Craving and personal functioning as mediators of extended‐release buprenorphine efficacy: A four‐way decomposition analysis from a randomised trial
John Marsden, Mike Kelleher, Fiona Cowden, Edward Day, Jonathan Dewhurst, Rachel Evans, Eilish Gilvarry, Natalie Lowry, Luke Mitcheson, Robert Murray, Sophie Quarshie, Zoë HoareAbstract
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.