BACKGROUND: Multiple treatments for painful diabetic peripheral neuropathy are available.PURPOSE: To evaluate the comparative effectiveness of oral and topical analgesics for diabetic neuropathy.DATA SOURCES: Multiple electronic databases between January 2007 and April 2014, without language restriction.STUDY SELECTION: Parallel or crossover randomized, controlled trials that evaluated pharmacologic treatments for adults with painful diabetic peripheral neuropathy.DATA EXTRACTION: Duplicate extraction of study data and assessment of risk of bias.DATA SYNTHESIS: 65 randomized, controlled trials involving 12 632 patients evaluated 27 pharmacologic interventions. Approximately one half of these studies had high or unclear risk of bias. Nine 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.LIMITATION: Confidence in findings was limited because most evidence came from indirect comparisons of trials with short (≤3 months) follow-up and unclear or high risk of bias.CONCLUSION: Several medications may be effective for short-term management of painful diabetic neuropathy, although their comparative effectiveness is unclear.PRIMARY FUNDING SOURCE: Mayo Foundation for Medical Education and Research.