TOPLINE

Extended-release buprenorphine (BUP-XR) increased the number of opioid-free days compared with methadone or sublingual buprenorphine (MET/BUP-SL) in adults with moderate-to-severe opioid use disorder (OUD) primarily through direct treatment pathways and targeted suppression of need-related craving rather than improved personal functioning, a causal mediation analysis found.

METHODOLOGY

• Researchers conducted an exploratory causal mediation analysis using data from a 24-week, multicentre, open-label, superiority randomised controlled trial comparing MET/BUP-SL with BUP-XR.
• A total of 314 adults (mean age, 42 years; 25.8% women) with moderate-to-severe OUD were randomly assigned to receive either daily doses of MET/BUP-SL (n = 156) or monthly injections of BUP-XR (n = 158).
• The primary outcome was the number of opioid-free days (0-84) during follow-up weeks 13-24, assessed using data from timeline followback interviews and point-of-care urine drug screens.
• Candidate mediators evaluated up to week 12 included visual analog scale ratings of maximum perceived "need" and "want" for opioids in the past 2 weeks (VAS-N and VAS-W, respectively).
• Craving experiences and personal functioning impairment were assessed using the Craving Experiences Questionnaire-frequency version (CEQ-F) and the Work and Social Adjustment Scale (WSAS), respectively.

TAKEAWAY

• During weeks 13-24, BUP-XR significantly increased the adjusted mean number of opioid-free days compared with MET/BUP-SL (58.5 vs 48.9 days; incidence rate ratio, 1.20; P < .001).
• VAS-N showed the clearest evidence of mediation, with BUP-XR linked to higher odds of craving absence (odds ratio, 2.83; P = .001) and a significant pure indirect effect (PIE, 1.05; P = .015).
• BUP-XR improved WSAS scores at week 12 (mean difference, -3.79; P = .014), although it showed no clear evidence of mediation (PIE, 1.05; P = .085), suggesting that personal functioning improved alongside.
• Small and non-statistically significant indirect effects were observed for VAS-W and CEQ-F (PIE, 1.02; P = .257 and PIE, 1.02; P = .178, respectively), with treatment effects expressed primarily through controlled direct pathways.

IN PRACTICE

"Our findings suggest that the therapeutic benefit of BUP-XR arises primarily through direct pathways, with additional benefit associated with suppression of need-based craving," the authors wrote.

SOURCE

The study was led by John Marsden, King's College London, London, England. It was published online on July 01, 2026, in Addiction.

LIMITATIONS

The study was limited by the evaluation of a selected subgroup of methadone-enrolled participants rather than the full population, a high treatment discontinuation rate as approximately one third of participants missed complete follow-up data, and differential treatment retention between groups. It was further limited by variations in complete case samples across models, the non-equivalent construction of mediators, the reliance on self-reported mediator measures subject to recall and response bias, and an inability to model the dynamic and potentially reciprocal longitudinal relationships between craving and opioid use over time.

DISCLOSURES

The study was funded by Indivior UK Limited. Many authors disclosed receiving collaborative research grants, institutional funding, consultancy fees, traveling support, or presentation honoraria from Indivior, Beckley Psytech, PCM Scientific, OPEN Health, the National Institute for Health and Care Research, and other national research or health institutes.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.