Skip to main content

Gabapentin Versus Tricyclic Antidepressants for Diabetic Neuropathy and Post-Herpetic Neuralgia: Discrepancies Between Direct and Indirect Meta-Analyses of Randomized Controlled Trials

Journal of General Internal Medicine volume 24, pages 178–188 (2009)Cite this article

An Erratum to this article was published on 07 April 2009

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Dworkin RH, O’Connor AB, Backonja M. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain. 2007;132:237–51.

    PubMed  Article  CAS  Google Scholar 

  2. 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.

    Article  Google Scholar 

  3. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305.

    PubMed  Article  CAS  Google Scholar 

  4. 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.

    PubMed  Article  CAS  Google Scholar 

  5. Wong MC, Chung JW, Wong TK. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ. 2007;335:87.

    PubMed  Article  CAS  Google Scholar 

  6. 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.

    PubMed  Article  CAS  Google Scholar 

  7. Glenny AM, Altman DG, Song F, et al. Indirect comparisons of competing interventions. Health Technol Assess. 2005;9:1–134.

    PubMed  CAS  Google Scholar 

  8. 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.

    PubMed  Article  CAS  Google Scholar 

  9. 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.

    PubMed  Article  Google Scholar 

  10. 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.

    CAS  Google Scholar 

  11. 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.

    PubMed  Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    PubMed  Article  CAS  Google Scholar 

  14. 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.

    PubMed  Article  Google Scholar 

  15. 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.

    Google Scholar 

  16. Wiffen PJ, McQuay, Edward JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005;3:CD005452.

    PubMed  Google Scholar 

  17. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for Meta-Analysis in Medical Research. West Sussex: John Wiley & Sons; 2000.

    Google Scholar 

  18. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;2:1539–58. Jun.

    Article  Google Scholar 

  19. Team RDC. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2006.

    Google Scholar 

  20. Song F. Exploring heterogeneity in meta-analysis: Is the L’Abbe plot useful. J Clin Epidemiol. 1999;52:725–30.

    PubMed  Article  CAS  Google Scholar 

  21. Egger M, Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    PubMed  CAS  Google Scholar 

  22. 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.

    PubMed  Article  CAS  Google Scholar 

  23. 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.

    PubMed  Article  CAS  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. Rice AS, Maton S, Postherpetic Neuralgia Study G. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–24.

    PubMed  Article  CAS  Google Scholar 

  27. 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.

    PubMed  Article  CAS  Google Scholar 

  28. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscular Dis. 2001;3:53–62.

    Article  CAS  Google Scholar 

  29. Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Therapeutics. 1990;47(3):305–12. Mar.

    CAS  Google Scholar 

  30. Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984;251:1727–30.

    PubMed  Article  CAS  Google Scholar 

  31. 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.

    PubMed  CAS  Google Scholar 

  32. 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.

    PubMed  Article  CAS  Google Scholar 

  33. Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988;38:1427–32.

    PubMed  CAS  Google Scholar 

  34. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59:1015–21.

    PubMed  CAS  Google Scholar 

  35. 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.

    PubMed  Article  CAS  Google Scholar 

  36. 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.

    CAS  Google Scholar 

  37. Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology. 1982;32:671–73.

    PubMed  CAS  Google Scholar 

  38. 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.

    PubMed  Article  Google Scholar 

  39. 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.

    PubMed  Article  Google Scholar 

  40. 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.

    PubMed  Article  Google Scholar 

  41. Dworkin R, O’Connor A, Backonja M, et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain. 2007;132(3):237–51.

    PubMed  Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Oregon Evidence-based Practice Center, 3181 SW Sam Jackson Park Road, Mail code: BICC, Portland, OR, 97239, USA

    Roger Chou MD, Susan Carson MPH & Benjamin K. S. Chan MS

  2. Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail code: BICC, Portland, OR, 97239, USA

    Roger Chou MD, Susan Carson MPH & Benjamin K. S. Chan MS

  3. Department of Medicine, 3181 SW Sam Jackson Park Road, Mail code: BICC, Portland, OR, 97239, USA

    Roger Chou MD

Authors
  1. Roger Chou MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan Carson MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benjamin K. S. Chan MS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger Chou MD.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s11606-009-0960-6

Electronic supplementary material

Below is the link to the electronic supplementary material.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11606-008-0877-5

KEY WORDS

  • meta-analysis
  • neuropathic pain
  • gabapentin
  • tricyclic antidepressant