Randomized controlled trial of extended-release buprenorphine vs. sublingual buprenorphine for the treatment opioid use disorder patients using fentanyl analogues

项目摘要 美国阿片类药物流行病继续发展，高效合成阿片类药物（HPSO）现在正在推动更高的 过量致死率自2013年以来，美国合成阿片类药物过量率增加了五倍 （3，105）至2016年（约20，000），约42，000例阿片类药物过量死亡。 芬太尼类似物和其他HPSO现在常见于海洛因和假冒处方止痛药中 丹由于非法药物供应的性质迅速变化， 阿片类药物使用障碍（OUD）的药物疗法（例如，丁丙诺啡、美沙酮、纳洛酮）治疗 HPSO的用户未知。过量死亡人数的增加加上可能的疗效降低 标准疗法的缺乏迫切需要为使用HPSO的患者开发新的策略。 尽管已知丁丙诺啡舌下（BSL）维持治疗的有效性， 继续非处方阿片类药物使用仍然存在显著限制，约50%或更多的患者 用BSL治疗的患者在3至6个月时退出治疗。第一种缓释注射剂 丁丙诺啡（Sublocade™）在FDA Fast Track和Priority之后于2018年上市 审查指定。这种每月丁丙诺啡制剂，有两种剂量（100毫克和300毫克）可供选择。 mg），可以达到超过BSL 24 mg/天所达到的血清丁丙诺啡浓度。 此外，如果经历了非预期的药物假期，在注射到期日后两周， 受体保持在70%以上，提供延长的保护，防止阿片类药物戒断和复发。虽然这 丁丙诺啡缓释（BXR）注射制剂尚未与BSL治疗进行比较， 延长释放注射剂的药理学优势有望改善治疗保留 和结果。缓释注射剂方面应通过以下方式提高依从性并减少复发： 与舌下制剂相比提供了更连续的丁丙诺啡血清水平。我们 假设BXR注射对使用芬太尼类似物的个人特别有益，因为 提供连续的治疗性血清丁丙诺啡水平， 不遵守和复发。停止BSL并使用含有阿片类药物的HPSO的个人可能有 更难重新开始舌下治疗，导致治疗失败。 我们建议进行一项早期II期临床试验，其中寻求OUD治疗的患者， 筛选时的HPSO（N = 40）将导入BSL，然后随机分配接受标准品 治疗（BSL维持）或BXR注射，在开放标签条件下，主要结局指标为 通过尿液毒理学确认的时间轴随访方法测量的每周阿片类药物使用天数。到 据我们所知，这将是第一次试验测试使用HPSO治疗OUD患者。

Project Summary The US opioid epidemic continues to evolve with highly potent synthetic opioids (HPSO) now driving higher overdose fatality rates. There has been a five-fold increase in US synthetic opioid overdose rate from 2013 (3,105) to 2016 (approximately 20,000) out of the approximately 42,000 overdose deaths due to opioids. Fentanyl analogs and other HPSO are now commonly found in heroin and counterfeit prescription painkiller pills. Due to the rapidly changing nature of the illicit drug supply, the efficacy of commonly used pharmacotherapies for opioid use disorder (OUD) (e.g., buprenorphine, methadone, naltrexone) in treating users of HPSO is unknown. The increasing number of overdose deaths combined with possible lower efficacy of standard therapies creates an urgent need to develop new strategies for the HPSO-using patient. Despite the known effectiveness of buprenorphine sublingual (BSL) maintenance treatment, retention and continued non-prescribed opioid use remain significant limitations, with approximately 50% or more of patients treated with BSL dropping out of treatment by 3 to 6 months. The first extended-release injectable buprenorphine (Sublocade™) became commercially available in 2018 after FDA Fast Track and Priority Review designation. This monthly buprenorphine formulation, which is available in two doses (100 mg and 300 mg), can achieve serum buprenorphine concentrations in excess of that achieved by BSL 24 mg per day. Moreover, if an unexpected drug holiday is experienced, at two weeks past the injection due date, µ-opioid receptor remains above 70%, providing extended protection against opioid withdrawal and relapse. While this buprenorphine extended-release (BXR) injection formulation has not yet been compared to BSL treatment, the pharmacologic advantages of an extended-release injection can be expected to improve treatment retention and outcomes. The extended-release injection aspect should improve compliance and reduce relapse by providing more continuous buprenorphine serum levels as compared to the sublingual formulation. We hypothesize that BXR injection will have particular benefit for individuals using fentanyl analogues because by providing continuous therapeutic serum buprenorphine levels there will be substantially less opportunity for non-compliance and relapse. Individuals who discontinue BSL and use HPSO containing opioids may have more difficulty restarting sublingual treatment, leading to treatment failure. We propose an early Phase II clinical trial, in which patients seeking treatment for OUD who are positive for HPSO at screening (N = 40) will be inducted onto BSL and then randomly assigned to receive either standard therapy (BSL maintenance) or BXR injection, under open label conditions, with a primary outcome measure of days of opioid use per week as measured by the timeline followback method confirmed by urine toxicology. To our knowledge, this would be the first trial testing a treatment for individuals with OUD using HPSO.