Stress-enhanced opioid self-administration in healthy men: A randomized controlled experimental medicine study

Men are disproportionately likely to develop opioid use disorder, yet the mechanisms of addiction risk in men and women remain poorly understood. Preclinical, epidemiological and clinical studies converge upon stress as a key risk factor. To determine the mechanisms through which stress alters abuse liability, we measured opioid self-administration after acute stress induction in healthy men and women. Sixty-three healthy participants (31 men) completed four sessions in this repeated-measures, double-blind placebo-controlled randomized study. Social stress or a neutral control state was induced before injection of oxycodone (3.1mg/70kg) or saline. The primary outcome was amount of additional oxycodone obtained in an effortful self-administration task (0-125% of the sampling dose effect). The resulting dose was administered ~40 minutes later. Subjective, autonomic and endocrine responses were collected throughout sessions. Data were analyzed using Hierarchical Bayesian regressions. Pre-exposure to stress increased oxycodone self-administration by 5 percentage points (95% credible interval, 1 to 10, Posterior probability (Pr) > 0.99), but with a robust sex difference (16 percentage points; 95% credible interval, 7 to 24; Pr > 0.99). Stress induction only increased self-administration in men, although women showed higher stress responses. In both sexes, oxycodone induced drug high but did not improve mood or cause clear stress relief. We found no evidence that stress-enhanced drug wanting was related to stress relief or drug liking in men or women. By demonstrating a robust sex difference in stress-enhanced opioid self-administration, the study unveils a putative mechanism for men’s higher vulnerability to opioid addiction.