep and change in
physical activity as efficacy measures. It was determined that amitriptyline did
not enhance global improvement/quality of life, nor did it demonstrate
statistical significance in improving sensory neuropathic symptoms.
5. Postherpetic neuralgia

Postherpetic neuralgia (PHN) is a term that is used to describe prolonged pain associated with herpes zoster or shingles. Among all of the neuralgic diseases, herpes zoster (HZ) has the highest incidence and occurs annually in Bryan S. Williams & Paul J. Christo approximately 500,000 people in the United States alone. Most of these individuals are 60 years of age and older and represent as much as 20 to 30% of the population. In fact, HZ occurs in as many as 50% of those people living until 85 years of age[140-146]. Herpes zoster typically erupts along one or two adjacent dermatomes. Thoracic, cervical, and ophthalmic involvement are the most common. Lesions progress from discrete patches of erythema to grouped vesicles which pustulate and crust in 7 to 10 days and may require a month to heal. The healed lesions often result in anesthetic scars, changes in pigmentation, and pain. Complete scab resolution usually occurs within 4 weeks. Thoracic dermatomes are affected in approximately 50% to 70% of all cases and cranial (e.g., especially the ophthalmic division of the trigeminal nerve), cervical, and lumbar dermatomes each account for 10% to 20% of cases. Affected sacral dermatomes represent only 2% to 8% of cases[142, 147- 153]. Herpes zoster is caused by viral replication. The virus spreads from a single sensory ganglion antidromically to the corresponding dermatome and eventually to the dorsal columns of the spinal cord[141, 147, 154]. The pain of acute zoster can be distinguished from postherpetic neuralgia (PHN), although the nature and timing of the symptoms may overlap. The most common definition of postherpetic neuralgia is the presence of pain for more than a month following the onset of the vesicular rash[141, 151, 152]. An algorithm for the treatment of PHN is suggested in Table 5. Multiple studies suggest that older age is a strong risk factor for the development of PHN. For instance, few children develop postherpetic neuralgia whereas 27, 47, and 73 percent of untreated adults over 55, 60, and 70 years of age respectively develop postherpetic neuralgia[142, 151, 152, 155-157]. Furthermore, greater severity of acute pain and greater rash severity represent risk factors for prolonged herpes zoster pain[153, 158-160]. Both the vaccine against varicella zoster virus (Varivax ®) and the newly released vaccine against herpes zoster (Zostavax ®) may lead to substantial reductions in morbidity from herpes zoster and PHN, respectively though long term epidemiological studies are needed to confirm the benefit of both vaccines. Table 5. Algorithm for Treatment of Postherpetic Neuralgia.
TCA ↔ Lidocaine 5% Patch ↔ Gabapentin ↔ Pregabalin ↔ SSRI Venlafaxine ↔ Opioids ↔ Duloxetine ↔ Tramadol ↔ Phenytoin ↔ Topiramate ↔ Lamotrigine ↔ Mexiletine ↔ Capsaicin Corticosteroids ↔ Antiviral Therapy ↔ VZV Vaccine (Preventive) Treatments of neuropathic pain a. Antidepressants
Tricyclic antidepressants (TCA's)

The tricyclic antidepressants (amitriptyline, imipramine, nortriptyline, and desipramine) have been successfully used for the treatment of PHN. For instance, multiple studies have established the TCAs as effective medications for PHN with a NNT ranging from 1.6-4.1[161-164]. Kishore-Kumar et al. in a randomized double-blind study examined the efficacy of desipramine in patients diagnosed with PHN and reported that the treatment group demonstrated statistically significant pain relief compared to placebo [162]. Raja et al. studied the effects of TCA's and opioids on pain relief, pain intensity, and cognitive function associated with PHN using a randomized, double-blind, placebo-controlled crossover study[163]. The investigators discovered that TCAs and opioids provided greater mean pain decreases than placebo (p < 0.001) with no statistical difference between opioids and TCA (p = 0.06)[163]. An early placebo-controlled study by Watson et al. highlighted the effectiveness of amitriptyline in treating PHN[161]. Watson et al. also showed no difference in the relief of continuous or brief pain, nor a difference in allodynia between amitriptyline compared to nortriptyline using a VAS pain scale [165]. This randomized, double-blind, crossover trial of amitriptyline versus nortriptyline was performed in 33 patients and further demonstrated equal drug effect on mood, disability, and satisfaction. However, a greater number of intolerable side effects were associated with amitriptyline compared to nortriptyline (p = 0.05). Most notably, patients more commonly reported xerostomia, constipation, and drowsiness. The beneficial effects of TCAs for the treatment of PHN have been replicated in several studies which support the use of these agents in PHN[164, 166]. Consistent with many pharmaceutical agents, TCAs may be contraindicated in patients with certain medical conditions and cause adverse effects that may require discontinuation. For example, clinicians should be mindful of using TCAs in older patients with cardiac rhythm disturbances[167-169]. One study indicated that 20% of patients treated with nortriptyline after a myocardial infarction developed adverse cardiac events[167, 170]. The overdose potential for TCAs is significant. That is, accidental or intentional overdose of TCAs can be lethal. In fact, the likelihood of successful suicide is 8-to 16-fold higher with TCAs compared to the non-tricyclic, serotonin-selective reuptake inhibitors (SSRI) such as trazodone and fluoxetine[171]. Accordingly, clinicians should use TCAs with the utmost caution in patients at risk for suicide or at risk of accidental death from overdose [40]. Although tricyclic antidepressants may be used for treating depression in patients with chronic pain, the risk of intentional overdose among depressed individuals must be Bryan S. Williams & Paul J. Christo acknowledged given a substantially greater risk of suicide associated with
TCA use compared to other antidepressants[5].
Other antidepressants
SSRIs may reduce pain in PHN. For example, Rowbotham et al.
examined TCAs and SSRIs for the treatment of PHN. No significant
differences (ANOVA p = 0.120) among desipramine, amitriptyline, and
fluoxetine were discovered in their randomized, double-blind, parallel design
study of 38 subjects[167]. More specifically, desipramine produced the greatest
reduction in pain intensity (47%), followed by amitriptyline (38%), and then
fluoxetine (35%) [167]. At time of publication, there were no published studies
examining the efficacy of serotonin-norepinephrine reuptake inhibitors (SNRI)
for the treatment of PHN.
b. Antiepileptic medications

The efficacy of gabapentin and pregabalin in relieving pain associated with PHN has been demonstrated in several randomized, placebo-controlled trials[172, 173]. In fact, gabapentin has produced greater pain reduction than placebo in RCTs of PHN[172-174]. In a multicenter, randomized, double-blind, placebo-controlled trial of 184 patients comparing gabapentin to placebo, gabapentin demonstrated greater effectiveness at treating PHN-associated pain than placebo[174]. The investigators used a change in average daily pain score based on an 11-point Likert scale as the primary efficacy variable. Patients receiving gabapentin showed a significant reduction in average daily pain score from 6.3 to 4.2 points compared to a reduction from 6.5 to 6.0 in the placebo group (p < 0.001)[174]. Dworkin et al. evaluated the efficacy of pregabalin for the treatment of PHN in a multicenter, parallel-group, double-blind, placebo-controlled trial [175]. His group used the mean of the last seven daily pain ratings as the primary efficacy variable. Dworkin et al. concluded that pregabalin was more efficacious in reducing mean pain ratings from the last 7 days compared to placebo. That is, the pregabalin-treated patients reported greater decreases in pain than the placebo group (endpoint mean scores 3.60 vs. 5.29, p = 0.0001). Further support for pregabalin's efficacy derives from another multicenter, double-blind, placebo-controlled trial of 238 patients[176]. Mean pain score was used as the primary efficacy variable while pregabalin was compared to placebo for response. Responders were defined as having a ≥ 50% reduction in pain. At study endpoint, there were statistically significantly greater proportions of responders in the pregabalin groups taking 150 mg per day (21/81, 26%, p = 0.006) and 300 mg per day (21/76, 28%, p = 0.003) than in the placebo group (8/81, 10%). Moreover, equally significant results were seen Treatments of neuropathic pain in assessing VAS scores. The 150 mg per day pregabalin group (VAS: 52.03,
p = 0.006) and the 300 mg per day group (VAS: 48.41, p = 0.0003)
demonstrated statistically significantly better mean VAS scores than in the
placebo group (62.05). In examining a reduction in sleep disturbance, the
investigators discovered a significant improvement in mean sleep interference
with the 150 mg per day group (3.13, p = 0.0003) and the 300 mg per day
(2.81, p = 0.0001) pregabalin group. Both groups were significantly superior to
placebo (4.24) in reducing pain-associated sleep interference[176].
c. Lidocaine 5% patch (Lignocaine)
The lidocaine patch received US FDA approval for the treatment of postherpetic neuralgia in 1999. Several trials have supported the efficacy of topical lidocaine. For instance, Rowbotham et al. demonstrated the efficacy of topically applied 5% lidocaine compared with both gel vehicle and observation (e.g., no treatment) for the treatment of PHN in a randomized, double-blind, vehicle-controlled study[177]. When compared to observation only, the five percent lidocaine patch was superior at all time points from 30 minutes to 12 h (individual time points p = 0.0001 to p = 0.021). In contrast to vehicle patch, the lidocaine patch (5%) provided superior relief at 4 h, 6 h, 9 h, and 12 h (individual time points p < 0.001 to p = 0.038). The vehicle patch, however was superior to observation only at 2 h and 6 h (individual time points p = 0.016 and p = 0.041)[177]. These findings have been replicated in subsequent studies[94] including a multicenter randomized, placebo-controlled, two-way, cross-over study utilizing VAS as the primary efficacy measure[178]. This study by Meier et al. found that the reported decrease in ongoing pain intensity and allodynia was highly significant in the lidocaine 5% patch group (p < 0.001) and even significant in the placebo group (p < 0.05) compared with the pre-treatment (basal) values at all time points of the assessment (2h, 4h, day 4, day 5, & day 7)[178]. A Cochrane Collaborative meta-analysis examining the efficacy of lidocaine 5% patches for the treatment of PHN concluded that topical lidocaine was better than placebo for pain relief (p = 0.003). However, the Collaborative did not recommend topical lidocaine as a first line treatment for postherpetic neuralgia[179]. Although the Cochrane Collaborative and select consensus statements and guidelines do not recommend topical lidocaine as an agent of first choice due to a of lack of comparison studies[7, 180], compelling arguments for its efficacy and value have been advanced by other publications[40, 181]. Topical lidocaine offers a good safety profile; therefore, it can provide excellent adjunctive therapy in older patients who may be more susceptible to the adverse effects of systemic medications. Bryan S. Williams & Paul J. Christo d. Mexiletine

Mexiletine is an oral analog of lidocaine. There is a paucity of data to support the use of mexiletine for the treatment of PHN. In fact, Finnerup et
al. concluded in an evidenced-based proposal for neuropathic pain treatment
that mexiletine seems to lack a pain relieving effect in HIV neuropathy, spinal
cord injury, and neuropathic pain conditions with prominent allodynia. He
further adds that mexiletine's proarrhythmic potential limits dose escalation and
consequently efficacy[6]. Dworkin et al. conclude that mexiletine shows only
modest or no benefit compared to placebo in treating NP[40]. Finally, a
Cochrane Collaborative meta-analysis of systemic lidocaine states that
intravenous lidocaine and mexiletine are more effective than placebo in
decreasing neuropathic pain; yet, the subgroup analysis reveals that lidocaine
and mexiletine are more effective for pain resulting from diabetes, trauma, and
cerebrovascular disease than from other causes[182]. In short, clinicians should
use mexiletine very cautiously in the older population given its significant risk
of adverse effects and poor evidence base for effectiveness.
e. Topical capsaicin

Capsaicin is a hot chili pepper extract that is available in the US as a cream or lotion in strengths of 0.025% and 0.075%. The mechanisms of action may include the release of substance P and other neuropeptides from nociceptive fibers (e.g., unmyelinated C fibers). Continued release of substance P depletes neuronal stores of neurotransmitters which ultimately inactivates local nociceptive function and therefore produces analgesia[183-185]. The topical application of capsaicin has been shown to relieve pain in postherpetic neuralgia, nerve injury pain, and mixed neuropathic pain conditions. For instance, a double-blind, vehicle-controlled study of 143 patients with chronic postherpetic changes in pain severity as reported on the categorical scale, visual analogue scale for pain severity, visual analogue scale for pain relief, and functional capacity scale showed significant improvement with capsaicin 0.075% cream[186]. The authors concluded from their study that capsaicin is safe and effective for controlling the pain of postherpetic neuralgia. In contrast, a review of six double-blind placebo controlled trials (656 patients) analyzing the efficacy of capsaicin for the treatment of neuropathic pain conditions found that capsaicin offered moderate to poor efficacy[187]. The relative benefit of topical capsaicin at 0.075% compared to placebo was 1.4 (95% confidence interval 1.2 to 1.7) and the NNT was 5.7 (4.0 to 10.0)[187]. Hence, capsaicin may be useful as adjunctive therapy or even monotherapy for a small number of patients who fail to respond to or become intolerant to other treatments. The application of capsaicin may cause discomfort and a burning sensation associated with initial nociceptor activation. However, it Treatments of neuropathic pain is not associated with systemic adverse effects and may serve as a beneficial
therapy in older patients who are more intolerant to systemic medications.
f. Dextromethorphan

Dextromethorphan acts as an NMDA receptor antagonist as well as a weak analgesic. It can be combined with opioids to reduce the development of tolerance. Data indicate that dextromethorphan provides little relief of PHN pain or neuropathic pain. For example, dextromethorphan reduced pain intensity by a mean of only 6.5% and did not show a significant reduction in baseline pain intensity (mean difference, - 0.9; 95% confidence interval, - 2.3 to 0.5) when studied a multicenter randomized, placebo-controlled, double-blinded trial for PHN and DPN[120]. These results are consistent with other studies that indicate the extent to which dextromethorphan is an ineffective treatment
for PHN[6, 7, 40, 122].
6. Trigeminal neuralgia

Trigeminal neuralgia (TN) occurs in one or more branches of the fifth cranial nerve and is described as an excruciating, stabbing, transient (< 2 minutes) and usually unilateral facial pain that may erupt spontaneously or can be triggered by gentle, innocuous stimuli and is separated by pain-free intervals of varying duration[188]. TN represents a well-known cause of recurrent facial pain and ranks as the most common cause of facial neuralgia. The incidence of TN is 4 to 5 per 100,000 people[189-191] and occurs in approximately 1% of patients with multiple sclerosis[190-192]. Approximately 2% to 8% of patients with TN suffer from multiple sclerosis[190-192]. TN is more common in females, ranging from 1:2 to 2:3 (male to female) and most commonly presents in the sixth decade of life[189-198]. Development of TN in a patient younger than 40 years of age (< 10%) suggests the possibility of multiple sclerosis as well as secondary (e.g., symptomatic) TN in which an underlying disease can be identified such as an intracranial tumor[191,192,194,199]. Idiopathic TN if often difficult to treat because the etiology remains unknown. Despite the availability of several successful treatment options, no universally accepted medical or surgical treatment protocol exists. It is important to differentiate TN from trigeminal neuropathy. For instance, trigeminal neuropathy presents with prominent sensory loss and only mild pain. This distinction can be detected with a careful history and physical examination. The pain of TN also differs from the pain following reactivation of the varicella zoster virus, which typically presents in older adults [195]. Table 6 provides a suggested algorithm for the treatment of TN. Bryan S. Williams & Paul J. Christo In many chronic neurogenic pain disorders, therapeutic options are limited and therapeutic responses may only be partial. TN is unique because the majority of patients respond to treatment and many have complete elimination of painful attacks for months or even years[200]. Anticonvulsants are one of the most effective classes of drugs for controlling the paroxysmal pain associated with trigeminal neuralgia. Consequently, they have become the mainstay of treatment despite the evidence from just a few RCTs. Although antidepressants can be quite effective agents for neuropathic pain, there is only one trial of their use in trigeminal neuralgia which demonstrated some improvement in pain[201]. Current evidence suggests the use of carbamazepine as a first line agent, and oxcarbazepine if patients experience inadequate analgesia or intolerable adverse effects. Limited evidence supports the use of lamotrigine and baclofen as alternative agents as well as antidepressants, pregabalin, gabapentin, opioids, and transdermal products[201]. Table 6. Algorithm for Treatment of Trigeminal Neuralgia.
First Line: Carbamazepine ↔ TCA ↔ Gabapentin ↔ Pregabalin ↔ Duloxetine Second Oxcarbazepine ↔ Venlafaxine ↔ Opioids ↔ Tramadol ↔ Lidocaine SSRI ↔ Phenytoin ↔ Capsaicin ↔ Topiramate ↔ Lamotrigine ↔ Mexiletine ↔ Corticosteroids ↔ Antiviral Therapy ↔ VZV Vaccine
a. Carbamazepine
Carbamazepine is FDA approved for the treatment of trigeminal
neuralgia (TN) and remains the treatment of choice for this painful condition.
Multiple studies have proven the efficacy of carbamazepine for the treatment of TN[202-205]. However, the drug has limited usage due to adverse effects such as drowsiness, dizziness, constipation, rash, leukopenia, abnormal liver function tests, ataxia and drug-drug interactions particularly with warfarin (NNH 3, 95% CI 2 – 4)[201]. Finnerup et al. calculated a NNT of 1.7 (1.3–2.2) for the treatment of trigeminal neuralgia[6]. In a Cochrane Collaborative meta analysis, carbamazepine was shown to be effective for treating pain caused by nerve damage, including TN and calculated a NNT of 2.5 (95% confidence interval 2.0 - 3.4)[70]. Notwithstanding carbamazepine's poor tolerability (e.g., thrombocytopenia, leukopenia, hyponatremia) and the introduction of newer agents to the market, carbamazepine probably remains the most effective drug for controlling TN[6, 201]. Treatments of neuropathic pain b. Oxcarbazepine
The use of carbamazepine is complicated by pharmacokinetic factors and sometimes severe adverse events, particularly in elderly patients. Oxcarbazepine,
a keto analog of carbamazepine is shown to be of comparable efficacy and is
significantly better tolerated than carbamazepine for the treatment of newly
diagnosed epilepsy[18, 206]. Multi center, randomized trials have reported
comparable efficacy between carbamazepine and oxcarbazepine for the
treatment of TN[207]. It is considered a second line therapy for trigeminal
neuralgia. The drug's more favorable adverse effect profile and reduced drug-
drug interactions make it especially useful for patients that typically require
multiple medications for the control of other systemic conditions [201].
Clinicians must carefully titrate higher doses while monitoring for
hyponatremia.
7. Central/post-stroke pain

Central pain (CP) can be defined as pain initiated or caused by a primary lesion or dysfunction in the CNS [208]. CP can occur after lesions of the spinal
cord caused by various mechanisms (e.g., injury, syringomyelia, infarction,
tumor, myelitis) or cerebral lesions of nonvascular origin (e.g., multiple
sclerosis, tumor)[209, 210]. The injury to the central nervous system is
insufficient to cause hypoalgesia; rather, the insult disrupts spinothalamic
pathways that may contribute to neuronal hyperexcitability, loss of
descending inhibitory control mechanisms, and alterations in the processing
of incoming noxious and non-noxious stimuli. This pathologic process results
in abnormal pain perception[211-213]. Regardless of the etiology, CP poses
many challenges to treatment. Similar to other neuropathic pain states, pain
control rather than complete pain relief should be the focus of therapy.
a. Tricyclic antidepressants

Tricyclic antidepressants (TCA) have been used for the treatment of neuropathic pain for several years and may confer additional benefit through their anxiolytic actions and sedative properties (antihistaminergic)[214]. In a double-blind, 3-phase, placebo controlled crossover trial, Leijon & Boivie studied the pain-relieving effect of amitriptyline and carbamazepine in 15 patients with central post-stroke pain[215]. Efficacy was measured by daily ratings of pain intensity, post-treatment global ratings of pain relief, and estimation of depression scores at the 28 day study end. The authors concluded that amitriptyline produced a statistically significant reduction in pain when compared to placebo (NNT = 1.7; CI 1.2–3.1) and compared to carbamazepine (800 mg)[7, 215]. In a meta-analysis by Finnerup et al., the Bryan S. Williams & Paul J. Christo calculated NNT for the treatment of central pain by TCAs was 4.0 (95%
confidence interval 2.6–8.5)[6]. In general, RCT's for pain therapy that
achieve a NNT of 5.5 or lower demonstrate statistically significant pain
reduction for active treatment compared to placebo. Therefore, a NNT of
4.0 for TCAs in central pain suggests an effective agent for this condition.
However, there is limited drug efficacy data across different etiologies of
central pain, and there are flaws in treatment recommendations based on
extrapolating data from peripheral neuropathic pain conditions rather than
studies on specific central pain states such as post-stroke pain or spinal cord
injury pain. Further, TCAs may not be well tolerated in older patients with
stroke; therefore clinicians should consider gabapentin or pregabalin in
these circumstances[6, 7].
b. Antiepileptic medications

Some anticonvulsants show benefit in treating central pain caused by stoke or spinal cord injury. For instance, carbamazepine and amitriptyline were studied for the treatment of CP and carbamazepine's effect showed no statistical significance in the treatment of central post-stroke pain compared to placebo[215]. Lamotrigine, however does appear to have benefit. For example, Vestergaard et al. showed that lamotrigine-treated patients with central post stroke pain achieved significantly lower pain scores with a reduction in the mean pain score of 2 points[216]. A reduction of 2 points was deemed clinically significant due to the generally poor response to treatment in CP states. Furthermore, Finnerup et al. reported that lamotrigine significantly reduced pain at or below the level of spinal cord injury in patients with incomplete damage to the spinal cord[217]. Both gabapentin and pregabalin have been investigated for the treatment of central pain. Levendoglu et al. studied gabapentin's effect on neuropathic pain associated with spinal cord injury in a randomized, double-blind, placebo-controlled, crossover trial[218]. VAS scores were significantly different between the gabapentin-treated group and placebo group at study end (p < 0.001), but the results failed to reach statistical significance for treating itchy, dull, sensitive, and cold type NP related to spinal cord injury. Pregabalin does demonstrate effectiveness in central pain. For example, Siddall et al. compared pregabalin to placebo in patients with spinal cord injury using the endpoint of mean pain score as the primary efficacy measure[219]. Pregabalin was superior to placebo using the primary efficacy variable. Efficacy comparison yielded a ≥ 30% reduction (42% vs. 16%; p < 0.001) and a ≥ 50% reduction (22% vs. 8%; p < 0.05) in pain scores from baseline at study endpoint for the pregabalin treated group versus the placebo group. Moreover, the 30% responder group yielded a Treatments of neuropathic pain NNT of 3.9 and the 50% responder group an NNT of 7.1[219]. Another study
by Vranken et al. evaluated pregabalin in patients with central pain induced
by brain or spinal cord injuries[213] and used pain intensity scores recorded
on the visual analog scale (VAS) as the primary efficacy measure. A
statistically significant decrease was shown in mean pain score at study
endpoint for pregabalin treatment (7.6 ± 0.8 to 5.1 ± 2.9) compared with
placebo (7.4 ± 1.0 to 7.3 ± 2.0). In fact, the visual analog scale-score
difference between pregabalin and placebo was 2.18 (95% CI: 0.57–3.80,
p = 0.01).
8. Postsurgical/traumatic and phantom limb pain

The incidence of persistent postsurgical pain (e.g., > 3–6 months) may be alarmingly high. However, incidence of persistent postoperative pain remains controversial, but has been reported following numerous surgical procedures including limb amputation, thoracotomy, mastectomy, cholecystectomy, and inguinal hernia repair[220]. Phantom limb phenomena have been described as abnormal sensations, with or without pain that is referred to the surgically or traumatically amputated limb[221]. The incidence of phantom pain ranges broadly from 0% to 100%[221, 222]. Distinctions should be noted between phantom limb pain (e.g., painful sensations referred to the absent limb), phantom limb sensation (e.g., any sensation except pain that is experienced in the absent limb), and stump pain (e.g., pain localized to the stump), although each of these may coexist in an individual patient at different times[220, 223]. In the immediate postoperative period, the incidence of phantom pain and phantom sensation is reported to be 72% and 84% respectively whereas 6 months after amputation, the incidence of each is 67% and 90% respectively[221, 224, 225]. Similar to the incidence of phantom pain, an estimation of the long-term prevalence of phantom pain varies considerably from 60% to 80%[221, 223]. Several risk factors have been identified for the development of phantom limb pain including the degree of preoperative pain, the magnitude of intraoperative noxious input, the intensity of postoperative pain, and psychological factors[220, 226, 227]. Post-thoracotomy pain syndrome is defined as pain that recurs or persists along a thoracotomy incision for at least 2 months after the surgical procedure[220, 228]. The true incidence of post-thoracotomy pain syndrome is difficult to determine and ranges from 5% to 80%[220, 229]. It has been estimated that 50% of all patients will suffer from persistent chest wall pain 1 to 2 years after thoracotomy. Indeed as many as 30% of patients may still experience pain 4 to 5 years after surgery [220, 230]. Postmastectomy pain syndrome consists of persistent pain in the anterior chest and axilla, as well as medial and posterior parts of the arm following Bryan S. Williams & Paul J. Christo breast surgery[220]. The reported incidence of postmastectomy pain after surgery for breast cancer varies between 4% to 100%[220, 231, 232]. This pain can be sufficiently severe to interfere with sleep and performance of daily activities[220, 233, 234]. Furthermore, inadequately treated postmastectomy pain may result in an immobilized arm, severe lymphedema, frozen shoulder syndrome, and even complex regional pain syndrome (CRPS)[220, 235]. Both TCAs and anticonvulsants have been studied in phantom limb phenomena and gabapentin seems to offer some benefit. For example, Robinson et al. investigated the efficacy of amitriptyline for the treatment of phantom limb pain and residual limb pain in a double-blind, randomized, active placebo-controlled study[236]. The authors concluded from the study that there was no significant statistical difference between amitriptyline and placebo for the treatment of phantom limb pain. In a study examining the effects of gabapentin on post-amputation pain, gabapentin was compared to placebo in patients undergoing limb amputation for peripheral vascular disease[237]. Primary outcome measures included rates of phantom pain and intensity of stump and phantom pain at the conclusion of the 30-day treatment period and then six months later. Secondary outcome measures were frequency, duration, intensity of phantom pain attacks, descriptions of pain (e.g., using the MPQ) and consumption of opioids. Treatment with gabapentin in the early postoperative period produced no short-term (e.g., 30 days) or long-term (e.g., 6 months) effect on post-amputation pain. These results are consistent with a study conducted by Smith et al. who found no reduction in phantom limb pain among post-amputee patients treated with gabapentin[238]. In contrast, gabapentin was found to be effective for phantom limb pain based on a study by Bone et al.[239]. This was a randomized, double-blind, placebo-controlled, cross-over study. Primary outcome measures included VAS pain intensity differences compared with baseline. At the end of the six-week treatment period, weekly VAS scores were 2.9 ± 2.2 in the gabapentin arm (baseline 6.1 ± 1.8) and 5.1 ± 2.2 for the placebo arm (baseline 6.7 ± 1.9), p = 0.025. The authors concluded that gabapentin was efficacious in reducing spontaneous phantom limb pain. Various other pharmacologic and interventional strategies have been proposed to reduce acute and chronic post-thoracotomy pain. Such therapies include NSAIDS, parenteral opioids, epidural and paravertebral infusions of local anesthetics, intercostal and phrenic nerve blockade, and cryotherapy[240, 241]. Each therapy, however has produced variable results and no single strategy demonstrates effectiveness in all patients[241]. Tricyclic antidepressants show mixed effectiveness for the treatment of chronic thoracic pain[242] and for other neuropathic pain conditions. Clinicians may initiate TCAs for chronic post-thoracotomy pain, but be Treatments of neuropathic pain mindful of their risks associated with patients having a history of myocardial infarction, heart block, and congestive heart failure. These cardiac conditions may indeed be more prevalent in the post-thoracotomy population. Gabapentin may offer a safer and more effective alternative to TCAs for post-thoracotomy pain. For instance, Sihoe et al. studied sixty consecutive patients complaining of refractory pain following thoracic surgery or trauma and in whom gabapentin was prescribed for a mean duration of 21.9 weeks[240]. At study termination, 73.3% of patients reported a reduction in their pain scores on a 10-point analog scale compared to their scores prior to gabapentin treatment. There were 19 patients (e.g., 42.2%) who reported a reduction in their pain scores of ≥ 50%. Furthermore, 75% of patients affected with chest wall paresthesia reported statistically significant relief. Solak et al. examined the efficacy of gabapentin and naproxen in a similar patient population of those suffering from post-thoracotomy pain[241]. The primary outcome measures included a reduction in VAS pain score to <5, and a Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score of <12 as evidence of pain reduction. At study conclusion, 17 (e.g., 85%) gabapentin-treated patients and 3 (e.g., 15%) naproxen-treated patients reported VAS scores <5 (p = 0.001), and 17 (85%) patients in the gabapentin group and 0 (e.g., 0%) patients in the naproxen group reported LANSS scores of <12 (p = 0.001). The authors concluded that gabapentin is safe and effective for the treatment of post-thoracotomy pain with minimal side effects and high patient compliance. The calculated NNT of the study was 1.4, indicating a clinically meaningful measure of effect and low risk liability related to gabapentin. Antidepressants have been used for the treatment of neuropathic pain following surgery for breast cancer. Kalso et al. studied amitriptyline in a randomized, double-blind placebo-controlled crossover trial, and used the VAS and verbal rating scale as outcome measures[243]. In this study, 8/15 patients experienced a ≥ 50% decrease in pain intensity, while only 2/15 in the placebo group responded favorably (e.g., NNT was 2.5). The serotonin- norepinephrine reuptake inhibitors (SNRI's) have also been studied in the treatment of neuropathic pain following surgery for breast cancer. For example, Tasmuth et al. examined venlafaxine in a randomized, double-blind placebo-controlled crossover trial using VAS and verbal rating scale (VRS) as outcome measures[244]. The authors concluded that average daily pain intensity was not significantly reduced by venlafaxine compared to placebo, but a statistically significant difference was observed in average pain relief and maximum pain intensity with venlafaxine compared with placebo. Bryan S. Williams & Paul J. Christo 9. Cancer pain
Fifteen to 40% of all persons with cancer are estimated to experience neuropathic pain[245-252]. Cancer patients may present with more than one source of their pain and describe features of both nociceptive and neuropathic pain. Neuropathic pain may be directly related to the malignant disease such as tumor infiltration of peripheral nerves, plexi, roots, or spinal cord. It may arise from efforts to treat the disease such as surgery, chemotherapy, or other drug induced neuropathy or neuritis, and even from radiation induced injury to peripheral nerves and the spinal cord. This type of pain is invariably associated with sensory changes caused by injury to the central or peripheral nervous system and may be incompletely responsive to opioid therapy. Patients typically describe this pain as burning, shooting, pins/needles, electrical or numb, and it tends to radiate over dermatomal distributions. In contrast, nociceptive pain is associated with tissue injury from surgery, trauma, inflammation, or tumor. The pain is caused by stimulation of pain receptors in cutaneous and deeper musculoskeletal structures. It is often proportional to the degree of nociceptor activation. Both somatic and visceral pain conditions may be characterized as nociceptive. Patients frequently describe features of both neuropathic and nociceptive pain. For instance, a patient with a solid-tumor may report painful symptoms of both a nociceptive and neuropathic nature. Cancer pain may result from direct invasion of tumor into nerves, bones, soft tissue, ligaments and fascia, and may induce visceral pain through distension and obstruction. While over two-thirds of cancer pain usually results from the tumor burden, a quarter of pain experienced by cancer patients can be attributed to the cancer-related treatments[253]. For instance, surgery, radiation, and chemotherapeutics may all elicit acute pain that diminishes in time while other therapies may cause chronic pain conditions[254]. Radiation treatment frequently causes acute muscle stiffness and aching, but carries the risk of chronic pain secondary to nerve injury, chronic inflammation, osteoradionecrosis, or myofascial injury. Surgery-associated pain may result from direct nerve injury, inflammation, post-amputation phantom pain conditions, and even the development of Complex Regional Pain Syndrome (CRPS). Many chemotherapeutic agents are known to cause pain. Several classes, such as the alkaloids, platinum-based compounds, and the antimitotics are known to contribute to peripheral neuropathies. The World Health Organization (WHO) has published three-step guidelines for the treatment of cancer pain which promote the use of systemic opioid therapy in concert with non-opioids and adjuvant medications (Figure 1)[255-257]. Some authors have found that application of these guidelines provides adequate Treatments of neuropathic pain analgesia in 75% to 95% of all patients with cancer pain[255-257]; however, others report that as many as 50% of cancer patients with pain may remain undertreated[258]. Clinical experience and literature-based reports suggest that neuropathic cancer pain may poorly respond to opioids, thus requiring other strategies to effectively treat a neuropathic component of cancer pain[259, 260]. For example, Arner and Meyerson's paper examining the effectiveness of opioids in treating neuropathic pain described that opioids failed to provide moderate or complete relief among this group of patients[261]. Kupers et al. found a similar result in their randomized double-blind placebo controlled trial examining opioids and their responsiveness to idiopathic pain and neuropathic pain states[262]. The group concluded that opioids more effectively reduce idiopathic pain compared to neuropathic pain. Yet, studies in non-cancer pain conditions do reveal the value of using opioids to control neuropathic pain. For instance, Agarwal et al. investigated the use of transdermal fentanyl in neuropathic pain of non-cancer origin and found that transdermal fentanyl significantly reduced pain intensity and increased levels of activity[116]. Moreover, Raja et al. found that opioids effectively treat neuropathic pain (e.g., postherpetic neuralgia) without impairing cognition[163]. Opioid for moderate to Pain persisting or increasing Opioid for mild to Pain persisting or increasing Figure 1. WHO Analgesic Ladder for Cancer Pain.
Bryan S. Williams & Paul J. Christo Adjuvants include non-opioids that confer analgesic effects in certain medical conditions, but primarily treat conditions that do not involve pain. Clinicians typically prescribe adjuvants for the treatment of neuropathic pain like postherpetic neuralgia (PHN) or painful diabetic neuropathy. The evidence for their effectiveness derives more from studies in the nonmalignant pain population rather than the cancer pain population. However, the pathologic processes of neuropathic pain are assumed to be similar in both groups of patients; therefore, these agents can be successfully used in treating neuropathic pain in cancer patients. Medications such as corticosteroids, topical local anesthetics, antidepressants, anticonvulsants, bisphosphonates, and radiopharmaceuticals are included among the group of agents viewed as adjuvants. For example, Stute et al. investigated the neuropathic pain presentation (e.g., nerve compression pain, nerve injury pain, and sympathetically-maintained pain) among 213 cancer patients and found that 79% exhibited nerve compression pain, 16% nerve injury pain, and 5% sympathetically-maintained pain[263]. Patients with nerve injury or sympathetically mediated pain were more likely to require adjuvant therapy including anticonvulsants or antidepressants in order to adequately control their pain. Along with anticonvulsants and antidepressants, clinicians may use corticosteroids while treating advanced malignancies which can improve pain, combat anorexia, ease nausea, and reduce malaise [259]. Adjuvants have been shown to improve pain ratings in several pain conditions and can confer meaningful relief to patients suffering from neurogenic cancer pain. The antidepressants can treat neuropathic pain and offer analgesic effects independent of their antidepressant effects[34, 35]. The strongest level of evidence for analgesic efficacy exists for the tricyclic antidepressants (TCA) and specifically the tertiary amines (e.g., doxepin, amitriptyline)[34]. The secondary amines (e.g., nortriptyline, desipramine) also produce analgesia and offer a more favorable side effect profile, especially if clinicians are concerned about sedation, anticholinergic effects, and dysrhythmias. Clinicians tend to use TCAs in cancer pain linked to surgery, chemotherapy, radiation therapy, or malignant neural infiltration. TCAs may also be useful as anxiolytics and sedatives, often promoting sleep. The selective serotonin reuptake inhibitors (SSRI) provide little analgesia based on clinical experience, and the literature demonstrates mixed results in RCTs. Some clinicians may use the SSRIs in managing neuropathic pain for patients who fail TCAs because SSRIs yield a lowered risk of adverse events[44]. Anticonvulsants may be effective for various types of neuropathic malignant pain. These medications typically attenuate shooting, stabbing, burning, and electric-like sensations associated with a dysfunctional nervous Treatments of neuropathic pain system. Gabapentin, for instance could be considered a first line agent for
treating neuropathic pain. High quality evidence (e.g., RCTs) supports its
analgesic effect, safety, good tolerability, and absence of drug-drug
interactions[56, 264, 265]. In the malignant pain population, Ross et al. examined
the effectiveness of gabapentin for the treatment of cancer-related neuropathic
pain [266]. Patients either presented with treatment-related (n = 25) or tumor-
related (n = 37) neuropathic pain. At a median gabapentin dose of 1200
(range of 300–1800) mg per day, there was a statistically significant
reduction in the worst (p < 0.0001), average (p < 0.0001), and current
(p = 0.0018) pain scores. Twenty-eight of sixty-two (28/62 [45.2%]) patients
achieved at least a one-third reduction in their pain score (95% CI 32.5–58.3).
This corresponds to a NNT of 2.2 (95% CI 1.7–3.1). The authors concluded
that gabapentin is an effective treatment for cancer-related neuropathic
pain[266]. Adding gabapentin to opioids substantially improves pain control
among cancer patients. For instance, Bennett conducted a multicenter RCT of
121 cancer patients with neuropathic pain and found that gabapentin provided
better pain relief when combined with systemic opioids[267]. Clinicians may
consider pregabalin for use in neuropathic cancer pain given strong evidence
for its analgesic effect, rapid titration schedule, and tolerability[5, 268]. Although
there is no evidence base for the use of pregabalin in cancer-related
neuropathic pain, clinicians may extrapolate its potential benefit in cancer
pain from studies in non-malignant neuropathic pain conditions[175, 268].

10. Complex regional pain syndrome (CRPS)
The term Complex Regional Pain Syndrome (CRPS) is broad, non- specific, and incorporates an array of signs and symptoms that this syndrome exhibits. Two subtypes exist: complex regional pain syndrome, Type I (RSD) and complex regional pain syndrome Type II (Causalgia)[269]. CRPS, Type I refers to a posttraumatic syndrome causing spontaneous pain not limited to the distribution of a single nerve and disproportionate to the inciting event. CRPS Type II represents a pain syndrome occurring after evidence of a specific nerve injury and not necessarily limited to the territory of the injured nerve. The syndrome is characterized by intense, excruciating (aching, burning, shooting, stabbing) pain usually in one extremity or part of an extremity. Manifestations of CRPS reflect pathologic changes in the autonomic, sensory, and motor systems. Patients typically report pain caused from stimuli that ordinarily do not provoke pain (allodynia) and/or describe exaggerated responses to stimuli that are normally painful (hyperalgesia). Other common CRPS symptoms include vasomotor disturbances such as temperature asymmetry and/or skin color changes as well as sudomotor Bryan S. Williams & Paul J. Christo changes in the form of asymmetry of hyperhidrosis (sweating), dryness, edema, or shiny skin in the affected region. Motor dysfunction may manifest as spasm, tremor, dystonia, weakness, atrophy, or contracture in the affected extremity and trophic disturbances may present as changes in skin, nails, or hair pattern. The name commonly used for this syndrome, reflex sympathetic dystrophy (RSD) is actually a misnomer in that it implies a reflex mechanism associated with a hyperactive sympathetic nervous system. However, animal models suggest that altered neuromodulation, nerve hyperexcitability, and central sensitization may all contribute to this complicated disease process known as CRPS. Generally, pain can be elicited by movements and pressure at the joints, even if these are not directly affected by the inciting lesion[270]. Weakness of all muscles of the affected extremity are often present[270, 271]. Furthermore, sequalae of persistent motor and trophic abnormalities may cause passive movement restrictions of the joints and tendons[270]. The tenets of proper CRPS treatment include pain control and functional restoration. Medications such as the TCAs, gabapentin, and opioids have shown broad enough analgesic activity in other neuropathic pain conditions (e.g., DPN and PHN) that they can be applied to the treatment of CRPS. Clinical goals focus on reducing stimulus-evoked pain, lessening pain associated with extremity movement, and increasing the functional state of the extremity through physical therapy. The initiation of early functional restorative therapy is critical and correlates with improved outcomes[272-274]. CRPS is complex and poorly understood. A lack of long-term evidence for conventional neuropathic medications such as the tricyclic antidepressants may not necessarily reflect a lack of efficacy. Researchers have avoided inclusion of patients with CRPS in the efficacy trials of neuropathic pain medications due to the lack of precise "diagnostic" criteria for this disease[275]. Consequently, multiple medications are currently used to ease the pain of CRPS with incomplete results including corticosteroids, nonsteroidal anti-inflammatory drugs, calcitonin, dimethylsulfoxide (DMSO), N-acetylcysteine, antidepressants, antiepileptics, clonidine, and opioids. An algorithm for the treatment of CRPS is outlined in table 7. Table 7. Algorithm for Treatment of Complex Regional Pain Syndrome.
TCA ↔ Gabapentin ↔ Pregabalin ↔ Bisphosphonate/Calcitonin SNRI ↔ Lidocaine 5% Patch ↔ Corticosteroids ↔ Lamotrigine ↔ Tramadol ↔ Opioids ↔ Pregabalin SSRI ↔ Phenytoin ↔ Capsaicin ↔ Topiramate ↔ Mexiletine ↔ Oxcarbazepine ↔ Carbamazepine ↔ Dextromethorphan Treatments of neuropathic pain a. NSAIDS and corticosteroids

There are few RCTs of oral medications that have been performed in CRPS patients; however, some controlled trials of oral therapies for
neuropathic pain have included CRPS patients. Features that may
characterize the acute phase of the disease, such as edema, warmth, and
erythema illustrate an inflammatory component[275, 276]. Consequently,
nonsteroidal anti-inflammatory drugs[275, 277] and corticosteroids have shown
some efficacy in relieving pain associated with early signs of CRPS[270,275, 278].
Numerous studies have examined the efficacy of nonsteroidal anti-
inflammatory drugs for the treatment of neuropathic pain and none have
proved effective for sustained use in CRPS. In contrast, corticosteroids have
shown efficacy for the treatment of CRPS and not only in the acute phase.
For example, Braus et al. evaluated the efficacy of systemic corticosteroids
combined with physical therapy for the prevention of CRPS following stroke
and discovered that systemic corticosteroids effectively treated 31/34 patients
(e.g., 91%)[279]. A previous study by Christensen et al. had also reported the
benefit of steroids[278]. This investigation studied 23 CRPS patients and
randomized them to a prednisone-treated group or placebo group. More than
75% clinical improvement was noted within the twelve-week study period for
the prednisone-treated group. In addition, a study by Grundberg reported
favorable results with the use of corticosteroids in CRPS[280].
b. Opioids

Intravenous morphine or morphine equivalents have shown efficacy in providing analgesia compared with placebo in neuropathic pain[111]. Opioids should be considered in CRPS if pain limits the patient's participation in physical restorative therapies that aim to establish, maintain, or enhance function of the affected extremity. Although opioids may control chronic neuropathic pain conditions less effectively than nociceptive pain conditions[281, 282] the data for opioid use do support improvements in quality of life for patients with neuropathic pain[113, 282]. Clinicians may titrate opioids to effect without a ceiling, though unwanted adverse effects (e.g., sedation, constipation, nausea and vomiting, hyperalgesia, pruritis, hypogonadism) may limit their use in patients with CRPS. Furthermore, tolerance, physical dependence, and addiction may all occur with chronic opioid use. The use of opioids in CRPS was recently studied by Agarwal et al. in a prospective, open-label trial[116]. Three groups of patients with neuropathic pain (e.g., small fiber or diabetic peripheral neuropathy), CRPS, and postamputation pain were investigated to determine the effect of transdermal fentanyl on pain and function. Primary outcome variables included change in pain intensity Bryan S. Williams & Paul J. Christo and daily activity and secondary outcomes included pain relief, cognition,
physical function, and mood. All three groups reported significant decreases
in pain at study conclusion. The CRPS group reported a reduction of 2.4 ±
0.40 (p < 0.001) from baseline on a 0-10 numerical rating scale. Moreover,
the CRPS group experienced a 37.5% increase in daily activities compared to
baseline[116].
Tramadol, a weak µ agonist with serotonin and norepinephrine
reuptake inhibition demonstrates effective pain control in neuropathic pain
conditions [108]. Its effectiveness may derive from serotonin/norepinephrine
reuptake inhibition at the level of the spinal cord. No RCTs have been
published supporting its efficacy in CRPS, however.
c. Antidepressants

Antidepressants (e.g., TCAs and SNRIs) are effective in treating a mix of neuropathic pain conditions[29, 163]. The literature does not yet support their
use in CRPS, though their success in treating PHN and DPN leads many to
believe that these agents will reduce CRPS-associated pain. TCA's may be
tailored to the individual patient. For instance, an overweight, lethargic
patient may benefit from an agent with more noradrenergic selectivity (e.g.,
desipramine) that may be activating and lead to appetite suppression. For
those with poor sleep hygiene, the sedating properties of amitriptyline may
be quite beneficial[36, 282]. Duloxetine, an FDA approved medication for diabetic
peripheral neuropathy may anecdotally help to relieve pain in CRPS[46, 47].
d. Antiepileptics

Antiepileptics for CRPS have shown mixed results. Gabapentin, in a double-blind, randomized, placebo-controlled study of mixed neuropathic pain states (n = 305) was investigated for its efficacy in treating CRPS (n = 85)[283]. The primary outcome variable was a change in average daily pain score from baseline to the final week, and the secondary outcome variable included the SF-36 Health Survey. Using an 11-point Likert scale, the treatment group showed a mean decrease in average daily pain score of 1.5 (e.g., 21%) (7.1 to 5.6) compared to 1.0 (14%) (7.3 to 6.3) for the placebo group (p = 0.048). Secondary outcome measures demonstrated that gabapentin-treated patients scored significantly better for the bodily pain improvement, social functioning, and role-emotional domains (p < 0.05) compared to those receiving placebo[283]. This study included 85 (28%) patients with CRPS, and concluded that gabapentin was effective in treating neuropathic pain in general; however, no specific outcome data were reported for CRPS patients. Furthermore, a randomized double-blind placebo controlled crossover study of 58 patients with CRPS I showed no Treatments of neuropathic pain Medicat
e 8.
Bryan S. Williams & Paul J. Christo Treatments of neuropathic pain Bryan S. Williams & Paul J. Christo improvement with gabapentin when measuring pain via the VAS[284].
Pregabalin, a new GABA analog similar to gabapentin has yet to be studied
in CRPS, but may show similar results to gabapentin.
e. Calcitonin and bisphosphonates

Calcitonin is a hormone secreted by the parafollicular cells of the thyroid gland. It acts on bone and kidneys to inhibit osteoclastic bone resorption and thereby reduces serum calcium and phosphate[275]. Gobelet et al. examined the efficacy of intranasal calcitonin in 63 patients with CRPS in a double-blind randomized study[285]. Treatment efficacy was assessed by pain at rest and during active movement, range of motion (ROM), degree of edema, and ability to work. At study conclusion, the treatment group showed significant reduction in pain at rest (p < 0.007), pain at motion (p < 0.04) and an increase in mobility (p < 0.04). Moreover, patients with CRPS of the wrist reported significant improvement (p < 0.03) in their ability to return to work, while those with CRPS of the ankle failed to show significant improvement and were not able to return to work[285]. A meta-analysis of RCTs on pharmacologic treatments for CRPS by Perez et al. concluded that calcitonin may provide effective pain relief in this group of patients[286]. Bisphosphonates, analogues have recently been promoted as effective agents for the treatment of CRPS. For instance, clodronate,
pamidronate, and alendronate have been tested in recent RCTs[275]. Patients
with CRPS do manifest some degree of regional osteoporosis in the involved
extremity, and some researchers hypothesize that the antinociceptive effect of
bisphosphonates relate to their capacity to inactivate osteoclasts and
antagonize osteoclastogenesis[275]. Verenna et al. demonstrated that intravenous
clodronate produced significant improvements in VAS pain (p = 0.002 and
clinical global assessment (p = 0.001) in a small (n = 32) randomized,
double-blind, placebo controlled trial[287]. Other studies support the benefit of
bisphosphonates for the treatment of CRPS[288-290].
11. Failed back surgery syndrome (FBSS)
Failed back surgery syndrome (FBSS) or post-laminectomy pain
syndrome describes a clinical syndrome in which patients report persistent
back and/or leg pain subsequent to one or more surgical procedures
performed to correct their lumbosacral spine disease [291]. Furthermore,
FBSS may reflect a failure of outcome agreement between patient and
surgeon prior to the procedure, resulting from an incorrect initial diagnosis,
poor patient selection, incomplete decompression, or decompression at the
incorrect level. The syndrome may result in recurrent disk herniation,
Treatments of neuropathic pain segmental spinal instability, facet joint disease, permanent nerve root
damage, epidural fibrosis, or arachnoiditis[292-295]. Many of these pathologic
processes can produce neuropathic pain. FBSS patients who have experienced
neuropathic pain and/or radicular symptoms prior to surgery may continue to
suffer from the same symptoms after the procedure which typically persist
and lead to debilitating pain as well as a reduced quality of life[296]. Medical
management of FBSS depends on the primary symptoms that the patient
exhibits. That is, patients may present with radicular symptoms, low back
pain, or both. Pharmacologic intervention should follow the treatment for
either low back pain or primary peripheral neuropathic pain to include
NSAIDS[297-300]. Clinical studies support the use of antiepileptic
medications[3,6,298], antidepressants[299, 301, 302], and opioids[275, 299, 303] for the
treatment of low back pain or neuropathic pain, and can be applied to the
treatment of FBSS patients. Interventionally, stimulation represents a
procedure that clinicians may incorporate into FBSS treatment. For instance,
Kumar et al. compared conventional medical management to spinal cord
stimulation for the treatment of FBSS and found in favor of spinal cord
stimulation[296]. More advanced strategies for FBSS will be discussed in the
following section entitled, "Interventional Techniques for Neuropathic Pain."
12. Interventional techniques for neuropathic pain
Interventional strategies can be employed in managing neuropathic pain when conventional medical management fails to achieve treatment goals
(Figure 2). These strategies include multiple neuromodulatory techniques (e.g.,
epidural injections, nerve blocks, spinal cord stimulation, and intrathecal drug
delivery systems). Practitioners may even incorporate interventional techniques
and pharmacologic strategies concurrently. Either way, the goal remains to
achieve adequate pain relief, functional improvement, and a satisfactiory
quality of life. We present the following neuropathic pain conditions with
proposed interventional strategies that may be useful in management.
A. Failed back surgery syndrome (FBSS)
1. Epidural steroid injections
Neuropathic pain associated with FBSS results in part from
proinflammatory substances that extrude from the nucleus pulposus into the
spinal canal after surgery. These foreign proteins initiate an inflammatory and
immunologic response that causes nerve root irritation. Inflammation renders
the nociceptors or nociceptive axons more sensitive to mechanical stimuli
such as pressure or movement. Fibrous tissue may entrap the nerve root
creating pain on movement[304, 305]. The clinical hallmark of FBSS is chronic
Bryan S. Williams & Paul J. Christo Figure 2. Analgesic Ladder for Neuropathic Pain.

postoperative pain. Two types of pain may be present: mechanical which is
exacerbated by weight-bearing activities such as standing and bending; and
neuropathic which is a more constant, insidious pain typically located in a
radicular distribution[306]. The back and lower extremities represent the most
common location of chronic neuropathic pain[5, 296] and 10–40% of patients
undergoing lumbosacral spine surgery to alleviate neuropathic radicular pain
experience persistent or recurrent pain instead of pain relief[296, 307]. Interlaminar
and transforaminal epidural steroid injections can provide diagnostic
information on the etiology of continued pain after surgery,[308] or may identify
a specific spinal nerve as a pain generator because there may be poor
concordance between radicular symptoms and standard dermatomal maps in as
many as 20% of patients[309-311]. Imaging modalities alone may fail to identify a
specific etiology in FBSS[312]. Some suggest that revision surgery may be
necessary to confirm or refute the diagnosis of FBSS. Neither surgery nor
imaging modalities provide an opportunity for the patient to provide feedback
Treatments of neuropathic pain in terms of pain relief[308]. Studies of lumbar interlaminar and transforaminal
injections for lower back pain and leg pain have produced equivocal
outcomes[313-315]; therefore, additional studies are needed better examine the
effectiveness of epidural steroid injections for patients with FBSS.
B. Postherpetic neuralgia (PHN)
1. Neuraxial steroids
Trials have investigated the utility of steroids administered to the
epidural space. Such injections theoretically reduce inflammation at the
dorsal root ganglion, a process which may be a causative factor for the
development of postherpetic neuralgia[316-318]. Kotani et al. injected
intrathecal methylprednisolone acetate as a treatment intervention for
intractable pain associated with postherpetic neuralgia[319]. The primary
outcome measures included severity of burning and lancinating pain, and
dynamic allodynia on a 10-cm visual-analogue scale. At study conclusion,
the burning, lancinating and allodynic component were significantly less in
the steroid-treated groups compared to placebo (p < 0.001). Furthermore,
global pain relief was significantly improved (p < 0.001) and diclofenac use
was decreased as well (p < 0.001)[319]. Pasqualucci et al. reported significant
pain reduction in patients treated with epidural local anesthetic and
methylprednisolone along with a substantial reduction in the number of
patients who progressed to PHN from acute herpes zoster [320]. In contrast,
van Wijck et al. investigated the efficacy of epidural steroid injection in an
open label, randomized multicenter trial (n = 598) for the prevention of
postherpetic neuralgia in older patients with herpes zoster[317]. Primary
endpoint included the presence of zoster-associated pain one month after
inclusion. At one month after inclusion, 48% of patients in the epidural group
reported zoster-associated pain compared with (58%) in the control group
(RR 0.83, 95% CI 0.71–0.97, p = 0.02). The NNT at one month was 10. At
three months and at six months, the modest difference between the treatment
and control groups diminished to 21% vs. 24% (RR 0.89, 95% CI 0.65-1.21,
p = 0.47 and 15% vs. 17% (RR 0.85, CI 0.57–1.13, p = 0.43), respectively.
The authors indicate that there was no difference in progression to PHN
between the epidural and control groups[317].
2. Sympathetic blockade
Traditionally, clinicians have performed sympathetic blocks for patients with herpes zoster and PHN. The therapeutic goals have been threefold: pain relief during acute herpes zoster, pain relief during PHN, and PHN prevention by treating acute zoster[321]. However, clinicians may limit the use of sympathetic Bryan S. Williams & Paul J. Christo blocks for persistent PHN given the lack of sufficient evidence for their
efficacy, and instead consider sympathetic blockade for occasions when short-
term relief is an important treatment goal[321-323]. Winnie et al. reported that
sympathetic blocks (e.g., stellate ganglion/epidural/paravertebral/intercostal) may
assist in treating the pain of herpes zoster or intractable PHN[316]. Although
such therapies may help reduce pain, they have been associated with
disappointing results. For instance, as many as 50% of patients fail to
experience acceptable pain relief following sympathetic blockade. Hence, it is
likely that the most effective future treatment for this disease may focus less on
procedural interventions and more on prevention of both varicella zoster
infection and herpes zoster infection with their respective vaccines[324].

C. Trigeminal neuralgia
1. Nerve blocks

Medical management remains the treatment of choice for trigeminal neuralgia (TN). In the event that medical management fails to relieve the symptoms or unacceptable side effects occur from pharmacotherapies, interventional options are available. For example, both percutaneous procedures and surgical procedures exist. Such strategies include radiofrequency ablation of the trigeminal nerve, fogarty balloon compression, neurolytic block (e.g., glycerol and alcohol), microvascular decompression and teflon padding, and gamma knife radiosurgery. The percutaneous procedures may produce procedure-related sensory deficits by creating lesions at the trigeminal nerve or trigeminal ganglion[325]. Non-ablative techniques include the use of local anesthetics, either at the trigeminal ganglion or post ganglion. For instance, Han et al. in a case-series (n = 35) examined the efficacy of high concentration lidocaine for the treatment of trigeminal neuralgia[326]. Ten percent lidocaine was injected after appropriate test dose at either the gasserian ganglion or appropriate pain-generating branch. The outcome measure included pain at 24 hrs following the block, and patients were followed for a mean of 43 months. The authors reported success (e.g., favorable results) as complete pain relief or mild pain without medication 1 day following treatment. Success was achieved in 12/35 patients (34.3%). The duration of pain relief in responders was reported to be between 3 weeks and 172 weeks (mean 79 weeks)[326]. In a case series of three patients receiving peripheral nerve blocks for TN, all patients reported pain relief beyond 3 months with a mixture of tetracaine and bupivacaine[327]. More rigorous RCTs of high concentration local anesthetic to the trigeminal ganglion must be conducted before application of this procedure is routinely adopted. Treatments of neuropathic pain D. Peripheral neuropathy (PN)/diabetic peripheral
neuropathy (DPN)
Multiple interventional techniques can be applied to relieve pain
associated with peripheral neuropathies. For instance, paravertebral
sympathetic blocks may be beneficial in relieving the pain associated with
DPN. One published case report highlights the value of lumbar sympathetic
blockade for the treatment of DPN and describes the patient's ability to return
to daily activities with near complete resolution of lower extremity pain [328].
Typically, patients with DPN may require several lumbar sympathetic blocks
for continued relief and although lumbar sympathetic blocks may provide
short-term benefit, they may not be practical in many clinical settings.
Moreover, the procedure is not without possible complications (e.g.,
infection, bleeding, orthostatic hypotension, perforation of abdominal
viscera) therefore, it may be reserved for intractable cases.
Advanced strategies for the treatment of neuropathic
pain
A. Spinal cord stimulation (SCS)

Despite advances in pharmacotherapy for neuropathic pain, less than half of patients achieve significant benefit with any pharmacological agent [5-7]. When sufficient pain relief is not achieved by pharmacological therapies, spinal cord stimulation serves as an alternative or supplement to medical management for treating patients with chronic intractable neuropathic pain[296, 329-335]. The proposed mechanism of SCS began with the "gate theory" advanced by Melzack and Wall in 1965[336]. Specifically, the "gate" represents the termination of painful peripheral stimuli carried by C fibers (e.g., burning sensation) and thinly myelinated A-δ fibers (e.g., sharp, intense, tingling sensation) in the dorsal horn of the spinal cord. Large, myelinated A-β fibers (e.g., light touch, pressure, vibration or hair movement) also terminate in the dorsal horn. Melzack and Wall hypothesized that sensory input could be manipulated in order to close the "gate" to the transmission of painful stimuli. The mechanisms by which dorsal column stimulation modulate pain perception have yet to be fully elucidated; however, current understanding attributes pain reduction to the activation of large-diameter afferent fibers (e.g., A-β fibers) by electrical stimulation. In addition, neurochemical modulation may play a role in the mechanism of action of dorsal column stimulation[337]. For instance, Stiller et al. examined extracellular [gamma]-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats. Utilizing a constrictive sciatic nerve injury model, Bryan S. Williams & Paul J. Christo concentrations of GABA were analyzed with spinal cord electrode leads[338]. The investigators found that extracellular GABA levels were significantly lower (p < 0.001) in rats with sciatic nerve lesions and allodynia (2.3 ± 0.5 nmol/L) than in control rats with intact sciatic nerves (8.1 ± 1.0 nmol/L. In non-allodynic rats, only a slight decrease in GABA levels was observed (5.7 ± 1.1 nmol/L). Among allodynic rats that responded to SCS by normalization of the tactile withdrawal threshold, GABA levels were significantly increased (6.7 ± 2.3 nmol/L; p < 0.001) after SCS[338]. Other neurochemical mechanisms of pain modulation associated with SCS include increased levels of substance P, serotonin, and glycine[337]. Also, adenosine delivered intraveneously or intrathecally has been shown to abolish neuropathic pain acutely[339] and spinal cord stimulation induces adenosine production[337]. The salutary effects of SCS are not equivalent for both acute and chronic pain,[337] nor does it affect nociceptive pain, neuropathic pain, or sympathetically mediated pain equally[329]. If cancer pain is believed to be predominantly nociceptive, it would respond poorly to stimulation of the dorsal columns[329]. In contrast, cancer-induced neuropathic pain may respond to SCS. In general, SCS can most effectively relieve symptoms such as burning pain and allodynia, and relief may persist beyond active stimulation[337].
Some evidence suggests that several neuropathic pain conditions may
respond to SCS therapy including CRPS, FBSS, DPN, and PHN.
1. Diabetic peripheral neuropathy

Spinal cord stimulation has established efficacy for the treatment of peripheral neuropathic pain and peripheral ischemic pain [340]. At least two
published studies report favorable results with SCS in the treatment of
DPN[341, 342]. Prevention, however remains the principle therapeutic tool
against DPN. Because diabetic neuropathy tends to progress, patients may
lose initial paresthesia coverage provided by the spinal cord stimulator, thus
rendering the treatment less effective in time.
2. Failed back surgery syndrome (FBSS)

Ten to 40% of patients who have undergone lumbosacral spine surgery in the United States experience persistent or recurrent pain[307, 343-347]. Multiple studies have been conducted examining SCS and FBSS. Success rates in long-term studies for FBBS and SCS range between 40% to 60%[294, 348, 349], though most are case series. Few RCTs exist and most studies rank at level IV or level V in quality of evidence. Higher quality studies do exist, however. Treatments of neuropathic pain For instance, North et al. conducted a randomized prospective crossover study and examined spinal cord stimulation versus reoperation utilizing frequency of crossover to the alternative procedure as the outcome measure[350]. Study patients complained of persistent radicular pain after spine surgery. Some patients suffered from concomitant low back pain and others did not. At 6 months, the authors reported a statistically significant crossover rate from reoperation to spinal cord stimulation (p = 0.018)[350]. A prospective multicenter trial by Burchiel et al. investigated the efficacy of spinal cord stimulation for chronic back and extremity pain[330]. Outcome measures included patient self-report and multiple other assessment tools: visual analogue scale, McGill Pain Questionnaire, Oswestry Disability Questionnaire, and Beck Depression Inventory. Fifty-six percent of study subjects reported at least 50% pain relief at the 1-year follow-up, and VAS pain scores decreased by 14% (p < 0.0005) compared to pre-implantation levels. Patient ratings of pain relief from SCS included: good or excellent – 35%, fair – 43%, poor – 20%, and no pain relief – 2%. Work status and opioid use did not significant change from pre-implantion values. The authors concluded that SCS is associated with improvements in multiple dimensions of the pain experience including quality-of-life measures such as sleep, depression and mobility. Further support for SCS derives from another RCT by North et al. in which they evaluated the effectiveness of SCS versus reoperation in 50 patients with previous lumbosacral spine surgery[344]. Fourteen out of 26 (54%) reoperation patients crossed over to SCS, and only 5/24 (21%) patients that were randomized to SCS crossed over to reoperation (p < 0.02). Nine of nineteen patients randomized to SCS (47%), and 3/26 (12%) of patients randomized to reoperation achieved ≥ 50% pain relief and were satisfied with treatment (p < 0.01). Fifteen patients randomized to SCS received an implant and did not crossover. Nine of 15 (60%) were deemed long-term successes with respect to pain relief and patient satisfaction. Among the 12 patients randomized to reoperation who did not cross over, only 3 (25%) were considered long-term successes. The authors concluded that SCS is more effective than reoperation for persistent radicular pain following lumbosacral spine surgery. More recently, a multicenter randomized controlled trial by Kumar et al. evaluated the effectiveness of SCS versus conventional medical management (CMM) in patients with failed back surgery syndrome[296]. Primary outcome measure included the proportion of patients achieving ≥ 50% relief of leg pain at 6 months. Secondary outcomes variables included improvement in back and leg pain, health-related quality of life, and functional capacity. In addition, the authors examined patient Bryan S. Williams & Paul J. Christo satisfaction and incidence of adverse effects. One hundred patients were
randomized to either SCS or CMM and 52 patients were included in the
SCS group and 48 in the CMM group. Nine of the 52 patients randomized
to the SCS group failed to achieve ≥ 50% leg pain relief or 80% paresthesia
coverage during the screening trial (5 of these 9 patients still requested
implantation). Crossover data indicate that at 6 months, 5/50 SCS patients
and 32/44 of the CMM patients crossed over to the alternate arm. Twenty-
eight of the 32 CMM patients that crossed over to SCS were implanted.
Twenty-four of the 50 patients who were primary implants achieved ≥ 50%
leg pain relief compared to 4/44 of the primary CCM group who achieved ≥
50% leg pain relief (p < 0.001, CI 99%). At 12 months, 48% of patients
implanted achieved ≥ 50% leg pain relief and 18% of CMM patients achieved
≥ 50% leg pain relief (p = 0.03)[296]. Moreover, secondary outcome measures
(e.g., improvement in back and leg pain, health related quality of life, and
functional capacity; change in the use of pain medication and non-drug pain
therapy; patient satisfaction with treatment; and incidence of adverse effects)
mirrored the results of the primary outcome measures. The authors
concluded that spinal cord stimulation provides better pain relief, better
health-related quality of life, and improved functional capacity compared to
traditional strategies for medical management.
3. Complex regional pain syndrome (CRPS)

Conventional pain medications, physical therapy, sympathetic blockade, and transcutaneous electrical nerve stimulation all represent modalities applied to the reduction of the intense pain caused CRPS with less than favorable results[333, 351, 352]. Among CRPS patients, only one in five is capable of returning to a normal level of functioning[333, 353]. CRPS symptoms rank as the second most frequent indicator for SCS therapy in the USA (FBSS ranks as the first indication), and pain relief as high as 70% has been reported with neurostimulation (e.g., SCS or peripheral nerve stimulation) when patients are properly selected[354-356]. Expert opinion suggests that SCS should be considered in the treatment algorithm when conservative or traditional therapies fail[354]. The literature supports the use of SCS in CRPS. For example, Kemler et al. studied the effectiveness of spinal cord stimulation and physical therapy versus physical therapy alone in CRPS affected patients[333]. Thirty six patients with diagnosed CRPS of either one hand or foot that was present for ≥ 6 months were included. Outcome variables included pain intensity, global perceived effect, functional status, and health-related quality of life. At 6 months, the SCS + physiotherapy group reported a significantly greater reduction in pain (mean reduction of 2.4 cm) on the VAS compared to the Treatments of neuropathic pain physiotherapy alone group (mean increase of 0.2 cm) (p < 0.001). Further, the SCS + physiotherapy group reported a greater percentage improvement on the global perceived effect (39 percent vs. 6 percent, p = 0.01) assessment. Another study by Harke et al. evaluated the long-term effect of SCS on improvement in functional status for patients with CRPS, Type I[357]. The authors hypothesized that patients with sympathetically-maintained pain diagnosed by successful sympathetic blockade would achieve a better outcome with SCS. Accordingly, a positive response to sympathetic blockade could be used as a prognostic indicator for successful SCS therapy. The study included 29 patients with sympathetically maintained CRPS, Type I. Outcome measures included pain intensity, allodynia, PDI, drug consumption, functional status of the limbs, back-to-work rate, and technical status of the device. Twelve month outcomes showed a reduction in mean deep pain as reported by VAS from 9.4 cm to 1.7 cm and mean allodynia from 7.2 cm to 0.03 cm. Furthermore, an "inactivation test" (e.g., cessation of SCS stimulation) caused deep pain as noted on VAS to escalate from a mean of 1.7 cm with SCS stimulation, to 7.1 cm with SCS inactivation. Also, an increase in allodynia from a mean VAS of 0.3 cm to 4.0 cm occurred with cessation of stimulation. Following SCS inactivation, the affected regions showed a mean skin temperature decline of 1.5 oC, compared to the contralateral (e.g., non-affected) areas. At study termination (mean 35.6 ± 21 months), SCS- treated patients reported sustained reduction in both deep pain (9.4 cm to 2.1 cm) and allodynia (7.2 cm to 0.0 cm) on the visual analogue scale (VAS) (p < 0.01) and a significant decrease in pain disability index (PDI) scores p < 0.01) compared to the period prior to SCS treatment. Importantly, 12/16 patients (75%) with impaired hand and finger function regained functional activity to near normal levels including increased grip strength to almost 50% of normal values (p < 0.01). Eight of ten patients (80%) with an affected lower extremity were able to resume ambulation without crutches and 70% were able to return to work. Finally, 17/29 (59%) of SCS-treated patients no longer required pain medication during stimulation periods, and a 70% back-to-work rate was observed. The authors concluded that in patients with CRPS Type I, long-term use of SCS combined with physiotherapy may improve functional status and quality of life[357]. Multiple cases series and a meta-analysis support the use of SCS for treatment of CRPS. For instance, Taylor conducted a meta-analysis of CRPS using the Harbour and Miller Scale for grading recommendations in evidence-based guidelines[358]. His analysis included 1 RCT, 25 case series, and one cost analysis. Spinal cord stimulation for CRPS, Type I was given grade A evidence (strong), and SCS for CRPS, Type II grade D evidence (weak)[334]. It seems reasonable to suggest that patients with CRPS, Type I Bryan S. Williams & Paul J. Christo who fail previous pharmacological and interventional therapies should be
considered for a trial of spinal cord stimulation.

4. Postherpetic neuralgia (PHN)
There is some evidence supporting the use of SCS for herpes zoster and post-herpetic neuralgia. For example, Meglio et al. retrospectively analyzed
the results of 10 patients suffering from postherpetic neuralgia treated with
spinal cord stimulation[359]. Six of ten patients underwent implantation and at
mean follow-up of 15 months, all 6 patients were still reporting satisfactory
pain relief with SCS. Harke et al. examined the effectiveness of SCS in 28
patients with intractable pain secondary to post-herpetic neuralgia and in 4
patients with herpes zoster[335]. Both VAS and Pain Disability Index (PDI) were
investigated along with consumption of analgesics, antidepressants, and
anticonvulsants. The efficacy of the SCS was assessed by an inactivation test.
Prior to SCS, the investigators conducted sympathetic blocks and obtained
favorable responses in all patients who were subsequently implanted. All PHN
and HZ patients were implanted. At study end twenty-three of 28 PHN patients
with SCS reported long-term pain relief and median VAS reduction from 9.0
cm to 1.0 cm (quartiles 1.0–2.75) for burning, lancinating, and allodynic pain
even at a median stimulation period of 29 months. Furthermore, an inactivation
test (e.g., cessation of SCS stimulation) caused a VAS increase from 1.0 cm to
7.0 cm. Responders showed significant improvement in PDI (p < 0.001) and
only one prescription opioid was continued during the stimulation period (p =
0.002). Among the herpes zoster patients, all were implanted and responded
favorably, reporting a decrement in median VAS values from 9.0 to 0.0 at
study completion. The investigators concluded that SCS was an effective
long-term treatment for medical non-responders with intractable pain
secondary to post-herpetic neuralgia and herpes zoster[335].

B. Implantable drug delivery system (IDDS)

The first clinical use of an implantable intrathecal opioid delivery device occurred in 1981 for the treatment of chronic malignant pain [360, 361], though trials of opioids for intractable cancer pain were begun by Wang in 1979[362]. Intrathecal medications for pain control were studied in malignant pain conditions because progression of solid organ tumors required large dose escalations of systemic medications to provide analgesia. Opioid escalation raised concerns of adverse effects such as drowsiness, respiratory depression, physical dependence, tolerance, lack of efficacy, and addiction. Intrathecally delivered medications however, could significantly reduce the systemic side effects of medications by delivering small doses of medication to its site of action in the spinal cord called the substantia gelatinosa. Treatments of neuropathic pain The burden of chronic pain is experienced by about one-third of all cancer patients, and 70-90% of those with advanced disease[363, 364]. For
example, Ground et al. found that 64.1%, 5.4% and 30.5% of study
participants experienced cancer related nociceptive, neuropathic, and mixed
(e.g., neuropathic and nociceptive) pain, respectively[247]. Application of the
WHO principles of systemic opioid therapy in combination with adjuvant
drugs can provide adequate analgesia in 75% to 95% of all patients with
cancer pain[257]. Yet, approximately 2% to 15% of cancer patients suffer
unrelieved and refractory pain and require advanced techniques such as
adjunctive medications, nerve/neurolytic blocks, or implantable drug delivery
systems (IDDS)[257, 365-368]. Currently, clinicians use IDDSs to help control
both malignant and non-malignant pain conditions. An important challenge
for the intrathecal delivery of medications relates to correctly targeting and
modulating specific receptor sites in the spinal cord for even better analgesia
and fewer adverse effects. The only drugs approved by the FDA for use
intrathecally include morphine and ziconitide, although hydromorphone,
fentanyl, bupivacaine and the alpha-2 agonist, clonidine are routinely used in
clinical practice. While evidence exists for long-term efficacy of intrathecal
analgesics, proper patient selection remains critical and must be predicated on
objective evidence of nonreversible pathology, coupled with a failure to
achieve adequate analgesia from oral/systemic therapies and/or an inability to
withstand the side-effects of conventional therapies.

In an RCT of 200 patients with advanced cancer and refractory pain, Smith et al. compared IDDS with medical management to medical management alone and demonstrated the effectiveness of intrathecal opioid therapy [366]. The primary outcome measure included at least a 20% reduction in the VAS pain scores from baseline. Also investigators compared quality of life in patients and caregivers by Brief Pain Inventory, SF-12 Health Survey, and Caregiver Quality of Life. Mortality was followed to identify any detrimental effects of therapy on survival, but was not a stated end point of the trial. The distribution of nociceptive, neuropathic pain, and mixed pain states for the medical management group was 14.3%, 25.5%, 60.2% respectively, and 12.9%, 25.7%, and 61.4% respectively for the IDDS plus medical management group. The results from the study indicated that 60/71 (84.5%) of the IDDS patients achieved clinical success (e.g., greater reduction in pain and toxicity) compared to 51/72 (70.8%) of the medical management group (p < .05). Further, IDDS patients reported a significant decrease in fatigue and an elevated level of consciousness (p < .05) compared with the CMM group. Most striking was the difference in the estimated cumulative survival. Nearly fifty-four percent (53.4) of the IDDS group were alive at 6 months compared to 37.2% in the CMM group (p = .06)[366]. Bryan S. Williams & Paul J. Christo Presumed reasons for the increased survival among the IDDS group focused on their ability to increase their activity level which lead to a decrease in the incidence of pulmonary emboli and improved nutrition. The authors noted that an enhanced quality of life may have lead to a greater "will to live" among the IDDS group. Positive results from retrospective studies, case series, and a meta-analysis also reflect the benefit of intrathecal therapies for refractory cancer pain[367, 369, 370]. There is broad understanding of oral and intravenous opioid administration for pain relief, but the systemic side effects of opioids often limit their use[371]. Properly dosed intrathecal opioids may circumvent the limitations of oral and intravenous agents including opioid-induced hyperalgesia[372]. Growing application but limited evidence for intrathecal opioid administration in non-malignant pain conditions exist. For example, Anderson et al. studied 40 patients with severe, chronic nonmalignant pain that was poorly managed by systemic medications, and evaluated the long-term efficacy of IT morphine[373]. Thirty patients were trialed and responded to intrathecal morphine and were subsequently implanted with permanent drug delivery systems. Among the 30 patients, 1/30 (3%) reported intractable nociceptive pain, 10/30 (33%) reported intractable neuropathic pain, 15/30 (50%) reported intractable mixed nociceptive/neuropathic pain, and 4/30 (13%) reported deafferentation pain. Included within the patient population were 14 patients diagnosed with FBSS. The primary outcome measures included VAS pain scores and the McGill Pain Questionnaire (MPQ). The initial mean VAS was 78.5 ± 15.9 (39-100) and pain was assessed at 3, 6, 12, and 18 months intervals. The decline in VAS was more significant at the 3, 6, 12, and 18 month intervals (p < 0.0001) than when the study ended at 24 months with a VAS of 58.5 ± 24.63 (p = 0.002). The initial MPQ score was 20.17 ± 8.78 and at study end, the initial significance had declined to 17.80 ± 9.22 (p = 0.1)[373]. The investigators concluded that continuous intrathecal morphine is efficacious and can result in long-term improvement in several areas of daily function for the management of severe, nonmalignant pain. Another study of severe, chronic, nonmalignant pain trialed 25 patients with intrathecal morphine and 16 responded favorably and were subsequently implanted with infusion pumps[374]. Three of 16 patients (19%) reported intractable nociceptive pain, 4 (25%) reported intractable neuropathic pain, 8 (50%) reported intractable mixed nociceptive/neuropathic pain, and 1 (6%) reported deafferentation pain. Outcome measures included VAS, MPQ, activity level, and additional medication use along with IT opioid treatment. The initial mean VAS was 91.8 ± 2.8 and at study conclusion (mean 29.14 months ± 12.44 months), the mean VAS score had dropped to 34.3 ± 13.2 (p = 0.0026). At last follow up, the nociceptive pain group reported pain Treatments of neuropathic pain relief of 57% the neuropathic group 37% relief, mixed group 61% relief, and the deafferentation group 75% relief. Furthermore, patients increased their daily activity compared to the period prior to IT therapy. The authors concluded that intrathecal opioids were important for the long-term management of intractable, non-malignant pain states. A systematic review by Turner highlighted the effectiveness and possible complications associated with programmable IDDSs using opioids or
ziconotide, and reported their effects on pain and functioning[375]. Six
observational studies were identified and deemed suitable for inclusion in the
review. Four of the studies included FBSS patients along with other pain
diagnoses, and 2 studies included just FBSS patients. None of the ziconitide
studies included in the review met inclusion criteria. All six of the studies
showed improvements on a 0 to 100 mm VAS, with a mean (weighted) pre-
IDDS rating of 82, and post-IDDS ratings of 45 at 6 months and 44 at 12
months follow up. Moreover, all 6 studies reported improvements in physical
functioning compared to baseline[375]. Success rates, defined as the proportion
of patients with greater than or equal to 50% relief ranged from 38%-56% at
6 months to 30%-44% at longer follow up intervals. The authors concluded
that IDDSs provide improvement in non-malignant pain conditions, but
acknowledged the uncertainty of long-term benefits on pain due to the lack of
data that extends beyond one year.
13. Combination therapy
Due to the diversity of underlying pathologic processes, patient
populations, and manifestations of painful conditions, it is impossible to
predict with certainty which patients will benefit from specific therapies.
Although there are many pharmacologic and interventional therapies
available, it is estimated that only 50-70% of neuropathic pain is
sufficiently relieved by current treatments[376, 377]. The 30-50% of patients
who fail to achieve adequate relief or who sustain dose-related adverse
effects may benefit from combination therapy. Clinicians should consider
drugs from diverse medication classes to enhance efficacy in treating
neuropathic pain. First line medications may fail to provide satisfactory
pain relief and dose escalations may lead to side effects. Therefore,
practitioners should consider adding additional first line medications and
then second line medications if patients fail to report sufficient analgesia.
Certain medications may need to be discontinued if adverse effects cannot
be managed or if they fail to provide adequate pain relief. Refractory pain
necessitates additional treatment strategies including medications listed in
the "other" category and/or interventional techniques.
Bryan S. Williams & Paul J. Christo 14. Conclusion

The varied etiologies and manifestations of neuropathic pain require the selection of treatment strategies that focus on functional restoration and meaningful pain relief. No singular medication or procedural intervention has shown promise in treating all neuropathic pain conditions. Many medications in the pain armamentarium are indicated for the treatment of other disease states, but a growing evidence base in the literature supports their application for neuropathic pain. We have developed certain algorithms for treatment that can serve as a framework for clinicians and patients in their quest to alleviate persistent and disabling neuropathic pain. Key points in the sequence of treating neuropathic pain are listed in Table 9. In general, first line medications offer the best established efficacy in various neuropathic conditions, and a favorably side effect profile. These include gabapentin, pregabalin, and TCAs. Serotonin-Norepinephrine Reuptake Inhibitors show equal promise in the treatment of neuropathic pain and are recommend as a first line medication in most neuropathic pain states. Carbamazepine is the drug of choice for the treatment of TN. Lidocaine 5% patch carries an FDA indication for the treatment of PHN and is recommended as a first line agent, though it fails to show equal efficacy in other NP conditions. Second line and "other" medications may show promise in treating neuropathic pain and should be considered when first-line medications fail or in combination therapy. Interventional strategies for treating neuropathic pain can offer pain amelioration and improvement of functional status. These strategies include spinal cord stimulation, implantable drug deliver systems, and neural blockade. Such modalities are often employed when medical management fails, but practitioners may consider joint therapy with both pharmacologic and interventional strategies as a means of earlier and more effective analgesia. The control of neuropathic pain requires a multidisciplinary approach involving physiotherapy, pharmacotherapy, psychology and procedural interventions. Future management will focus on targeted therapies that modulate specific mechanisms involved in each neuropathic pain condition. Table 9. Key Points in the Treatment of Neuropathic Pain.
Expectation setting with realistic treatment goals Multimodal treatment plan (pharmacological management, physical therapy, emotional support (e.g., pain psychology), interventional strategies) Adequate trial of medications Mechanistically-based treatment strategies Cycling first line medications and combination therapy Prevention (e.g., VZV vaccine, glycemic control) Treatments of neuropathic pain References
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