Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews

OBJECTIVE: To provide a comprehensive overview of the efficacy, safety, and tolerability of antidepressants for pain according to condition. DESIGN: Overview of systematic reviews. DATA SOURCES: PubMed, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to 20 June 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews comparing any antidepressant with placebo for any pain condition in adults. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data. The main outcome measure was pain; for headache disorders it was frequency of headaches. Continuous pain outcomes were converted into a scale of 0 (no pain) to 100 (worst pain) and were presented as mean differences (95% confidence intervals). Dichotomous outcomes were presented as risk ratios (95% confidence intervals). Data were extracted from the time point closest to the end of treatment. When end of treatment was too variable across trials in a review, data were extracted from the outcome or time point with the largest number of trials and participants. Secondary outcomes were safety and tolerability (withdrawals because of adverse events). Findings were classified from each comparison as efficacious, not efficacious, or inconclusive. Certainty of evidence was assessed with the grading of recommendations assessment, development, and evaluation framework. RESULTS: 26 reviews (156 unique trials and >25 000 participants) were included. These reviews reported on the efficacy of eight antidepressant classes covering 22 pain conditions (42 distinct comparisons). No review provided high certainty evidence on the efficacy of antidepressants for pain for any condition. 11 comparisons (nine conditions) were found where antidepressants were efficacious, four with moderate certainty evidence: serotonin-norepinephrine reuptake inhibitors (SNRIs) for back pain (mean difference −5.3, 95% confidence interval −7.3 to −3.3), postoperative pain (−7.3, −12.9 to −1.7), neuropathic pain (−6.8, −8.7 to −4.8), and fibromyalgia (risk ratio 1.4, 95% confidence interval 1.3 to 1.6). For the other 31 comparisons, antidepressants were either not efficacious (five comparisons) or the evidence was inconclusive (26 comparisons). CONCLUSIONS: Evidence of efficacy of antidepressants was found in 11 of the 42 comparisons included in this overview of systematic reviews—seven of the 11 comparisons investigated the efficacy of SNRIs. For the other 31 comparisons, antidepressants were either inefficacious or evidence on efficacy was inconclusive. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain conditions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022311073.