Journal of General Internal Medicine

, Volume 24, Issue 2, pp 178–188 | Cite as

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

  • Roger Chou
  • Susan Carson
  • Benjamin K. S. Chan
Original Article



Previous systematic reviews concluded that tricyclics antidepressants are superior to gabapentin for neuropathic pain, but were based on indirect comparisons from placebo-controlled trials.


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.


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.


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.


meta-analysis neuropathic pain gabapentin tricyclic antidepressant 


Conflict of Interest

None disclosed.


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).


This study is based on work funded by the Drug Effectiveness Review Project ( 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.

Supplementary material

11606_2008_877_MOESM1_ESM.doc (34 kb)
ESM Appendix 1 Search strategy for neuropathic pain drugs. (DOC 34.0 KB)
11606_2008_877_MOESM2_ESM.doc (29 kb)
ESM Appendix 2 Quality assessment criteria for randomized controlled trials. (DOC 29.0 KB)
11606_2008_877_MOESM3_ESM.doc (66 kb)
ESM Appendix 3 Adverse events, trials of gabapentin and tricyclic antidepressants for diabetic neuropathy or post-herpetic neuralgia. (DOC 66.5 KB)
11606_2008_877_MOESM4_ESM.doc (38 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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Copyright information

© Society of General Internal Medicine 2008

Authors and Affiliations

  • Roger Chou
    • 1
    • 2
    • 3
  • Susan Carson
    • 1
    • 2
  • Benjamin K. S. Chan
    • 1
    • 2
  1. 1.Oregon Evidence-based Practice CenterPortlandUSA
  2. 2.Oregon Health & Science UniversityPortlandUSA
  3. 3.Department of MedicinePortlandUSA

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