{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:39:56Z","timestamp":1792381196176,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100011404","name":"Indivior UK Limited","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011404","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To investigate whether the treatment effect of extended\u2010release buprenorphine (BUP\u2010XR) on opioid\u2010free days in opioid use disorder (OUD) is mediated by reductions in opioid craving and improvements in personal functioning.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design and setting<\/jats:title>\n                    <jats:p>Exploratory causal mediation analysis using VanderWeele's four\u2010way decomposition framework in a 24\u2010week, multi\u2010centre, open\u2010label, superiority, randomised controlled trial comparing methadone or sublingual buprenorphine (MET\/BUP\u2010SL) with extended\u2010release buprenorphine (BUP\u2010XR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>\n                      Adults with\n                      <jats:italic>Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition<\/jats:italic>\n                      moderate to severe OUD (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009314; 98% severe). Mean age was 42\u2009years, 32% were female and 44% were using non\u2010medical opioids, predominantly heroin, at study baseline.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Intervention and comparator<\/jats:title>\n                    <jats:p>MET\/BUP\u2010SL vs. BUP\u2010XR (1:1 randomisation).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements<\/jats:title>\n                    <jats:p>The outcome was the number of opioid\u2010free days (0\u201384) during weeks 13\u201324. Candidate mediators were visual analogue scale ratings of opioid \u2018need\u2019 and \u2018want\u2019 (VAS\u2010N, VAS\u2010W), craving imagery and intrusiveness [Craving Experiences Questionnaire \u2013 frequency version (CEQ\u2010F)] 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\u2010up assessments vs. present at any assessment. WSAS was assessed at week 12 and retained as a continuous mediator.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      During weeks 13\u201324, the adjusted mean number of opioid\u2010free days was 48.9 in the MET\/BUP\u2010SL group and 58.5 in the BUP\u2010XR group [incidence rate ratio (IRR) = 1.20, 95% confidence interval (CI) = 1.10\u20131.30;\n                      <jats:italic>P<\/jats:italic>\n                      \u2010value &lt;0.001]. Across the four mediator\u2010specific models, BUP\u2010XR was associated with more opioid\u2010free days (total\u2010effect IRRs = 1.10\u20131.18; all\n                      <jats:italic>P<\/jats:italic>\n                      \u2010values &lt;0.05). BUP\u2010XR increased the odds of craving absence for VAS\u2010N and VAS\u2010W. VAS\u2010N was the only mediator showing evidence of indirect mediation [pure indirect effect (PIE) = 1.05, 95% CI = 1.01\u20131.10;\n                      <jats:italic>P<\/jats:italic>\n                      \u2010value = 0.015], indicating that reduced opioid \u2018need\u2019 contributed to the treatment effect. CEQ\u2010F and VAS\u2010W showed small, non\u2010statistically significant indirect effects. BUP\u2010XR improved personal functioning (WSAS mean difference \u22123.79;\n                      <jats:italic>P<\/jats:italic>\n                      \u2010value = 0.014), although WSAS showed no clear evidence of mediation (PIE = 1.05;\n                      <jats:italic>P<\/jats:italic>\n                      \u2010value = 0.085). Findings were broadly consistent across deterministic and multiple imputation sensitivity analyses, with VAS\u2010N remaining the clearest candidate mediator.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In a pre\u2010registered exploratory secondary analysis of a randomised controlled trial, the beneficial effect of extended\u2010release buprenorphine among people with opioid use disorder (OUD) on opioid\u2010free days appeared to operate mainly through direct pathways, with additional evidence that reduced need\u2010related craving contributed to benefit. Improved personal functioning occurred alongside, rather than clearly mediating, treatment benefit. Need\u2010related craving may represent a useful proximal mechanistic endpoint in OUD pharmacotherapy trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/add.70521","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:23:12Z","timestamp":1782933792000},"page":"3010-3024","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Craving and personal functioning as mediators of extended\u2010release buprenorphine efficacy: A four\u2010way decomposition analysis from a randomised trial"],"prefix":"10.1111","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1307-2498","authenticated-orcid":false,"given":"John","family":"Marsden","sequence":"first","affiliation":[{"name":"Addictions Department, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience King's College London  London UK"},{"name":"South London and Maudsley NHS Foundation 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