A systematic review and comparative effectiveness network meta-analysis assessing 27 pharmacologic interventions included 65 randomized, controlled trials involving 12 632 patients with painful diabetic neuropathy. Half of these studies had high or unclear risk of bias. 9 head-to-head trials showed greater pain reduction associated with serotonin-norepinephrine reuptake inhibitors (SNRIs) than anticonvulsants (standardized mean difference [SMD] -0.34, 95% credible interval [CrI], -0.63 to -0.05) and with tricyclic antidepressants (TCAs) than topical capsaicin 0.075%. Network meta-analysis showed that SNRIs (SMD -1.36, CrI -1.77 to -0.95), topical capsaicin (SMD -0.91, CrI, -1.18 to -0.08), TCAs (SMD -0.78,CrI, -1.24 to -0.33), and anticonvulsants (SMD -0.67, CrI -0.97 to -0.37) were better than placebo for short-term pain control. Specifically, carbamazepine (SMD -1.57, CrI -2.83 to -0.31), venlafaxine (SMD -1.53, CrI -2.41 to -0.65), duloxetine (SMD -1.33, CrI -1.82 to -0.86), and amitriptyline (SMD -0.72, CrI -1.35 to -0.08) were more effective than placebo. Adverse effects included somnolence and dizziness with TCAs, SNRIs, and anticonvulsants; xerostomia with TCAs; and peripheral edema and burning sensation with pregabalin and capsaicin.
A Cochrane review included 61 studies with a total of 3 293 subjects. Tricyclic antidepressants including amitriptyline, imipramine and desipramine had an NNT of 3.1 (95% CI 2.5 to 4.2) for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer selective serotonin reuptake inhibitor antidepressant drugs (SSRIs) but no studies of SNRIs. Venlafaxine (three studies) has an NNT of 3.1 (95% CI 2.2 to 5.1) RR 2.2 (95% CI 1.5 to 3.1) with global improvement or pain relief measurements. There were insufficient data for an assessment of evidence of effectiveness for other antidepressants such as St Johns Wort and L-tryptophan. For diabetic neuropathy the NNT for effectiveness of TCA was 1.3 (95% CI 1.2–1.5), RR 12.4 (95% CI 5.2–29.2; five studies); for postherpetic neuralgia 2.7 (95% CI 2 to 4.1), RR 2.2 (95% CI 1.6 to 3.1; four studies). There was evidence that tricyclic antidepressants are not effective in HIV-related neuropathies.
The number needed to harm (NNH) for major adverse effects defined as an event leading to withdrawal from a study was 28 (95% CI 17.6 to 68.9) for amitriptyline and 16.2 (95% CI 8 to 436) for venlafaxine. The NNH for minor adverse effects was 6 (95% CI 4.2 to 10.7) for amitriptyline and 9.6 (95% CI 3.5 to 13) for venlafaxine.