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

Importance: 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 down-regulate pain in humans remains unclear, however. Objective: To determine whether and under which conditions pharmacological opioid receptor blockade is associated with increased pain responses in healthy volunteers.Data Sources: We searched Web of Science, Scopus, PubMed and EMBASE between October 7, 2020 and June 10, 2025. Study selection: Double-blind, randomized, and placebo-controlled studies that used peripheral pain interventions and administered a centrally active opioid antagonist were included. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 5 reviewers. Individual study quality was rated on the Jadad scale, while Egger’s test and funnel plots were used to evaluate reporting bias. Three-level random-effects meta-regressions were used to estimate pain perception during mu-opioid blockade compared to placebo. The reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIS-MA) guidelines.Main Outcomes and Measures: The primary outcomes were estimated standardized mean difference (Hedges’ g) in pain intensity, tolerance, unpleasantness and threshold between antagonist and placebo. 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, non-drug interventions, and sample sex distributions.Results: A total of 67 studies were included (N=2706). Across the four pain outcomes, pain was slightly higher during mu-opioid antagonism compared to placebo (Hedges’ g [95% CI]=0.18 [0.11, 0.25]), approximately 2.8 points on a 0-100 pain intensity scale. Due to indications of re-porting bias, the effect size was suggested to be slightly overestimated. There was substantial residual heterogeneity (I2=66%), but study characteristics explained little or none of this variance. The most credible evidence of endogenous opioid pain regulation was found for placebo hypoalgesia. Conclusion and Relevance: Overall, the slightly higher pain sensitivity during experimental pain in healthy humans during opioid blockade indicates a minor role of endogenous opioids in human pain regulation.