Abstract
Background
Previous systematic reviews concluded that tricyclics antidepressants are superior to gabapentin for neuropathic pain, but were based on indirect comparisons from placebo-controlled trials.
Purpose
To evaluate gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia, using direct and indirect comparisons.
Data Sources
MEDLINE (1966 to March Week 4 2008), the Cochrane central register of controlled trials (1st quarter 2008), and reference lists.
Study Selection
We selected randomized trials directly comparing gabapentin versus tricyclic antidepressants or comparing either of these medications versus placebo.
Data Extraction
Studies were reviewed, abstracted, and quality-rated by two independent investigators using predefined criteria.
Data Synthesis
We performed a meta-analysis of head-to-head trials using a random effects model and compared the results to an adjusted indirect analysis of placebo-controlled trials.
Results
In three head-to-head trials, there was no difference between gabapentin and tricyclic antidepressants for achieving pain relief (RR 0.99, 95% CI 0.76 to 1.29). In adjusted indirect analyses, gabapentin was worse than tricyclic antidepressants for achieving pain relief (RR = 0.41, 95% CI 0.23 to 0.74). The discrepancy between direct and indirect analyses was statistically significant (p = 0.008). Placebo-controlled tricyclic trials were conducted earlier than the gabapentin trials, reported lower placebo response rates, had more methodological shortcomings, and were associated with funnel plot asymmetry.
Conclusions
Though direct evidence is limited, we found no difference in likelihood of achieving pain relief between gabapentin and tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia. Indirect analyses that combine data from sets of trials conducted in different eras can be unreliable.
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References
Dworkin RH, O’Connor AB, Backonja M. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain. 2007;132:237–51.
Gilron I, Watson CPN, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ Can Med Assoc J. 2006;175:265–75.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305.
Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83:389–400.
Wong MC, Chung JW, Wong TK. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ. 2007;335:87.
Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50:683–91.
Glenny AM, Altman DG, Song F, et al. Indirect comparisons of competing interventions. Health Technol Assess. 2005;9:1–134.
Chou R, Fu R, Huffman LH, Korthuis PT. Initial highly-active antiretroviral therapy with a protease inhibitor versus a non-nucleoside reverse transcriptase inhibitor: discrepancies between direct and indirect analyses. Lancet. 2006;368:1503–15.
Song F, Altman D, Glenny A-M, Deeks J. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ. 2003;326:472.
Chandra K, Shafiq N, Pandhi P, Gupta S, Malhotra S. Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial–the GONIP Trial. Int J Clin Pharmacol Therapeutics. 2006;44:358–63.
Dallocchio C, Buffa C, Mazzarello P, Chiroli S. Gabapentin vs amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage. 2000;20:280–85.
Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Internal Med. 1999;159:1931–37.
Toma M, McAlister FA, Bialy L, Adams D, Vandermeer B, Armstrong PW. Transition from meeting abstract to full-length journal article for randomized controlled trials. JAMA. 2006;295:1281–87.
Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol. 2002;31:140–49.
Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med/Public Library Sci. 2005;2:e164.
Wiffen PJ, McQuay, Edward JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005;3:CD005452.
Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for Meta-Analysis in Medical Research. West Sussex: John Wiley & Sons; 2000.
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;2:1539–58. Jun.
Team RDC. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2006.
Song F. Exploring heterogeneity in meta-analysis: Is the L’Abbe plot useful. J Clin Epidemiol. 1999;52:725–30.
Egger M, Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.
Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR. Empirical assessment of effect of publication bias on meta-analyses. BMJ. 2000;320:1574–77.
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831–36.
Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. New England J Med. 2005;352:1324–34.
Gorson KC, Schott C, Herman R, Ropper AH, Rand WM. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol, Neurosurgery & Psychiatry. 1999;66:251–52.
Rice AS, Maton S, Postherpetic Neuralgia Study G. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–24.
Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837–42.
Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscular Dis. 2001;3:53–62.
Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Therapeutics. 1990;47(3):305–12. Mar.
Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984;251:1727–30.
Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37:589–96.
Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45:3–9.
Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988;38:1427–32.
Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59:1015–21.
Sindrup SH, Ejlertsen B, Froland A, Sindrup EH, Brosen K, Gram LF. Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function. Eur J Clin Pharmacol. 1989;37(2):151–3.
Sindrup SH, Gram LF, Skjold T, Grodum E, Brosen K, Beck-Nielsen H. Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study. British J Clin Pharmacol. 1990;30(5):683–91.
Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology. 1982;32:671–73.
Lathyris D, Trikalinos T, Ioannidis JP. Evidence from crossover trials: empirical evaluation and comparison against parallel arm trials. Int J Epidemiol. 2007;36:422–30.
Ferreira-Gonzalez I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol. 2007;60:651–7.
Gartlehner G, Hansen RA, Nissman D, Lohr KN, Carey TS. A simple and valid tool distinguished efficacy from effectiveness studies. J Clin Epidemiol. 2006;59:1040–48.
Dworkin R, O’Connor A, Backonja M, et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain. 2007;132(3):237–51.
Conflict of Interest
None disclosed.
Contributors
All authors participated in the conception and design, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content, and final approval of the version to be published. There were no other contributors to this manuscript. The guarantor of this manuscript is Roger Chou (corresponding author).
Funding
This study is based on work funded by the Drug Effectiveness Review Project (http://www.ohsu.edu/drugeffectiveness/). The funder had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
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An erratum to this article can be found at http://dx.doi.org/10.1007/s11606-009-0960-6
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ESM Appendix 1
Search strategy for neuropathic pain drugs. (DOC 34.0 KB)
ESM Appendix 2
Quality assessment criteria for randomized controlled trials. (DOC 29.0 KB)
ESM Appendix 3
Adverse events, trials of gabapentin and tricyclic antidepressants for diabetic neuropathy or post-herpetic neuralgia. (DOC 66.5 KB)
ESM Appendix 4
Pooled results, adverse events in placebo-controlled trials of tricyclic antidepressants for neuropathic pain. (DOC 38.5 KB)
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Chou, R., Carson, S. & Chan, B.K.S. Gabapentin Versus Tricyclic Antidepressants for Diabetic Neuropathy and Post-Herpetic Neuralgia: Discrepancies Between Direct and Indirect Meta-Analyses of Randomized Controlled Trials. J GEN INTERN MED 24, 178–188 (2009). https://doi.org/10.1007/s11606-008-0877-5
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DOI: https://doi.org/10.1007/s11606-008-0877-5