Evaluation of Novel Pharmacotherapies for the Treatment of Opioid Dependence

描述（由申请人提供）：处方阿片类药物滥用和依赖正在增加美国的公共卫生问题，近200万人符合DSM-IV处方阿片类药物使用障碍的标准。虽然治疗需求持续增长，但只有三种药物获得FDA批准，需要更广泛的治疗选择。大量证据支持大麻素（CB）激动剂可能是治疗阿片类药物依赖的有用药物的假设。CB激动剂已经获得批准，可用于人体试验，并用于与阿片类药物戒断相关的适应症。提出了两项概念验证、安慰剂对照、基于住院实验室的研究，以评价CB激动剂屈大麻酚和那比隆的疗效。实验1和2将采用具有经典吗啡替代程序的受试者内交叉设计，其中阿片样物质依赖性志愿者（n=10/研究）稳定于固定剂量的吗啡（15 mg/qid）。在计划的基础上，受试者接受安慰剂替代吗啡的双盲治疗，以诱导一段时间的自发阿片类戒断。然后给予双盲测试剂量以确定其抑制阿片类戒断体征和症状的能力，作为治疗中潜在功效的初始目标。Exp. 1将检查屈大麻酚（5、10、20和30 mg）和Exp. 2将检查nabilone（1，2，4和6 mg）的疗效和安全性;这些研究中的每一项都包括阳性（吗啡15和30 mg）和阴性（安慰剂）对照条件。将收集广泛的生理、主观、主观评分和心理表现指标，以评估戒断抑制时的安全性、耐受性和疗效。这些研究具有创新性和重要性，因为据我们所知，它们是第一个检查CB 1激动剂作为治疗人类阿片类药物依赖的潜在药物疗法的有效性的研究，并将产生关于CB 1和阿片系统相互作用的新数据。此外，他们将提供关键数据，以指导未来研究的药物和剂量选择，旨在检查其用于阿片类药物依赖维持治疗、预防复发、门诊戒毒和/或作为启动阿片类药物拮抗剂治疗的过渡药物的潜在疗效。

DESCRIPTION (provided by applicant): Prescription opioid abuse and dependence are increasing public health problems in the U.S. with nearly 2 million people meeting DSM-IV criteria for a prescription opioid use disorder. While treatment demand continues to grow, only three medications are FDA-approved and a broader spectrum of treatment options is needed. A large body of evidence supports the hypothesis that cannabinoid (CB) agonists may be useful pharmacotherapies for the treatment of opioid dependence. CB agonists are already approved, available for human testing, and used for indications relevant to opioid withdrawal symptomatology. Two proof-of-concept, placebo-controlled, inpatient laboratory-based studies are proposed to evaluate the efficacy of the CB agonists, dronabinol and nabilone. Experiments 1 and 2 will employ within-subject crossover designs with the classic morphine substitution procedure whereby opioid dependent volunteers (n=10/study) are stabilized on a fixed dose of morphine (15 mg/qid). On a scheduled basis, subjects receive double-blind substitution of placebo for morphine to induce a period of spontaneous opioid withdrawal. Double-blind test doses are then administered to determine their ability to suppress opioid withdrawal signs and symptoms as the initial target for potential efficacy in treatment. Exp. 1 will examine dronabinol (5, 10, 20 and 30 mg) and Exp. 2 will examine nabilone (1, 2, 4 and 6 mg) for efficacy and safety; each of these studies includes positive (morphine 15 and 30 mg) and negative (placebo) control conditions. A broad array of physiological, subjective, observer-rated and psychomotor performance measures will be collected to assess safety, tolerability and efficacy at withdrawal suppression. These studies are innovative and significant as they are the first, to our knowledge, to examine the efficacy of CB1 agonists as potential pharmacotherapies for the treatment of opioid dependence in humans and will yield new data on the interaction of CB1 and opioid systems. Moreover, they will provide critical data to guide drug and dose selection for future studies aimed at examining their potential efficacy for use in the treatment of opioid dependence for maintenance, relapse prevention, ambulatory detoxification and/or as transitional agents for initiating opioid antagonist therapy.