Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis

Abstract

Background: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.

Methods: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.

Findings: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

Interpretation: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.

Funding: NeuPSIG of the International Association for the Study of Pain.

Conflict of interest statement

Conflicts of interest

NA has served on the advisory boards or speakers panels of Astellas Pharma, Adir Servier, Eli Lilly, Grunenthal, Johnson and Johnson, Sanofi Pasteur Merieux and Pfizer and has been investigator of studies sponsored by Astellas, Grunenthal and Astra Zeneca. RB has received grant/research support from Pfizer, Genzyme, Grünenthal, German Federal Ministry of Education and Research (BMBF): German Research Network on Neuropathic Pain, NoPain system biology and German Research Foundation (DFG). He has received speaker honorarium from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD and served as consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol-Myers Squibb, Biogenidec, AstraZeneca, Merck, Abbvie. RHD has received research grants from US Food and Drug Administration and US National Institutes of Health, and compensation for activities involving clinical trial research methods from Acorda, Adynxx, Allergan, Analgesic Solutions, Anika, Astellas, AstraZeneca, Avanir, Axsome, Bayer, Biogen, Bioness, Bristol-Myers Squibb, Cardiome, Centrexion, Charleston, Chromocell, Collegium, Concert, Daiichi Sankyo, Depomed, Depuy, Eli Lilly, Epicept, Flexion, Genzyme, Glenmark, Inhibitex, Johnson & Johnson, Lpath, Medicinova, Merck, Metys, MMS Holdings, Nektar, Neura, NeurogesX, Olatec, Ono, Periphagen, Pfizer, Phillips, Phosphagenics, Prolong, Q-Med, QRx Pharma, Regenesis, Relmada, Sanofi-Aventis, Salix, Smith & Nephew, Sorrento, Spinifex, Takeda, Taris, Teva, Theravance, and Xenon. NBF has received speaker’s honorarium from Pfizer, Grunenthal, and Norpharma, research grant from Grünenthal, and consultancy fee from Astellas. MH has received honoraria from Eli Lilly, Janssen-Cilag, MSD, Mundipharma, Orion, Sanofi-Aventis for lecture, honoraria from Pfizer, Allergan, Astellas for lecture and consulting and honoraria from Abbvie for consulting TSJ have received honoraria from Pfizer, Grünenthal, Astellas, Orion and Sanofi Pasteur as speaker, advisory Board participant or grant. PK has served on advisory board for Reckitt Benckizer, and received speakers’ honoraria from Pfizer. KL has received travel grants from Pfizer and Astellas. EM reports grants from Richard Saltonstall Charitable Foundation, USA, during the conduct of the study. AM has received speaker’s honorarium from Pfizer, speaker’s honorarium and consultancy fees from Eli Lilly and Grünental and research grant from Grünenthal. SNR has served on the advisory boards of Purdue Pharma, QRx pharma, Salix Pharmaceuticals, and Shionogi. ASCR has share options in Spinifex Pharmaceuticals. He undertakes consulting for Imperial College Consultants, and has received fees from Spinifex Pharmaceuticals, Astellas, Servier, Allergan, Asahi Kasei, and Medivir. Through EuroPain, ASCR’s laboratory has received funding for research studentships from Pfizer and Astellas. Other recent or current grant/studentship funding for ASCR’s laboratory are: Wellcome Trust (London Pain Consortium), Dunhill Medical Trust, NC3Rs, Westminster Medical School Research Trust, International Association for the Study of Pain, National Institute of Academic Anaesthesia, Derek Butler Trust, Medical Research Council Industrial, Biotechnology and Biological Sciences Research Council and Pfizer/Christian-Albrechts University of Kiel (Neuropain). ASCR is a member of the England and Wales Joint Committee on Vaccination and Immunisation (varicella subgroup). MR reports personal fees and other from Afferent Pharmaceuticals, Centrexion, Nektar Therapeutics, Xenoport, ViroBay, Chromocell, Adynxx, Lilly, Zalicus, Biogen IDEC outside the submitted work. PS has a patent System and method for detecting pain and its components using magnetic resonance spectroscopy, US Patent 08755862 issued. BHS has consulted for Pfizer and Napp, and received unconditional educational grants from Pfizer to support epidemiological research. MW reports personal fees from Boston Scientific, Jazz Pharmaceutical, Spinal Modulations, Depomed and Inergetics. RB, NBF, KL, TSJ and ASCR are also members of the IMI “Europain” collaboration and industry members of this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, Boehringer Ingelheim, Astellas, Abbott and Lundbeck. The other authors have no conflicts of interest to disclose.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1

PRISMA flow chart

Figure 2. Forest plot for data included in meta-analysis

Numbers needed to treat (NNTs) with 95% confidence intervals (CI) are shown for each trial and for the overall estimate (fixed effects, Mantel-Haenszel) for first-line drugs. The size of the squares represents the Mantel-Haenszel weight that the corresponding study exerts in the meta-analysis. The full line indicates an NNT of ∞ corresponding to an absolute risk difference of 0, ie. no effect. Numbers to the right of the line indicate effect and numbers to the left harm. The dotted line represents the overall estimate. 2a) TCAs=Tricyclic antidepressants. 2b) SNRIs=serotonin noradrenaline reuptake inhibitors. 2c) Pregabalin. 2d) Gabapentin including gabapentin ER and Enacarbil. MS=multiple sclerosis pain. PHN=postherpetic neuralgia. PNI=peripheral nerve injury. RADIC=painful radiculopathy. SCI=spinal cord injury pain. CPSP=Central poststroke pain. PPN=painful polyneuropathy.

Figure 2. Forest plot for data included in meta-analysis

Numbers needed to treat (NNTs) with 95% confidence intervals (CI) are shown for each trial and for the overall estimate (fixed effects, Mantel-Haenszel) for first-line drugs. The size of the squares represents the Mantel-Haenszel weight that the corresponding study exerts in the meta-analysis. The full line indicates an NNT of ∞ corresponding to an absolute risk difference of 0, ie. no effect. Numbers to the right of the line indicate effect and numbers to the left harm. The dotted line represents the overall estimate. 2a) TCAs=Tricyclic antidepressants. 2b) SNRIs=serotonin noradrenaline reuptake inhibitors. 2c) Pregabalin. 2d) Gabapentin including gabapentin ER and Enacarbil. MS=multiple sclerosis pain. PHN=postherpetic neuralgia. PNI=peripheral nerve injury. RADIC=painful radiculopathy. SCI=spinal cord injury pain. CPSP=Central poststroke pain. PPN=painful polyneuropathy.

Figure 2. Forest plot for data included in meta-analysis

Numbers needed to treat (NNTs) with 95% confidence intervals (CI) are shown for each trial and for the overall estimate (fixed effects, Mantel-Haenszel) for first-line drugs. The size of the squares represents the Mantel-Haenszel weight that the corresponding study exerts in the meta-analysis. The full line indicates an NNT of ∞ corresponding to an absolute risk difference of 0, ie. no effect. Numbers to the right of the line indicate effect and numbers to the left harm. The dotted line represents the overall estimate. 2a) TCAs=Tricyclic antidepressants. 2b) SNRIs=serotonin noradrenaline reuptake inhibitors. 2c) Pregabalin. 2d) Gabapentin including gabapentin ER and Enacarbil. MS=multiple sclerosis pain. PHN=postherpetic neuralgia. PNI=peripheral nerve injury. RADIC=painful radiculopathy. SCI=spinal cord injury pain. CPSP=Central poststroke pain. PPN=painful polyneuropathy.

Figure 2. Forest plot for data included in meta-analysis

Numbers needed to treat (NNTs) with 95% confidence intervals (CI) are shown for each trial and for the overall estimate (fixed effects, Mantel-Haenszel) for first-line drugs. The size of the squares represents the Mantel-Haenszel weight that the corresponding study exerts in the meta-analysis. The full line indicates an NNT of ∞ corresponding to an absolute risk difference of 0, ie. no effect. Numbers to the right of the line indicate effect and numbers to the left harm. The dotted line represents the overall estimate. 2a) TCAs=Tricyclic antidepressants. 2b) SNRIs=serotonin noradrenaline reuptake inhibitors. 2c) Pregabalin. 2d) Gabapentin including gabapentin ER and Enacarbil. MS=multiple sclerosis pain. PHN=postherpetic neuralgia. PNI=peripheral nerve injury. RADIC=painful radiculopathy. SCI=spinal cord injury pain. CPSP=Central poststroke pain. PPN=painful polyneuropathy.

Figure 3. Evidence of publication (reporting) bias

(a) Funnel plot showing the precision (inverse of the standard error) against the effect size; in the absence of bias the points should resemble a symmetrical inverted funnel, (b) Egger’s regression showing the precision plotted against the standardised effect size, the 95% confidence intervals of the regression line do not include the origin suggesting funnel plot asymmetry, and (c) Funnel plot showing the additional missing studies imputed by trim-and-fill in red. The red vertical line indicates the possible summary if the theoretical missing studies were to be included.