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BUP's partial agonism and ceiling effect on respiratory depression enhance its safety profile. However, BUP can induce precipitated withdrawal when administered after a full agonist, leading to severe withdrawal symptoms. This Perspective builds on prior work that has linked BUP's high\u2010affinity partial agonism to precipitated withdrawal and low\u2010dose induction strategies. We focus on how BUP's capacity to promote MOR externalization, together with its activity at the nociceptin opioid peptide (NOP) receptor, can help explain why it precipitates withdrawal when administered in the presence of full agonists yet relieves withdrawal once spontaneous withdrawal has begun. Understanding these mechanisms is critical for optimizing BUP protocols in OUD treatment and informs the potential development of new biased MOR agonists (i.e., ligands that preferentially activate specific signalling pathways) for addiction therapy.<\/jats:p>","DOI":"10.1111\/adb.70126","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T22:39:51Z","timestamp":1773095991000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Buprenorphine Paradox: How Buprenorphine Triggers and Resolves Opioid Withdrawal"],"prefix":"10.1111","volume":"31","author":[{"given":"Mehdi","family":"Haghdoost","sequence":"first","affiliation":[{"name":"Aidos Innovation  Sheridan Wyoming USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"LaBranche","sequence":"additional","affiliation":[{"name":"Complex Pain and Addiction Service, Department of Psychiatry Vancouver Coastal Health  Vancouver Canada"},{"name":"Department of Psychiatry, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Roberts","sequence":"additional","affiliation":[{"name":"Aidos Innovation  Sheridan Wyoming USA"},{"name":"Complex Pain and Addiction Service, Department of Psychiatry Vancouver Coastal Health  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor\u00a0W.","family":"Li","sequence":"additional","affiliation":[{"name":"Complex Pain and Addiction Service, Department of Psychiatry Vancouver Coastal Health  Vancouver Canada"},{"name":"Department of Psychiatry, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane\u00a0J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Complex Pain and Addiction Service, Department of Psychiatry Vancouver Coastal Health  Vancouver Canada"},{"name":"Department of Psychiatry, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James\u00a0S.\u00a0H.","family":"Wong","sequence":"additional","affiliation":[{"name":"Complex Pain and Addiction Service, Department of Psychiatry Vancouver Coastal Health  Vancouver Canada"},{"name":"Department of Psychiatry, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3030-311X","authenticated-orcid":false,"given":"Pouya","family":"Azar","sequence":"additional","affiliation":[{"name":"Aidos Innovation  Sheridan Wyoming USA"},{"name":"Complex Pain and Addiction Service, Department of Psychiatry Vancouver Coastal Health  Vancouver Canada"},{"name":"Department of Psychiatry, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2020.108350"},{"key":"e_1_2_8_3_1","unstructured":"\u201cCanada PHA of. 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