Evaluating Suvorexant for Sleep Disturbance in Opioid Use Disorder

超过50万人从国家认证的成瘾治疗中寻求阿片使用障碍(OUD)治疗 2016年，最常使用的治疗形式是有监督的阿片类药物戒断(也 即所谓的解毒)。令人惊讶的是，对潜在机制的实证研究很少。 个别阿片类药物戒断症状及其管理的相应最佳做法。FDA最近发布的一份 包括OUD患者的公开会议，确定睡眠障碍是OUD的主要原因 治疗失败。这一分阶段UG3/UH3提案的科学前提是Suvorexant(Suvo； BelSomra®)将改善接受常规监督戒断阿片类药物的患者的总睡眠时间 (UG3)，并且Suvo将优于通常用于该适应症的药物 (曲唑酮；UH3)。Suvo是一种双重增食欲素受体拮抗剂，已获FDA批准用于治疗失眠，效果良好 适合这项研究，因为它具有较低的滥用可能性，通过 单剂量，具有极其安全和轻微的副作用，与阿片系统有明确的相互作用， 并且还没有在OUD患者中进行评估。我们的跨学科研究团队包括几位专家 OUD和睡眠，我们的建议提供了在OUD停药期间睡眠受损的初步证据。 UG3(N=36)和UH3(N=60)研究将使用相同的方法，只在药物方面有所不同 检查过了。OUD患者将在住院研究单元住院11天，并将稳定在 丁丙诺啡3天，然后进行4天常规减量和4天后减量。学习 药物治疗将是双盲的，从第一天开始。主要结果将是客观睡眠 测量(通过睡眠状况分析器TM和手腕佩戴的活动记录仪进行不显眼的脑电检查)和滥用责任。次要的 措施将包括客观的、生物学的和自我报告的阿片戒断严重程度、治疗措施 留存、渴望和压力。UG3期的剂量发现研究将与Suvo(10 mg，20 mg)进行比较 敬安慰剂。UH3过渡的去向决定(即里程碑)将是如果任何一种Suvo剂量产生 在缩减期间，相对于安慰剂，总睡眠时间平均增加至少10分钟。UH3阶段 将进行曲唑酮(100 Mg)与UG3中确定的Suvo剂量的疗效比较试验，以评估 在阿片类药物戒断期间，Suvo与经常使用的睡眠辅助剂相比是否能改善睡眠。在UH3之后， 结果将在这两项研究中崩溃，以更普遍地检查睡眠和戒断之间的联系，以及 男性和女性将平等地参加这两项研究，以进行性别亚组比较。我们假设 Suvo将改善戒断期间的总睡眠时间，不会显示滥用责任的证据，并将 比曲唑酮更有效。结果将促进对OUD的治疗，对睡眠和 阿片类药物，以及临床人群中苏沃的使用。这些数据也可能支持更具前瞻性的 对苏沃作为一种令人渴望的药物的使用进行评估。

More than 500,000 people sought opioid use disorder (OUD) treatment from state-certified addiction treatment facilities in 2016, and the most frequently accessed form of treatment was supervised opioid withdrawal (also known as detoxification). There has been surprisingly little empirical investigation into mechanisms underlying individual opioid withdrawal symptoms and corresponding best practices for their management. A recent FDA public meeting that included patients with OUD identified sleep disturbance as a primary contributor to OUD treatment failure. The scientific premise of this phased UG3/UH3 proposal is that suvorexant (SUVO; Belsomra®) will improve total sleep time in patients undergoing routine supervised withdrawal from opioids (UG3), and that SUVO will outperform a medication that is commonly administered for that indication (trazodone; UH3). SUVO is a dual orexin receptor antagonist that is FDA-approved for insomnia and is well- suited for this study because it has low abuse potential, improves sleep continuity and architecture with a single dose, has an extremely safe and mild side effect profile, has clear interactions with the opioid system, and has not yet been evaluated in OUD patients. Our interdisciplinary study team includes several experts in OUD and sleep and our proposal provides preliminary evidence of sleep impairment during OUD withdrawal. The UG3 (N=36) and UH3 (N=60) studies will use identical methods and will vary only in the medications examined. OUD patients will be admitted to a residential research unit for 11 days, and will be stabilized on buprenorphine for 3 days before undergoing a 4-day routine taper and a 4-day post-taper period. Study medication will be double-blinded and will begin on Taper day 1. Primary outcomes will be objective sleep measures (unobtrusive EEG via the Sleep ProfilerTM and wrist-worn actigraph) and abuse liability. Secondary measures will include objective, biological, and self-report measures of opioid withdrawal severity, treatment retention, craving, and stress. The UG3 phase will be a dose-finding study of SUVO (10mg, 20mg) compared to placebo. The go-no go decision (i.e. milestone) for UH3 transition will be if either SUVO dose produces a mean increase in total sleep time of at least 10 minutes relative to placebo during the taper. The UH3 phase will be a comparative efficacy trial of trazodone (100mg) vs. the SUVO dose identified in the UG3, to evaluate whether SUVO improves sleep compared to a regularly used sleep aid during opioid withdrawal. After the UH3, results will be collapsed across both studies to examine sleep and withdrawal associations more generally, and men and women will be equally enrolled in both studies to enable sex subgroup comparisons. We hypothesize SUVO will improve total sleep time during withdrawal, will not show evidence of abuse liability, and will be more efficacious than trazodone. Results will advance the treatment of OUD, the understanding of sleep and opioids, and the use of SUVO in clinical populations. These data may also support more prospective evaluations into the use of SUVO as an OUD craving medication.