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

使用芬太尼类似物缓释丁丙诺啡与舌下含服丁丙诺啡治疗阿片类药物使用障碍患者的随机对照试验

• 批准号: 9979016
• 负责人: Frances Rudnick Levin
• 金额: $ 23.87万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979016
• 关键词: Adverse effects; Analgesics; Automobile Driving; Buprenorphine; Clinical Treatment; Development; Dose; Dropout; Drops; Effectiveness; Epidemic; Fatality rate; Fentanyl; Formulation; Heroin; Holidays; Illicit Drugs; Individual; Injectable; Injection product; Injections; Maintenance; Measures; Methadone; Methods; Morphine; Naltrexone; Nature; New York City; Opioid; Opioid replacement therapy; Outcome; Outcome Measure; Overdose; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase II Clinical Trials; Pilot Projects; Randomized; Randomized Controlled Trials; Relapse; Serious Adverse Event; Serum; Subgroup; Testing; Therapeutic; Time; TimeLine; Toxicology; Treatment Failure; Treatment outcome; U-47700; Urine; Withdrawal Symptom; analog; buprenorphine treatment; carfentanil; craving; effective therapy; experience; improved; mu opioid receptors; non-compliance; open label; opioid epidemic; opioid overdose; opioid use; opioid use disorder; opioid user; opioid withdrawal; overdose death; pill; pilot trial; primary outcome; reduce symptoms; screening; synthetic opioid; trial comparing

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.

项目概要 美国阿片类药物流行病继续发展，高效合成阿片类药物 (HPSO) 目前正在推动更高的价格 自 2013 年以来，美国合成阿片类药物过量死亡率增加了五倍。 (3,105) 至 2016 年（约 20,000）人，其中约 42,000 人因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 由于非法药物供应的性质迅速变化，常用药物的功效也随之变化。 阿片类药物使用障碍 (OUD) 的药物疗法（例如丁丙诺啡、美沙酮、纳曲酮） HPSO 的使用者尚不清楚，过量死亡人数的增加以及可能的疗效较低。 标准疗法的发展迫切需要为使用 HPSO 的患者制定新策略。 尽管丁丙诺啡舌下含服 (BSL) 维持治疗的有效性已知，但保留和 持续使用非处方阿片类药物仍然受到很大限制，大约 50% 或更多的患者 接受 BSL 治疗后 3 至 6 个月退出治疗。 丁丙诺啡 (Sublocade™) 在获得 FDA 快速通道和优先批准后于 2018 年上市 审查指定。每月一次的丁丙诺啡制剂有两种剂量（100 毫克和 300 毫克）。 mg），可以达到超过每天 BSL 24 mg 所达到的血清丁丙诺啡浓度。 此外，如果经历了意外的药物假期，则在注射到期日后两周，μ-阿片类药物 受体保持在 70% 以上，为防止阿片类药物戒断和复发提供长期保护。 丁丙诺啡缓释 (BXR) 注射制剂尚未与 BSL 治疗进行比较， 缓释注射剂的药理学优势有望提高治疗保留率 缓释注射方面应提高依从性并减少复发。 与舌下制剂相比，我们提供更连续的丁丙诺啡血清水平。 特别是 BXR 注射对于使用芬太尼类似物的个体特别有益，因为 提供连续的治疗性血清丁丙诺啡水平，发生这种情况的机会将大大减少 停止 BSL 并使用含有阿片类药物的 HPSO 的个人可能会出现不依从和复发。 重新开始舌下治疗更加困难，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 治疗且呈阳性的患者 筛选时的 HPSO (N = 40) 将被纳入 BSL，然后随机分配接受任一标准 治疗（BSL 维持）或 BXR 注射，在开放标签条件下，主要结果指标为 通过尿液毒理学证实的时间线回溯法测量每周阿片类药物的使用天数。 据我们所知，这将是第一个使用 HPSO 测试 OUD 患者治疗方法的试验。