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Kappa (<jats:italic>\u03ba<\/jats:italic>) opioid receptor antagonists may address this unmet need. Buprenorphine is a <jats:italic>\u03ba<\/jats:italic>\u2010opioid antagonist and a partial agonist of mu (<jats:italic>\u03bc<\/jats:italic>) opioid receptors. Whereas naltrexone blocks all <jats:italic>\u03bc<\/jats:italic>\u2010mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no <jats:italic>\u03ba<\/jats:italic>\u2010opioid receptor antagonist it available for clinical use, we tested this combination in a proof\u2010of\u2010concept study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Consenting participants were enrolled in a Phase II, multisite, double\u2010blind, randomized, placebo\u2010controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended\u2010release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (<jats:italic>n<\/jats:italic>\u2009=\u200975) were randomized (1:1:1) to receive either buprenorphine 2\u2009mg\/day plus naltrexone\u2010XR (<jats:italic>n<\/jats:italic>\u2009=\u200935), buprenorphine 8\u2009mg\/day plus naltrexone\u2010XR (<jats:italic>n<\/jats:italic>\u2009=\u20096) or SL plus injectable placebo (<jats:italic>n<\/jats:italic>\u2009=\u200934) for 12\u2009weeks. The buprenorphine 8\u2009mg\/day plus naltrexone\u2010XR arm was dropped early in the trial due to the negative impact of COVID\u201019 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of \u226510 points on the past week Clinician\u2010Administered PTSD Scale (CAPS\u20105) <jats:italic>and<\/jats:italic> a reduction of \u22651 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow\u2010Back.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone\u2010XR and placebo group for the primary composite outcome (OR\u2009=\u20090.63; <jats:italic>p<\/jats:italic>\u2010value\u2009=\u20090.52), or the subcomponents of the PTSD outcome (OR\u2009=\u20090.76; <jats:italic>p<\/jats:italic>\u2010value\u2009=\u20090.69) and AUD outcome (OR\u2009=\u20090.17; <jats:italic>p<\/jats:italic>\u2010value\u2009=\u20090.08). The placebo arm had a significantly higher proportion of participants with \u22651 WHO risk level reduction than the buprenorphine plus naltrexone\u2010XR arm (OR\u2009=\u20090.18, <jats:italic>p<\/jats:italic> value\u2009=\u20090.02).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first study to evaluate the potential of <jats:italic>\u03ba<\/jats:italic>\u2010opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone\u2010XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15155","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T01:08:31Z","timestamp":1689815311000},"page":"1756-1772","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Comorbid alcohol use disorder and posttraumatic stress disorder: A proof\u2010of\u2010concept randomized placebo\u2010controlled trial of buprenorphine and naltrexone combination treatment"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-5986","authenticated-orcid":false,"given":"Lori L.","family":"Davis","sequence":"first","affiliation":[{"name":"Tuscaloosa VA Medical Center  Alabama Tuscaloosa USA"},{"name":"University of Alabama at Birmingham  Alabama Birmingham USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismene L.","family":"Petrakis","sequence":"additional","affiliation":[{"name":"VA Connecticut Healthcare System  Connecticut West Haven USA"},{"name":"Yale University  Connecticut New Haven USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia D.","family":"Pilkinton","sequence":"additional","affiliation":[{"name":"Tuscaloosa VA Medical Center  Alabama Tuscaloosa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Nolen","sequence":"additional","affiliation":[{"name":"RTI International  North Carolina Research Triangle Park USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Vandergrift","sequence":"additional","affiliation":[{"name":"RTI International  North Carolina Research Triangle Park USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Hirsch","sequence":"additional","affiliation":[{"name":"RTI International  North Carolina Research Triangle Park USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth D.","family":"Norrholm","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine  Michigan Detroit USA"},{"name":"United States Air Force Academy  Colorado Colorado Springs USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Kosten","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine  Texas Houston USA"},{"name":"Michael E. 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