Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials

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.

Figure 1

Literature search results.

Figure 2

Relative risk for pain relief from head-to-head trials of gabapentin versus tricyclic antidepressants.

Figure 3

Relative risk for pain relief from placebo-controlled trials of gabapentin.

Figure 4

Relative risk for pain relief from placebo-controlled trials of tricyclic antidepressants.

Figure 5

Funnel plot, placebo-controlled trials of tricyclic antidepressants, on relative risk for pain relief.

Figure 6

L’Abbe plot, placebo-controlled trials of tricyclic antidepressants, on relative risk for pain relief.