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 systematic review including 16 RCTs was abstracted in DARE. 12 RCTs (n=251) investigated the use of antidepressants or antidepressant-fluphenazine combinations, and 4 (n=247) investigated anticonvulsants in the treatment of diabetic neuropathy. The pooled NNT for at least 50% pain relief was 3.4 (95% CI 2.6 to 4.7) with antidepressants, and 2.7 (95% CI 2.2 to 3.8) with anticonvulsants. The majority of adverse effects observed with antidepressants were dry mouth, constipation, and blurred vision. With anticonvulsants, the most common adverse effects were dizziness, somnolence, or disturbance in gait.
Another systematic review including 25 RCTs (16 parallel, 9 crossover design) on the effectiveness of analgesics for the management of painful diabetic neuropathy, with a total of 3 290 subjects, was abstracted in DARE. 17 of the studies were included in the meta-analysis. Traditional anticonvulsants showed an overall beneficial treatment effect compared with placebo (OR 5.33, 95% CI 1.77 to 16.02; 3 RCTs, n=111). When categorised by level of pain relief, there was a beneficial treatment effect for moderate relief of pain (OR 10.63; 95% CI 2.25 to 50.13) but no difference between groups for a 50% reduction in pain (OR 3.04; 95% CI 0.88 to 10.54). There was no difference in the number of withdrawals related to adverse events between the groups. An overall beneficial treatment effect was also found with newer generation anticonvulsants (OR 3.25, 95% CI 2.27 to 4.66; 4 RCTs, n=623). Categorisation by pain relief (50% reduction or moderate pain relief) did not substantially alter this result. Withdrawals were more frequent with newer generation anticonvulsants than with placebo. A significant effect in favour of tricyclic antidepressants (TCAs) was found compared with placebo (OR 22.24, 95% CI 5.83 to 84.75; 3 RCTs, n=122). Categorisation by outcome (notable improvement in global assessment of pain or moderate pain relief) did not substantially alter this result. A beneficial effect of duloxetine (60 mg and 120 mg; OR 2.55, 95% CI 1.73 to 3.77 and OR 2.10, 95% CI 1.03 to 4.27, respectively) as well as mexiletine and opioids (weighted mean difference, WMD –1.87, 95% CI –2.64 to –1.11 and OR 4.06, 95% CI 1.16 to 14.21, respectively) was also found compared with placebo. Withdrawals due to adverse events were more frequent for duloxetine and opioids but not for TCAs or mexiletine compared with placebo.