Neuropathic Pain Pharmacotherapy



Neuropathic Pain Pharmacotherapy


Elon Eisenberg

Simon Vulfsons

David M. Peterson



Neuropathic pain is pain caused by a lesion or disease affecting the somatosensory nervous system.1,2 According to a recent systematic review of epidemiologic studies on neuropathic pain, the estimated prevalence of neuropathic pain is between 6.9% and 10% of the general population.3 Neuropathic pain may result from a large variety of insults, examples of which are listed in Table 81.1. Common examples of peripheral neuropathic pain include lumbar radiculopathy, painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), and posttraumatic/surgical neuropathy. Neuropathic pain of central origin includes central poststroke pain, pain due to multiple sclerosis, and post-spinal cord injury pain.

Neuropathic pain may be continuous or intermittent and is often described as burning or hot, electric shocks or shooting, pricking or pins, and needles. Pain evoked by nonpainful stimuli such as light touching or cold (allodynia) and accompanying nonpainful sensations such as numbness and tingling are all suggestive of neuropathic pain. The combination of several descriptors is a strong indicator of neuropathic pain. The neurologic examination is aimed primarily at detecting reproducible negative sensory signs, such as partial or complete loss to one or several sensory modalities (e.g., light touch, cold sensation) with distinct neuroanatomical borders. Positive sensory signs, especially when accompanying negative signs, are also supportive of neuropathic pain.1

Neuropathic pain has negative effects on multiple domains of life resulting in poor quality of life, comparable to that experienced by patients suffering from cancer or chronic heart failure. This is explained, at least in part, by misdiagnosis, undertreatment, and lack of substantial analgesic efficacy of most existing treatments.4,5

Neuropathic pain pharmacotherapy is a key therapeutic element, which involves different drug classes including, but not limited to, antidepressants, anticonvulsants, opioids, and topical agents. However, even with the newest of these drugs, effective pain relief occurs in less than half of patients with chronic neuropathic pain.1 Meta-analyses of trials in neuropathic pain commonly report outcomes in terms of the number needed to treat (NNT) to provide 50% pain relief for one patient. Even highly recommended first-line agents result in NNTs ranging from 3.6 to 7.7, meaning that only 1 out 3.6 to 7.7 patients will experience a 50% reduction in pain.6 Most clinical trials related to neuropathic pain pharmacotherapy were conducted with a specific agent in patients who had a specific cause of the underlying disorder, with PDN or PHN being the most frequently tested disorder. At the same time, meta-analyses show that the efficacy of any given drug is generally not dependent on the cause of the underlying disorder.1 In patients with refractory neuropathic pain, combination therapy with two or more agents possessing different mechanisms has been suggested.7








TABLE 81.1 Causes of Neuropathic Pain (Examples)







  • Trauma (surgery, frostbite, amputation)



  • Inflammation (Guillain-Barré syndrome)



  • Infection (AIDS neuropathy, acute zoster, postherpetic neuralgia)



  • Degenerative spine disease



  • Ischemic disorders



  • Metabolic disorders (diabetes mellitus)



  • Neoplastic disorders (tumor invasion, paraneoplastic)



  • Congenital disorders (Fabry’s disease)



  • Toxicity (chemotherapy)



  • Immunologic disorders


A different approach of selecting patients to clinical trials, not based on the specific causes of the underlying disorder, has recently been introduced. According to this approach, standardized quantitative sensory testing (QST) is used for subgrouping patients with peripheral neuropathic pain of different etiologies into different clusters. For example, patients with sensory loss, patients with thermal hyperalgesia and those with mechanical hyperalgesia, regardless of the underlying cause. It is proposed that these profiles may be related to different pathophysiologic mechanisms and may be useful in future clinical trial design.8

This chapter reviews pharmacotherapy for neuropathic pain and emphasizes the strengths and the limitations of different treatments. It also addresses unresolved issues related to pharmacologic treatment of neuropathic pain.


Antidepressants

Four classes of antidepressant medications have been studied in neuropathic pain treatment: tricyclic antidepressants (TCAs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs). Certain drugs in the first two classes are commonly considered first-line recommended treatments for neuropathic pain.6,9,10 Table 81.2 lists major properties of common antidepressants.


TRICYCLIC ANTIDEPRESSANTS

Table 81.3 summarizes the placebo-controlled trials of various drugs for neuropathic pain and shows efficacy for amitriptyline, imipramine, nortriptyline, desipramine, clomipramine, and maprotiline at daily doses ranging from 30 to 200 mg for PHN, PDN, postmastectomy pain, central poststroke pain, and mixed type neuropathies. These results are commonly extrapolated to all types of neuropathic pain, and clinical experience suggests some broad utility for the drugs. A recent systematic review and meta-analysis found TCAs the most efficacious antidepressants for neuropathic pain with an overall NNT of 3.6 (95% confidence interval [CI], 3.0 to 4.4) and the number needed to harm (NNH) was 13.4 (95% CI, 9.3 to 24.4). The level of evidence was considered moderate.6 A Cochrane collaboration review of the efficacy of amitriptyline for neuropathic pain found evidence for a statistically significant benefit with an NNT of 4.6 (95% CI, 1.8 to 3.1) and NNH of 4.1 (95% CI, 3.2 to 5.7),29 and finally, another Cochrane collaboration review found the NNT of TCAs for neuropathic pain to be 3.6 (95% CI, 3.0 to 4.5).30 However, a few trials failed to demonstrate TCA efficacy for spinal cord injury pain,13 cisplatin-induced neuropathy,31 HIV neuropathy,16,17 phantom limb pain,15 lumbar radiculopathy,20 and neuropathic cancer pain.32
Inability to demonstrate effectiveness of the TCAs in these neuropathic pain types may represent a true lack of therapeutic benefit, or it may be due to study design weaknesses or other factors. More studies are needed to clarify the value of specific TCAs in different types of neuropathic pain.








TABLE 81.2 Comparison of Antidepressants in Neuropathic Pain11,12,233,234,235,236,237,238




































































































































Agent


Normal Adult Daily Dose in Psychiatric Disordersa


Usual Number of Doses per Day


Elimination Half-life (t1/2)


Dosing Adjustments


Serotonin: Norepinephrine Selectivity Ratiob


Selective Serotonin Receptor Inhibitors


Citalopram


20-40 mg


1


35 h


20 mg/d in hepatic impairment or elderly


3,500-3,900


Escitalopram


10-20 mg


1


27-32 h


10 mg/d in hepatic impairment or elderly


7,100


Fluoxetine


20-80 mg


1


24-72 h (acute), 96-144 h (chronic), norfluoxetine 96-384 h


Decrease dose in hepatic impairment.


300-545


Fluvoxamine


100-300 mg


1-2


16 h


Decrease dose in hepatic impairment and elderly.


580-620


Paroxetine HCL


20-60 mg


IR: 1 XR: 1


21 h


Maximum dose = 40 mg/d in hepatic impairment or elderly


300-450


Paroxetine mesylate


20-60 mg


1


33 h


Maximum dose = 40 mg/d in renal or hepatic impairment or elderly


300-450


Sertraline


50-200 mg


1


62-104 h


Decrease dose in hepatic impairment and elderly.


1,400-2,750


Serotonin and Norepinephrine Reuptake Inhibitors


Desvenlafaxine


50-100 mg


1


11 h


Decrease dose in moderate or severe renal disease.


85


Duloxetine


40-120 mg


1-2


8-17 h


Do not give to patients with hepatic impairment.


Decrease dose in severe renal disease.


9


Venlafaxine


75-375 mg


IR: 2-3 XR: 1


3-7 h, ODV 9-13 h


Decrease dose in hepatic or renal impairment.


115-120


Tricyclic Antidepressantsc


Amitriptyline


100-300 mg


1-4


9-27 h


Lower doses in elderly and hepatic impairment


8


Clomipramine


100-300 mg


1-3


15-60 h


Lower doses in elderly and hepatic impairment


130


Desipramine


75-300 mg


1-3


10-30 h


Lower doses in elderly and hepatic impairment


0.05


Imipramine


100-300 mg


1-4


5-30 h


Lower doses in elderly and hepatic impairment


27


Maprotiline


100-225 mg


1-3


25-50 h


Lower doses in elderly and hepatic impairment


0.002


Nortriptyline


50-150 mg


1-4


20-55 h


Lower doses in elderly and hepatic impairment


0.24


a Dosing is per product U.S. approved dosing; dosing in pain syndromes may vary from that listed.

b These are estimates of selectivity ratio; actual selectivity ratios are concentration-dependent; numbers <1 indicate greater affinity for norepinephrine than serotonin.

c Tricyclic antidepressants may be safely administered once daily; some practitioners prefer to dose them more frequently.


IR, immediate release; ODV, O-desmethylvenlafaxine; XR, extended release.


In many countries, TCAs may be overlooked as first-line neuropathic pain drugs because they are generic and are not actively marketed. Newer, more expensive drugs for neuropathic pain may be selected despite comparatively lower effectiveness (higher NNTs). The analgesic efficacy of the TCAs is likely to be independent of their antidepressant effect.14 In a large survey, over one-fifth (21%) of the patients with chronic pain have been diagnosed with depression associated with their pain.33 Concomitant chronic pain and depression favor the use of an antidepressant (TCA or another) over other medication classes.

TCAs are associated with dose-dependent adverse events, the most common being sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension. TCAs can be administered once daily, usually at bedtime, exploiting their sedating properties. The dose used for neuropathic pain, typically 75 mg a day or less, is below the antidepressant dose for most patients, lowering the risk of side effects. Secondary amine TCAs (e.g., desipramine, nortriptyline) are better tolerated than tertiary amine TCAs (e.g., amitriptyline, imipramine) but are equally effective.24,28 Nonetheless, TCAs may not be tolerated by many patients. The anticholinergic effects of TCAs are a relative contraindication in patients with benign prostatic hyperplasia, cardiac conduction defects, and other morbidities sensitive to parasympatholytic action. Desipramine has only one-quarter of the anticholinergic and sedative activity of amitriptyline at comparable doses, making desipramine a TCA of choice.34 Use of a low initial dose and slow dose titration of all TCAs is important to minimize premature discontinuation due to side effects. Dry mouth is the most common adverse event, and it is often best managed with sugarless candies or chewing gum, especially sugarless lemon
candy to stimulate serous saliva flow. Sips of water provide only transient relief. The most common starting dose for TCAs is 25 mg, but frail elderly and other highly sensitive patients may tolerate an initial dose of 5 to 10 mg better. Increase the dose by the same number of milligram as the starting dose every 3 to 5 days until some diminution of pain complaints occurs or the daily dose totals 100 mg. The maximal effect often occurs within 3 weeks at that dose, generally before antidepressant effects peak.








TABLE 81.3 Summary of Randomized Controlled Trials of Antidepressants in Treatment of Neuropathic Pain Published as Peer-Reviewed Articles


































































































































































































































































































































Study


Drug


Diagnosis


Design


Number of Patients Treated with Active Drug


Maximal Dosage (mg) per Day


Treatment Duration (wk)


Results


Leijon and Boivie239


Amitriptyline


CPSP


Crossover


15


75


4


A > P


Cardenas et al.13


Amitriptyline


SCI


Parallel


44


125


6


A = P


Max et al.14


Amitriptyline


PDN


Crossover


29


150


6


A > P


Vrethem et al.240


Amitriptyline


PDN and other polyneuropathies


Crossover


33


75


4


A > P


Watson et al.241


Amitriptyline


PHN


Crossover


24


137.5


3


A > P


Max et al.242


Amitriptyline


PDN


Crossover


34


150


6


A > P


Robinson et al.15


Amitriptyline


Phantom limb


Parallel


39


125


6


A = P


Kalso et al.243


Amitriptyline


Postmastectomy


Crossover


15


100


4


A > P


Kieburtz et al.16


Amitriptyline


HIV neuropathy


Parallel


46


100


10


A = P


Shlay et al.17


Amitriptyline


HIV neuropathy


Parallel


58


75


14


A = P


Kvinesdal et al.244


Imipramine


PDN


Crossover


12


100


5


A > P


Sindrup et al.245


Imipramine


PDN


Crossover


18


150


2


A > P


Sindrup et al.18


Imipramine


PDN


Crossover


29


150


4


A > P


Gomez-Perez et al.19


Nortriptyline


PDN


Crossover


18


60


4


A > P


Raja et al.246


Nortriptyline


PHN


Crossover


46


140


8


A > P


Panerai et al.247


Nortriptyline


Mixed neuropathies


Crossover


24


100


3


A > P


Khoromi et al.20


Nortriptyline


Radiculopathy


Crossover


34


100


9


A = P


Sindrup et al.248


Clomipramine


PDN


Crossover


19


75


2


A > P


Panerai et al.247


Clomipramine


Mixed neuropathies


Crossover


24


100


3


A > P


Sindrup et al.248


Desipramine


PDN


Crossover


19


200


2


A > P


Max et al.249


Desipramine


PDN


Crossover


20


250


6


A > P


Kishore-Kumar et al.250


Desipramine


PHN


Crossover


19


250


6


A > P


Raja et al.246


Desipramine


PHN


Crossover


13


160


8


A > P


Vrethem et al.240


Maprotiline


PDN and other polyneuropathies


Crossover


33


75


4


A > P


Goldstein et al.21


Duloxetine


PDN


Parallel


342


120


12


A > P


Raskin et al.22


Duloxetine


PDN


Parallel


232


120


12


A > P


Wernicke et al.23


Duloxetine


PDN


Parallel


226


120


12


A > P


Sindrup et al.18


Venlafaxine


Mixed neuropathies


Crossover


30


225


4


A > P


Rowbotham et al.24


Venlafaxine


PDN


Crossover


163


225


6


A > P


Tasmuth et al.25


Venlafaxine


Postmastectomy


Crossover


13


75


4


A = P


Yucel et al.251


Venlafaxine


Mixed neuropathies


Parallel


8


150


8


A = Pa


Sindrup et al.26


Paroxetine


PDN


Crossover


20


40


2


A = P


Sindrup et al.27


Citalopram


PDN


Crossover


20


40


3


A > P


Max et al.28


Fluoxetine


PDN


Crossover


46


40


6


A > P


a The study showed significant effect of venlafaxine in the manifestations of hyperalgesia and temporal summation but not on the ongoing pain intensity.


CPSP, central poststroke pain; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; SCI, spinal cord injury; A, active drug; P, placebo; > indicates that active drug was superior to the comparator in terms of pain reduction; < indicates that active drug was not superior to the comparator in terms of pain reduction; = indicates that active drug was equal to the comparator in terms of pain reduction.


The anticholinergic effects of TCAs can cause cardiac toxicity including ventricular ectopic activity, prolonged QT interval, myocardial infarction, and sudden death.35 A screening electrocardiogram (ECG) might be considered in patients over 40 years of age or who have other risk factors prior to initiating a TCA. Use TCAs with caution in patients with a history of ischemic heart disease or increased risk of sudden cardiac death; if TCA treatment is selected in these patients, consider limiting the maximum dose to 100 mg per day or less.6,11,36


SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS

The SNRIs duloxetine and venlafaxine are newer antidepressants with effectiveness for neuropathic pain. Results with venlafaxine for neuropathic pain have been inconsistent. Venlafaxine was effective for PDN and for various forms of polyneuropathy at daily doses of 150 to 225 mg.18,24 In one placebo-controlled trial, perioperative venlafaxine at a daily dose of 75 mg prevented the development of postmastectomy pain syndrome,37 but in other trials on patients with postmastectomy pain25 syndrome and mixed type neuropathies, efficacy at a dose range of 75 to 150 mg could not be demonstrated.

Three large randomized controlled trials21,22,23 and one open-label 52-week extension trial38 showed that duloxetine was effective for PDN at daily doses of 60 to 120 mg. Duloxetine 60 mg per day has similar efficacy to duloxetine 120 mg per day, but the lower dose is far more tolerable. It can be administered once daily. At that dose, the drug significantly improved sleep and quality of life. The most common adverse effects reported
in these clinical trials were nausea, somnolence, dizziness, and constipation, all of which tended to decrease over time. Initiating treatment at a daily dose of 30 mg for 1 week followed by an increase to 60 mg per day during the second week is likely to improve tolerability.39 Duloxetine has not been associated with cardiac toxicity. It should not be used concomitantly with MAOIs or in patients with markedly impaired liver function.

A meta-analysis of trials for the SNRIs (i.e., duloxetine, venlafaxine, desvenlafaxine) across neuropathic pain types resulted in an NNT of 6.4 (95% CI, 5.2 to 8.4), indicating that they are less effective than the far less expensive TCAs.6 In the systematic review and meta-analysis cited earlier, the final quality of evidence for SNRI efficacy in the treatment of neuropathic pain was deemed high. Combined NNT was 6.4 (95% CI, 5.2 to 8.4), and NNH was 11.8 (95% CI, 9.5 to 15.2).6


SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Reports of the effectiveness of SSRIs in neuropathic pain management are generally not favorable. Some reports may not have separated analgesic effect from the effects of mood elevation on pain perception. One well-controlled trial documented that fluoxetine was no more effective than placebo, whereas both amitriptyline and desipramine were efficacious.28 Two other trials support efficacy of citalopram27 and paroxetine26 (both at 40 mg per day) in PDN. Although SSRIs show a favorable safety profile compared to TCAs and are generally well tolerated, a meta-analysis of available trials in neuropathic pain did not detect significant overall pain reduction with the SSRIs, and therefore, they should not be regarded as first-line agents.6


Antiepileptics

Interest in the antiepileptics for pain management dates back to the 1940s.40 Dozens of randomized controlled trials have attempted to describe the role of different antiepileptic drugs in neuropathic pain treatment. The majority of antiepileptic trials are in PHN or PDN, with less data available for other neuropathic pain types. Recent meta-analyses strongly support the use of the calcium channel α2δ ligands pregabalin and gabapentin (including gabapentin ER and gabapentin enacarbil) as first-line therapy for PHN and PDN.6,41 Data also support the use of pregabalin for treating central neuropathic pain.41 Carbamazepine is likely effective for trigeminal neuralgia and possibly for PDN and central poststroke pain, but studies of carbamazepine were generally of short duration (i.e., less than 4 weeks) and poor methodologic quality.42 Although other antiepileptics may be beneficial in individual patients or specific types of neuropathic pain, pooled data either suggested minimal effectiveness or were inconclusive.6,41 Table 81.4 summarizes trials of the antiepileptics in neuropathic pain.


PREGABALIN

Pregabalin is the most extensively studied drug of any type for treating neuropathic pain.6 Pregabalin is believed to exert its analgesic effect by binding to the α2δ subunit of voltage-gated calcium channels on primary afferent neurons, reducing the release of neurotransmitters from their central terminals.132 A recent meta-analysis of 25 placebo-controlled trials of pregabalin in various types of neuropathic pain reported an NNT of 7.7 (95% CI, 6.5 to 9.4).6 Pregabalin was effective for treating PHN and PDN in numerous multicenter, randomized, controlled trials.74,97,101,102,103,104,105,106,107,108,109,110,111,112,116,133,134 Pregabalin was also effective for treating spinal cord injury pain,114,115 posttraumatic peripheral neuropathy,113 neuropathic cancer pain,61,100 and mixed types of neuropathic pain.116,117,119,120,121,122 Pregabalin did not significantly improve acute herpetic neuralgia or prevent progression to PHN in one clinical trial,96 but it did significantly reduce acute herpetic neuralgia and subacute herpetic neuralgia in another trial.118 Pregabalin did not significantly improve neuropathic pain associated with HIV98,99 or central poststroke pain.97 The effective daily dose of 300 to 600 mg reduces pain and improves sleep, functioning, and quality of life. Response rates are higher when a maintenance dose of 600 mg per day is used.6 Pregabalin has several advantages compared to other anticonvulsants: It is usually administered twice daily, can be rapidly titrated, has early onset of analgesic effect, and has linear pharmacokinetics. No common drug interactions occur with pregabalin. The most commonly reported adverse events were dose-dependent and included dizziness, somnolence, dry mouth, abnormal vision, confusion, weight gain, and edema.11


GABAPENTIN

There is also strong evidence of gabapentin’s effectiveness for PHN and PDN at doses of 900 to 3600 mg per day.7,54,55,56,62,63,64,70,71,72,73,74,75 Gabapentin is available as immediate-release (IR), extendedrelease (ER), and gabapentin enacarbil formulations, and available data suggest similar effectiveness for the different formulations.6 Gabapentin IR is normally dosed thrice daily and is commonly the least expensive dosage form. Gabapentin enacarbil is dosed twice daily, and gabapentin ER may be dosed once daily. Across 14 studies, for all gabapentin dosage forms, the overall NNT to reduce pain intensity by 50% was 7.2 (95% CI, 5.9 to 9.1). For gabapentin IR, the NNT was 6.3 (95% CI, 5.0 to 8.3). The NNT for gabapentin enacarbil and gabapentin ER was 8.3 (95% CI, 6.2 to 13.0).6 In addition to PHN and PDN, gabapentin has demonstrated efficacy in HIV-associated painful neuropathy, pain in Guillain-Barré syndrome, and phantom limb pain.57,58,59,65 Gabapentin was not effective for peripheral nerve injury pain in one trial.66 An 8-day trial of gabapentin was effective for treating neuropathic cancer pain in one trial,60 but in a smaller 4-week trial, gabapentin was no more effective than placebo.61 Results for gabapentin in spinal cord injury were mixed in three small trials.67,68,69 Gabapentin is believed to have similar mechanism of action to pregabalin. However, unlike pregabalin, it has nonlinear pharmacokinetics and may take days or weeks to reach an effective dose. Gabapentin is relatively safe, with few clinically relevant drug interactions. The main adverse effects are somnolence, dizziness, and peripheral edema.11 Some clinicians report that some patients who fail to respond to gabapentin may respond to pregabalin and vice versa.


CARBAMAZEPINE

Carbamazepine is commonly used to treat trigeminal neuralgia. Most carbamazepine studies in trigeminal neuralgia were conducted in the 1960s and 1970s using small samples sizes. In these studies, pain relief was superior with carbamazepine compared to placebo.45,46,47,135 In a more recent trial, carbamazepine was more effective than lamotrigine for treating pain associated with trigeminal neuralgia.48 Carbamazepine was also one of the first anticonvulsants used in PDN and was superior to placebo in two small trials.43,44 Pain reduction was similar between carbamazepine and the TCA nortriptyline in a more recent trial.19 Carbamazepine was more effective than placebo in patients with mixed types of neuropathic pain in one controlled trial.49 Effective doses of carbamazepine ranged from 800 to 2,400 mg per day in trigeminal neuralgia, but lower doses of 200 to 600 mg per day were effective for treating other neuropathic pain types. NNT to achieve 50% pain relief with carbamazepine in a meta-analysis of trials in trigeminal neuralgia, PDN, and central poststroke pain was 1.9 (95% CI, 1.6 to 2.5).42 However, this figure is based primarily on old trials, most of which were conducted in small patient groups for relatively short treatment periods. All of the carbamazepine trials were classified as third tier trials, and heterogeneity associated with pooling the trials was moderately high (I2 = 50%).42 The analgesic mechanism of carbamazepine is related to voltage-dependent sodium


channel blocking, which results in decreased ectopic nerve discharges and neural membrane stabilization.136 Adverse events are common and include dizziness, nausea, drowsiness, blurred vision, and ataxia.44 Carbamazepine can cause Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Rare, but serious, side effects include blood dyscrasias, impairment of liver function, and reduction of sodium plasma levels and require routine blood tests to monitor them. Serum carbamazepine concentration monitoring is recommended to maximize efficacy, monitor compliance, and reduce toxicity.11








TABLE 81.4 Summary of the Randomized Controlled Trials of Antiepileptic Drugs in Treatment of Neuropathic Pain Published as Peer-Reviewed Articles





































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Study


Drug


Diagnosis


Design


Number of Patients Treated with Active Drug


Maximal Dosage (mg) per Day


Treatment Duration (wk)


Results


Rull et al.43


Carbamazepine


PDN


Crossover


30


400


2


A > P


Wilton44


Carbamazepine


PDN


Crossover


40


400


2


A > P


Gomez-Perez et al.19


Carbamazepine


PDN


Crossover


16


200


4


A = nortriptyline


Nicol45


Carbamazepine


TN


Crossover


20


2,400


2


A > P


Campbell et al.46


Carbamazepine


TN


Crossover


77


800


2


A > P


Killian and Fromm47


Carbamazepine


TN


Crossover


27


1,000


5 d


A > P


Vilming252


Carbamazepine


TN


Parallel


6


900


3


A > tizanidine


Lechin et al.253


Carbamazepine


TN


Crossover


48


1,200


8


A < pimozide


Lindstrom254


Carbamazepine


TN


Crossover


12


Maximal tolerated


2


A = tocainide


Shaikh et al.48


Carbamazepine


TN


Crossover


21


1,200


6


A > lamotriginea


Harke et al.49


Carbamazepine


Mixed types


Parallel


43


600


8 d


A > P


Dogra et al.50


Oxcarbazepine


PDN


Parallel


69


1,800


16


A > P


Grosskopf et al.51


Oxcarbazepine


PDN


Parallel


71


1,200


16


A = P


Beydoun et al.52


Oxcarbazepine


PDN


Parallel


258


1,800


16


A = P


Demant et al.53


Oxcarbazepine


Mixed types


Crossover


83


2,400


6


A > P


Backonja et al.54


Gabapentin


PDN


Parallel


84


3,600


8


A > P


Morello et al.255


Gabapentin


PDN


Crossover


26


1,800


6


A = amitriptyline


Dallocchio et al.55


Gabapentin


PDN


Parallel


13


2,400


12


A > amitriptyline


Simpson et al.56


Gabapentin


PDN


Parallel


30


3,600


8


A > P


Pandey et al.57


Gabapentin


GBS


Crossover


18


15 mg/kg


1


A > P


Pandey et al.58


Gabapentin


GBS


Parallel


12


900


1


A > P


Hahn et al.59


Gabapentin


HIV-N


Parallel


15


2,400


4


A > P


Caraceni et al.60


Gabapentin


NCP


Parallel


79


1,800


8 d


A > P


Mishra et al.61


Gabapentin


NCP


Parallel


30


1,800


4


A = P


A = amitriptyline


A < pregabalina


Rice and Maton62


Gabapentin


PHN


Parallel


223


2,400


7


A > P


Rowbotham et al.63


Gabapentin


PHN


Parallel


113


3,600


8


A > P


Chandra et al.64


Gabapentin


PHN


Parallel


34


2,700


8


A = nortriptyline


Bone et al.65


Gabapentin


PLP


Crossover


19


2,400


6


A > P


Gordh et al.66


Gabapentin


PNI


Crossover


98


2,400


7


A = P


Levendoglu et al.67


Gabapentin


SCI


Crossover


20


3,600


8


A > P


Tai et al.68


Gabapentin


SCI


Crossover


7


1,800


4


A > Pb


Rintala et al.69


Gabapentin


SCI


Crossover


32


3,600


8


A < amitriptyline


A = diphenhydramine (active control)


Gilron et al.7


Gabapentin


PDN + PHN


Crossover


57


3,200


5


A > P; A = morphine


A < A + morphine


Gilron et al.70


Gabapentin


PDN + PHN


Crossover


46


3,600


6


A < A + nortriptyline


A = nortriptyline


Smith et al.256


Gabapentin


PLP + RLP


Crossover


24


3,600


6


A = P


Serpell257


Gabapentin


Mixed types


Parallel


153


2,400


8


A > P


Sandercock et al.258


Gabapentin ER


PDN


Parallel


96


3,000


4


A > P


Wallace et al.71


Gabapentin ER


PHN


Parallel


269


1,800


10


A = P


Sang et al.72


Gabapentin ER


PHN


Parallel


221


1,800


10


A > P


Irving et al.73


Gabapentin ER


PHN


Parallel


107


1,800


4


A > P


Jensen et al.259


Gabapentin ER


PHN


Parallel


102


1,800


4


A = Pc


Rauck et al.74


Gabapentin


Enacarbil


PDN


Parallel


235


3,600


13


A = P


A = pregabalina


Backonja et al.260


Gabapentin


Enacarbil


PHN


Parallel


47


1,200


2


A > P


Zhang et al.75


Gabapentin


Enacarbil


PHN


Parallel


263


3,600


14


A > P


Rauck et al.76


Lacosamide


CPSP


Parallel


60


400


6


A > P


Shaibani et al.77


Lacosamide


PDN


Parallel


403


600


18


A = P


Wymer et al.78


Lacosamide


PDN


Parallel


277


600


18


A = P


Ziegler et al.79


Lacosamide


PDN


Parallel


281


600


18


A = P


Breuer et al.80


Lamotrigine


CPMS


Crossover


17


400


11


A = P


Vestergaard et al.81


Lamotrigine


CPSP


Crossover


30


200


8


A > P


Vinik et al.82


Lamotrigine


PDN


Parallel


360


400


10


A = P


Vinik et al.82


Lamotrigine


PDN


Parallel


360


400


10


A = P


Eisenberg et al.83


Lamotrigine


PDN


Parallel


29


400


8


A > P


Simpson et al.84


Lamotrigine


HIV-N


Parallel


20


300


14


A > P


Simpson et al.85


Lamotrigine


HIV-N


Parallel


150


600


11


A = P; A > Pd


Finnerup et al.86


Lamotrigine


SCI


Crossover


22


400


8


A = P; A > Pe


Zakrzewska et al.87


Lamotrigine


TN


Crossover


14


400


2


A > P


Shaikh et al.48


Lamotrigine


TN


Crossover


21


400


6


A < carbamazepinea


McCleane88


Lamotrigine


Mixed types


Parallel


50


200


8


A = P


McCleane89


Lamotrigine


Mixed types


Parallel


36


200


8


A = P


Silver et al.90


Lamotrigine


Mixed types


Parallel


111


400


14


A = P


Jungehulsing et al.261


Levetiracetam


CPSP


Crossover


42


3,000


8


A = P


Rossi et al.91


Levetiracetam


CPMS


Parallel


12


3,000


12


A > P


Falah et al.92


Levetiracetam


CPMS


Crossover


30


3,000


6


A = P


Vilholm et al.93


Levetiracetam


Postmastectomy


Crossover


26


3,000


4


A = P


Finnerup et al.94


Levetiracetam


SCI


Crossover


34


3,000


5


A = P


Holbech et al.95


Levetiracetam


Mixed types


Crossover


35


3,000


6


A = P


Krcevski and Kamenik96


Pregabalin


AHN


Parallel


14


300


3


A = Pf


Kim et al.97


Pregabalin


CPSP


Parallel


110


600


13


A = P, A > Pg


Simpson et al.98


Pregabalin


HIV-N


Parallel


151


600


14


A = P


Simpson et al.99


Pregabalin


HIV-N


Parallel


183


600


17


A = P


Mishra et al.61


Pregabalin


NCP


Parallel


30


600


4


A > P


A > gabapentina


A > amitriptyline


Raptis et al.100


Pregabalin


NCP


Parallel


60


600


4


A > fentanyl transdermal


Richter et al.101


Pregabalin


PDN


Parallel


161


600


6


A > P


Lesser et al.102


Pregabalin


PDN


Parallel


240


600


5


A > P


Rosenstock et al.103


Pregabalin


PDN


Parallel


76


300


8


A > P


Tolle et al.104


Pregabalin


PDN


Parallel


299


600


12


A > P


Arezzo et al.105


Pregabalin


PDN


Parallel


82


600


12


A > P


Satoh et al.106


Pregabalin


PDN


Parallel


179


600


13


A > P


Rauck et al.74


Pregabalin


PDN


Parallel


56


300


13


A = P


A = gabapentin enacarbila


Irving et al.262 and Tanenberg et al.263


Pregabalin


PDN


Parallel


134


300


12


A = duloxetine


A = duloxetine + gabapentin


Smith et al.107


Pregabalin


PDN


Parallel


99


300


15


A = P


A = carisbamate


Raskin et al.108


Pregabalin


PDN


Crossover


301


300


6


A = P


Sabatowski et al.109


Pregabalin


PHN


Parallel


157


300


8


A > P


Dworkin et al.110


Pregabalin


PHN


Parallel


89


600


8


A > P


van Seventer et al.111


Pregabalin


PHN


Parallel


273


600


13


A > P


Stacey et al.112


Pregabalin


PHN


Parallel


179


600


4


A > P


Achar et al.264


Pregabalin


PHN


Parallel


25


150


8


A > amitriptyline


van Seventer et al.113


Pregabalin


PNI


Parallel


127


600


8


A > P


Siddall et al.114


Pregabalin


SCI


Parallel


70


600


12


A > P


Cardenas et al.115


Pregabalin


SCI


Parallel


108


600


16


A > P


Freynhagen et al.116


Pregabalin


PDN + PHN


Parallel


273


600


12


A > P


Vranken et al.117


Pregabalin


CPSP + SCI


Parallel


20


600


4


A > P


Liang et al.118


Pregabalin


AHN + SHN


Parallel


150


600


4


A > P


Guan et al.119


Pregabalin


PDN + PHN


Parallel


206


600


8


A > P


Moon et al.120


Pregabalin


Mixed types


Parallel


162


600


9


A > P


Holbech et al.265


Pregabalin


Mixed types


Crossover


61


300


5


A > P


A < imipramine


A < imipramine + pregabalin


Haanpaa et al.121


Pregabalin


Mixed types


Parallel


277


600


8


A = capsaicin 8% patch


Gatti et al.266


Pregabalin


Mixed types


Parallel


134


290h


13


A < oxycodone CR


A < A + oxycodone CR


Gilron et al.122


Pregabalin


Mixed types


Parallel


80


600


4-9


A > P


Kochar et al.123


Sodium valproate


PDN


Parallel


29


1,200


4


A > P


Kochar et al.124


Sodium valproate


PDN


Parallel


21


500


12


A > P


Kochar et al.125


Valproic acid + sodium valproate


PHN


Parallel


22


1,000


8


A > P


Drewes et al.126


Sodium valproate


SCI


Parallel


20


2,400


3


A = P


Otto et al.127


Valproic acid


Mixed types


Crossover


31


1,500


4


A = P


Thienel et al.128


Topiramate


PDN


Parallel


878


400


22


A = Pi


Raskin et al.129


Topiramate


PDN


Parallel


214


400


12


A > P


Khoromi et al.130


Topiramate


LR


Crossover


42


400


8


A = P; A > Pj


Atli and Dogra131


Zonisamide


PDN


Parallel


13


600


12


A = P


a Trial compared two antiepileptics to each other, and the same trial is displayed twice in this table (once for each antiepileptic).

b A significant decrease of “unpleasant feeling” and a trend toward a decrease in both the “pain intensity” and “burning sensation.”

c Significant difference in “itchy pain sensations” but no difference in global pain intensity or other measures of pain.

d Lamotrigine was superior to placebo in patients who received antiviral neurotoxic therapy but not in patients who did not receive this therapy.

e Lamotrigine was superior to placebo in patients with incomplete spinal cord injury and evoked pain but equal to placebo in patients with complete injury and without evoked pain.

f Pregabalin was not effective for preventing subacute herpetic neuralgia or postherpetic neuralgia.

g No significant difference between pregabalin and placebo in pain score (primary outcome measure) but significant difference in sleep, anxiety, and clinical global impression scores.

h Mean dose reported rather than maximum.

i Findings from three double-blind, placebo-controlled trials.

j No significant difference between topiramate and placebo in pain score (primary outcome measure) but significant difference in global pain relief score.


AHN, acute herpetic neuralgia; CPMS, central pain due to multiple sclerosis; CPSP, central poststroke pain; ER, extended release; GBS, Guillain-Barré syndrome; HIV-N, HIV neuropathy; LR, lumbar radiculopathy; NCP, neuropathic cancer pain; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; PLP, phantom limb pain; PNI, peripheral nerve injury; RLP, residual limb pain; SCI, spinal cord injury; SHN, subacute herpetic neuralgia; TN, trigeminal neuralgia; A, active drug; P, placebo; > indicates that active drug was superior to the comparator in terms of pain reduction; < indicates that active drug was not superior to the comparator in terms of pain reduction; = indicates that active drug was equal to the comparator in terms of pain reduction.

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Sep 21, 2020 | Posted by in PAIN MEDICINE | Comments Off on Neuropathic Pain Pharmacotherapy
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