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<p>Preclinical, epidemiological and clinical studies converge upon psychosocial stress as a key risk factor for opioid misuse. Opioids are nevertheless frequently administered under conditions of stress, such as trauma or surgery. Here we tested the hypothesis that acute psychosocial stress would increase opioid self-administration in healthy men and women with limited prior opioid exposure. In this triple-blind, block-randomized, placebo- and state-induction controlled, four-way crossover trial, social stress or a neutral control state was induced in a laboratory setting (2021–2022) before administration of a sampling dose of oxycodone (3 mg 70 kg<sup>−1</sup> intravenous) or saline. The primary outcomes were amount of oxycodone self-administered in an effortful task and self-reported drug desire (stress versus control). Changes in mood ratings, heart rate and cortisol were also determined. Of 85 randomized participants (<i>N</i> = 20–22 to each of four sequences), data from 66 participants comprising 257 sessions were eligible for analysis. Oxycodone induced a drug high but did not improve mood ratings or relieve stress compared with placebo. Expected opioid side effects were reported, but no serious adverse events occurred. Hierarchical ordinal Bayesian regression models showed that stress credibly increased oxycodone self-administration by 6 percentage points (95% credible interval 1 to 10, posterior probability &gt;0.99). Moreover, a robust sex difference (19 percentage points, 95% credible interval 10 to 28, posterior probability &gt;0.99) reflected that this effect was driven by male participants. Stress-enhanced opioid self-administration was not observed in the women tested here nor linked to positive drug effects or stress relief in men or women. The results are consistent with heightened risk for persistent opioid use after exposure to opioid analgesics during high psychosocial stress burden. ClinicalTrials.gov registration: <a href="http://clinicaltrials.gov/ct2/show/NCT06485817">NCT06485817</a>. Funded by the European Research Council (grant no. 802885) and the Swedish Research Council (grant no. 2013-07434).</p>

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Effects of psychosocial stress on opioid self-administration in healthy participants: a randomized, placebo-controlled crossover trial

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Marie Eikemo,
  • Guro E. Løseth,
  • Molly Carlyle,
  • Martin Trøstheim,
  • Gernot Ernst,
  • Claudia Pazmandi,
  • Matthew Thompson,
  • Cecilia Vezzani,
  • Isabell M. Meier,
  • Mathias Nikolai Roland,
  • Tom Johnstone,
  • Markus Heilig,
  • Guido Biele,
  • Siri Leknes

摘要

Preclinical, epidemiological and clinical studies converge upon psychosocial stress as a key risk factor for opioid misuse. Opioids are nevertheless frequently administered under conditions of stress, such as trauma or surgery. Here we tested the hypothesis that acute psychosocial stress would increase opioid self-administration in healthy men and women with limited prior opioid exposure. In this triple-blind, block-randomized, placebo- and state-induction controlled, four-way crossover trial, social stress or a neutral control state was induced in a laboratory setting (2021–2022) before administration of a sampling dose of oxycodone (3 mg 70 kg−1 intravenous) or saline. The primary outcomes were amount of oxycodone self-administered in an effortful task and self-reported drug desire (stress versus control). Changes in mood ratings, heart rate and cortisol were also determined. Of 85 randomized participants (N = 20–22 to each of four sequences), data from 66 participants comprising 257 sessions were eligible for analysis. Oxycodone induced a drug high but did not improve mood ratings or relieve stress compared with placebo. Expected opioid side effects were reported, but no serious adverse events occurred. Hierarchical ordinal Bayesian regression models showed that stress credibly increased oxycodone self-administration by 6 percentage points (95% credible interval 1 to 10, posterior probability >0.99). Moreover, a robust sex difference (19 percentage points, 95% credible interval 10 to 28, posterior probability >0.99) reflected that this effect was driven by male participants. Stress-enhanced opioid self-administration was not observed in the women tested here nor linked to positive drug effects or stress relief in men or women. The results are consistent with heightened risk for persistent opioid use after exposure to opioid analgesics during high psychosocial stress burden. ClinicalTrials.gov registration: NCT06485817. Funded by the European Research Council (grant no. 802885) and the Swedish Research Council (grant no. 2013-07434).