Minor role of endogenous opioids for acute pain regulation in humans: a systematic review and meta-analysis of placebo-controlled antagonist studies

Why clinicians should know about it

• Picked for Pharmacology (medical) (top studies of the week, 20 September 2026): Meta-analysis of endogenous opioids, not PK/PD

Abstract

Endogenous opioids are widely regarded as the body's natural painkillers, lending credibility to the status of opioid medications as the gold-standard analgesics. When and how much endogenous opioids downregulate pain in humans remains unclear. To determine whether and under which conditions pharmacological opioid receptor blockade increased pain in healthy volunteers, we conducted a systematic review and meta-analysis of double-blind, randomized, placebo-controlled studies administering centrally active opioid antagonists during peripheral pain testing. Literature searches were performed in Web of Science, Scopus, PubMed, and EMBASE between October 7, 2020, and June 10, 2025. Three-level random-effects meta-regressions estimated standardized mean differences (Hedges' g) in pain intensity, tolerance, unpleasantness, and threshold between antagonist and placebo conditions. In secondary analyses, to determine under which conditions pain would be higher during mu-opioid blockade, we assessed the potential moderating role of study characteristics including pain modality, location, duration, nondrug interventions, and sample sex distributions. Sixty-seven studies were included (N = 2706). Across all pain outcomes, mu-opioid blockade was associated with slightly higher pain compared with placebo (Hedges' g [95% CI] = 0.18 [0.11, 0.25]), an increase of 2.8 points on a 0 to 100 pain intensity scale. Evidence of reporting bias suggested that the effect size was slightly overestimated. Although residual heterogeneity was substantial (I2 = 66%), study characteristics explained little or none of this variance. The most credible evidence of endogenous opioid pain regulation was found for the placebo hypoalgesia category. Overall, the slight increase in pain sensitivity during opioid blockade in healthy volunteers indicates a minor role of endogenous opioids in human pain regulation.

Abstract as published, via PubMed.