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继续演变，高效合成阿片类药物(HPSO)现在推高 过量服药的死亡率。自2013年以来，美国合成阿片类药物过量比率增加了五倍 在约42,000例阿片类药物过量死亡中，有3,105例至2016年(约20,000例)。 芬太尼类似物和其他HPSO现在经常在海洛因和假冒处方止痛药中发现 药片。由于非法药物供应的性质迅速变化，常用药物的疗效 阿片使用障碍(OUD)的药物治疗(如丁丙诺啡、美沙酮、纳曲酮) HPSO的用户是未知的。服药过量死亡人数的增加与可能的低疗效相结合 标准疗法的出现迫切需要为使用HPSO的患者开发新的策略。 尽管已知丁丙诺啡舌下含服(BSL)维持治疗的有效性，但保留和 持续非处方阿片类药物的使用仍然存在重大限制，大约50%或更多的患者 BSL治疗后停药3~6个月。首个缓释注射剂 丁丙诺啡(亚布洛韦™)在FDA快速跟踪和优先考虑后于2018年开始上市 审核指定。这个每月的丁丙诺啡配方有两种剂量(100毫克和300毫克) Mg)，可使丁丙诺啡血药浓度超过BSL每天24 mg。 此外，如果经历了意想不到的药物假期，在注射预产期后两周，µ-阿片类药物 受体保持在70%以上，为阿片类药物的戒断和复发提供了更广泛的保护。虽然这件事 丁丙诺啡缓释(BXR)注射制剂尚未与BSL治疗进行比较， 缓释注射剂的药理优势有望改善治疗保留 和结果。缓释注射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，提供更连续的丁丙诺啡血药浓度。我们 假设BXR注射剂对使用芬太尼类似物的个人有特别的好处，因为 提供持续的治疗血丁丙诺啡水平将大大减少 不遵守和故态复萌。停止使用BSL并使用含有阿片类药物的HPSO的个人可能有 较难重新开始舌下治疗，导致治疗失败。 我们建议进行早期II期临床试验，在该试验中，寻求治疗的OUD患者的病毒感染呈阳性。 筛选时的HPSO(N=40)将被诱导到BSL上，然后随机分配以接受任一标准 治疗(BSL维持)或BXR注射，在开放标签条件下，主要结果衡量 每周使用阿片类药物的天数由尿毒学证实的时间线回溯法测量。至 据我们所知，这将是第一次试验使用HPSO来测试OUD患者的治疗方法。

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.