Evaluation of Novel Pharmacotherapies for the Treatment of Opioid Dependence

描述(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，有近200万人符合DSM-IV的处方阿片类药物使用障碍标准。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依赖的有效药物疗法的假设。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症状相关的适应症。建议进行两项概念验证、安慰剂对照、住院患者实验室研究，以评估CB激动剂屈诺比诺和纳比隆的疗效。实验1和实验2将采用受试者内交叉设计，采用经典的吗啡替代程序，即阿片依赖志愿者(n=10/研究)稳定在固定剂量的吗啡(15 mg/qd)上。在预定的基础上，受试者接受安慰剂的双盲替代吗啡，以诱导一段时间的自发阿片类药物戒断。然后进行双盲试验剂量，以确定它们抑制阿片类药物戒断体征和症状的能力，作为治疗潜在疗效的初始目标。实验1将检测屈诺比诺(5、10、20和30毫克)和Exp.2将检查纳比隆(1、2、4和6毫克)的有效性和安全性；每项研究都包括阳性(吗啡15和30毫克)和阴性(安慰剂)对照条件。将收集广泛的生理、主观、观察者评级和精神运动表现测量，以评估戒断抑制的安全性、耐受性和有效性。这些研究具有创新性和重要意义，因为据我们所知，它们是第一次考察CB1激动剂作为治疗人类阿片依赖的潜在药物疗法的有效性，并将产生关于CB1和阿片系统相互作用的新数据。此外，它们将为今后的研究提供关键数据，以指导药物和剂量的选择，这些研究旨在审查它们在阿片依赖维持治疗、复发预防、门诊戒毒和/或用作启动阿片拮抗剂治疗的过渡剂方面的潜在疗效。

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.