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

Objectives: To provide a comprehensive overview of the efficacy, safety, and tolerability of antidepressants for pain conditions.Design: Overview of systematic reviews.Data sources: PubMed, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to June 20, 2022.Eligibility criteria: Systematic reviews comparing any antidepressant to placebo for any pain condition in adults.Data extraction and synthesis: Two reviewers independently extracted data. Pain was our primary outcome; for headache disorders it was headache frequency. When reviews reported pain on a continuous scale, we converted scores to a scale of 0 (no pain) to 100 (worst pain) and presented results as mean differences (MD) and 95% confidence intervals (95% CI). We converted dichotomous outcomes to risk ratios (RR) (95% CI). We extracted data from the time point closest to the end of treatment. When end of treatment was too variable across trials for a pain condition review, we extracted data from the outcome or time point with the largest number of trials and participants. Safety and tolerability (withdrawals because of adverse events) were secondary outcomes. We classified findings from each comparison as either efficacious, not efficacious, or inconclusive. Certainty of evidence was assessed with the GRADE framework.Results: We included 26 reviews (158 unique trials and over 26,000 participants). These reviews reported on the efficacy of 8 antidepressant classes covering 22 pain conditions (43 distinct comparisons). 46% of trials had industry ties. No review provided high certainty evidence on the efficacy of antidepressants for pain for any condition. We found 11 comparisons (10 conditions) where antidepressants were efficacious, five with moderate certainty evidence: serotonin-norepinephrine reuptake inhibitors (SNRI) for back pain (MD: -5.3, 95% CI -7.3 to -3.3), postoperative pain (MD: -7.2, 95% CI -12.2 to -2.2), neuropathic pain (MD: -6.9, 95% CI -9 to -4.8), and fibromyalgia (RR: 1.4, 95% CI 1.3 to 1.6); and selective serotonin reuptake inhibitors (SSRI) for people with depression and comorbid chronic pain (standardised mean difference: -0.24, 95% CI -0.36 to -0.13). For the other 32 comparisons presented in this review, antidepressants were either not efficacious (5 comparisons) or the evidence was inconclusive (27 comparisons).Conclusions: Some antidepressants, particularly SNRIs, are efficacious in selected pain conditions. For most comparisons in this review, antidepressants were either inefficacious or there was inconclusive evidence on their efficacy. Our findings suggest a more nuanced approach to prescribing antidepressants for pain is needed.