Minimal Evidence Supports Antidepressants for Chronic Pain

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An international review of data show certain antidepressants may benefit conditions like fibromyalgia, but many trials are actually inconclusive.

Despite it being a frequent practice, there is limited evidence supporting the prescription of antidepressant drugs to help treat pain conditions.

In new data from an overview of systematic reviews conducted by an international team of investigators, approximately 1 in every 4 comparison trials showed an efficacy of antidepressants in the treatment of pain conditions including back, neuropathic and fibromyalgia pain.1 The findings elucidate a need to improve guidance and rationale behind the use of drug classes including serotonin-norepinephrine reuptake inhibitors (SNRIs) in matters of pain management.

Led by Dr. Giovanni E. Ferreira, a research fellow at the Sydney School of Public Health’s Faculty of Medicine and Health, investigators sought to review the efficacy, safety and tolerability of antidepressants for treating pain, based on the pain condition itself. With most common pain conditions being difficult to treat, management strategies are “suboptimal” and dependent on individual benefit-risk profiles (i.e, the utility of opioid analgesics or non-steroidal anti-inflammatory drugs [NSAIDs]).

Antidepressants have globally become more commonplace among chronic pain patients, despite 2021 National Institute for Health and Care Excellence guidelines for chronic primary pain “explicitly” recommended against their use in such circumstances.

“Given the heterogeneity in the types of pain conditions for which the efficacy of antidepressants has been documented by existing systematic reviews, we chose to conduct an overview of systematic reviews to appraise efficacy estimates for each condition individually,” they wrote.

The team conducted the review of research comparing any antidepressant with a placebo control for any pain condition in adults. A pair of independent reviewers had extracted data from relevant trials at the time point closes to end of treatment. They sought a primary outcome measure of pain for standard trials, and frequency of headaches for trials involving headache disorders.

The investigators converted continuous pain outcomes on a scale of 0-100 for severity and presented as mean differences. Dichotomous trial outcomes were presented as risk ratios. They additionally sought secondary outcomes for safety and tolerability based on adverse event withdrawals. Findings were defined as either efficacious, non-efficacious or inconclusive.

Their final assessment included 26 reviews assessing 156 unique trials and more than 25,000 participants, and pertained to 8 antidepressant classes treating 22 pain conditions; a total of 42 distinct therapy-placebo comparisons to a unique pain condition were identified.

None of the reviews provided a high certainty of evidence on the efficacy of antidepressants to treat pain. Eleven comparisons across 9 conditions showed the drug class’s efficacy; 4 showed moderate certainty evidence:

  • SNRIs for back pain (mean difference, -5.3; 95% CI, -7.3 to -3.3)
  • SNRIs for postoperative pain (mean difference, -7.3; 95% CI, -12.9 to -1.7)
  • SNRIs for neuropathic pain (mean difference, -6.8; 95% CI, -8.7 to -4.8)
  • SNRIs for fibromyalgia (risk ratio [RR], 1.4; 95% CI, 1.3 – 1.6)

Among the 31 (73.8%) other comparisons, antidepressants were either not efficacious (n = 5) or the data were inconclusive (n = 26).

As antidepressant use has doubled in OECD countries including the US from 2000 to 2015—with off-label prescriptions that buck against even guideline recommendations playing a driving role in this trend—investigators stressed these findings show how little is understood behind the prescription of antidepressants for chronic pain conditions, let alone differing conditions.

“We found evidence of efficacy of antidepressants in 11 of the 42 comparisons included in this overview of systematic reviews,” they concluded. “For the other 31 (74%) comparisons, antidepressants were either inefficacious or evidence on their efficacy was inconclusive. Our findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain.”

In an editorial accompanying the research, a pair of experts stressed the shared decision making and continued communication between chronic pain patients and their prescribing clinicians in circumstances when the care strategy—such as using antidepressants—is lesser defined and not recommended by leading organizations.2

“Ferreira and colleagues’ overview adds to mounting evidence challenging the use of medicines for pain,” they wrote. “In consequence, a real opportunity is emerging to focus more on what living with pain means for individuals and to change how we think about pain. Effective care and research can only grow from new, more equal partnerships between clinicians, people living with pain, and researchers.”


  1. Ferreira GE, Abdel-Shaheed C, Underwood M, et al. Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews. BMJ. 2023;380:e072415. Published 2023 Feb 1. doi:10.1136/bmj-2022-072415
  2. Stannard C, Wilkinson C. Rethinking use of medicines for chronic pain. BMJ. 2023;380:p170. Published 2023 Feb 1. doi:10.1136/bmj.p170