Craving and personal functioning as mediators of extended‐release buprenorphine efficacy: A four‐way decomposition analysis from a randomised trial

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