AIMS: To investigate whether the treatment effect of extended-release buprenorphine (BUP-XR) on opioid-free days in opioid use disorder (OUD) is mediated by reductions in opioid craving and improvements in personal functioning.

DESIGN AND SETTING: Exploratory causal mediation analysis using VanderWeele's four-way decomposition framework in a 24-week, multi-centre, open-label, superiority, randomised controlled trial comparing methadone or sublingual buprenorphine (MET/BUP-SL) with extended-release buprenorphine (BUP-XR).

PARTICIPANTS: Adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition moderate to severe OUD (n = 314; 98% severe). Mean age was 42 years, 32% were female and 44% were using non-medical opioids, predominantly heroin, at study baseline.

INTERVENTION AND COMPARATOR: MET/BUP-SL vs. BUP-XR (1:1 randomisation).

MEASUREMENTS: The outcome was the number of opioid-free days (0-84) during weeks 13-24. Candidate mediators were visual analogue scale ratings of opioid 'need' and 'want' (VAS-N, VAS-W), craving imagery and intrusiveness [Craving Experiences Questionnaire - frequency version (CEQ-F)] and personal functioning impairment [Work and Social Adjustment Scale (WSAS)]. Craving measures were assessed at baseline and weeks 4, 8 and 12, then reduced to binary summaries indicating craving absent at all follow-up assessments vs. present at any assessment. WSAS was assessed at week 12 and retained as a continuous mediator.

FINDINGS: During weeks 13-24, the adjusted mean number of opioid-free days was 48.9 in the MET/BUP-SL group and 58.5 in the BUP-XR group [incidence rate ratio (IRR) = 1.20, 95% confidence interval (CI) = 1.10-1.30; P-value <0.001]. Across the four mediator-specific models, BUP-XR was associated with more opioid-free days (total-effect IRRs = 1.10-1.18; all P-values <0.05). BUP-XR increased the odds of craving absence for VAS-N and VAS-W. VAS-N was the only mediator showing evidence of indirect mediation [pure indirect effect (PIE) = 1.05, 95% CI = 1.01-1.10; P-value = 0.015], indicating that reduced opioid 'need' contributed to the treatment effect. CEQ-F and VAS-W showed small, non-statistically significant indirect effects. BUP-XR improved personal functioning (WSAS mean difference -3.79; P-value = 0.014), although WSAS showed no clear evidence of mediation (PIE = 1.05; P-value = 0.085). Findings were broadly consistent across deterministic and multiple imputation sensitivity analyses, with VAS-N remaining the clearest candidate mediator.

CONCLUSIONS: In a pre-registered exploratory secondary analysis of a randomised controlled trial, the beneficial effect of extended-release buprenorphine among people with opioid use disorder (OUD) on opioid-free days appeared to operate mainly through direct pathways, with additional evidence that reduced need-related craving contributed to benefit. Improved personal functioning occurred alongside, rather than clearly mediating, treatment benefit. Need-related craving may represent a useful proximal mechanistic endpoint in OUD pharmacotherapy trials.