Dronabinol naltrexone treatment for opioid dependence

描述（由申请人提供）：阿片类药物滥用和依赖仍然是美国的一个重大问题;特别是，过去几年中处方阿片类药物的非医疗使用率有所增加。主要的治疗方法包括戒毒，然后进行心理社会治疗或激动剂维持治疗。不幸的是，仅使用解毒方法的复发率很高，并且基于激动剂的治疗具有几个局限性并且仍然存在争议。替代药理学策略，纳洛酮维持，具有明显的优势。然而，由于在开始治疗时的困难和在治疗的第一周期间的耐受性差，其使用受到限制。针对阿片类药物戒断和纳洛酮诱导相关的厌恶症状的药理学策略可以显著改善其早期耐受性，允许扩大临床使用，并改善阿片类药物依赖治疗的长期结局。有强有力的支持，从临床前和初步的临床研究表明，屈大麻酚，大麻素受体激动剂，可能是有效的，在改善耐受性的纳洛酮诱导。屈大麻酚可减轻与纳洛酮诱导相关的体征和症状（与急性和残留阿片类药物戒断一致），如失眠、运动不能、痛觉过敏、GI不适、食欲不振、焦虑、易怒、应激反应性增强、烦躁不安和快感缺乏。我们的非对照观察结果表明，在纳洛酮治疗的阿片类药物依赖患者中，适度使用大麻与改善治疗保留相关。这项为期三年的研究的目的是测试屈大麻酚作为阿片类药物依赖者纳洛酮维持治疗的辅助治疗的疗效。我们提出了一个随机，双盲，安慰剂对照，平行组，8周的研究复发预防阿片类药物依赖的个人。受试者将被随机分配至两种条件之一：（1）纳洛酮+安慰剂和（2）纳洛酮+屈大麻酚20 mg bid（每组N=40）。除了为期8天的住院戒毒初期外，治疗将在门诊进行。长效注射形式的纳洛酮380 mg（Vivitrol）将每月给药一次（共注射两次），而屈大麻酚或安慰剂将每天服用。此外，患者将接受心理社会干预，其中包括动机访谈和认知行为复发预防治疗。主要结局指标为研究结束时的治疗保留率。主要目的是测试屈大麻酚在减少戒毒期间和纳洛酮治疗前两个月的消耗方面的疗效。 公共卫生相关性：类阿片依赖率在过去几年中稳步上升，主要是由于处方止痛剂的非法使用增加。现有的治疗方法（基于激动剂或仅治疗方法）并不适用于所有患者，并且有效性有限。开发一种改进的基于拮抗剂的方法将使其成为更大人群阿片类药物依赖个体的可行治疗替代方案。

DESCRIPTION (provided by applicant): Opioid abuse and dependence continues to be a significant problem in the US; in particular, rates of non-medical use of prescription opioids have increased in the past several years. The main treatment approaches include detoxification followed by psychosocial treatment or agonist maintenance. Unfortunately, rates of relapse are high with detoxification only approaches, and agonist-based treatments have several limitations and remain controversial. The alternative pharmacological strategy, naltrexone maintenance, has clear advantages. However, its use has been limited due to difficulties in initiating treatment and poor tolerability during the first weeks of treatment. Pharmacological strategies targeting aversive symptoms associated with opioid withdrawal and naltrexone induction could significantly improve its early tolerability, permit expansion of clinical use, and improve long-term outcome of opioid dependence treatment. There is strong support, from preclinical and preliminary clinical studies suggesting that dronabinol, a cannabinoid receptor agonist, may be effective in improving tolerability of naltrexone induction. Dronabinol may diminish signs and symptoms associated with naltrexone induction consistent with acute and residual opioid withdrawal, such as insomnia, anergia, hyperalgesia, GI distress, lack of appetite, anxiety, irritability, heightened stress reactivity, dysphoria, and anhedonia. Our uncontrolled observations suggest that among naltrexone-treated opioid dependent patients, moderate use of cannabis was associated with improved treatment retention. The goal of this three-year study is to test the efficacy of dronabinol as an adjunct to maintenance treatment with naltrexone in opioid-dependent individuals. We are proposing a randomized, double-blind, placebo controlled, parallel-groups, 8-week study of relapse prevention in opioid-dependent individuals. Participants will be randomized into one of two conditions: (1) Naltrexone + Placebo and (2) Naltrexone + dronabinol 20 mg bid (N=40 per group). Treatment will be delivered in an outpatient setting except for the initial phase of inpatient detoxification, lasting 8 days. A long-acting, injectable form of naltrexone 380 mg (Vivitrol) will be administered once per month (the total of two injections), while dronabinol or placebo will be taken daily. In addition, patients will receive a psychosocial intervention that will include elements of motivational interviewing and cognitive-behavioral relapse prevention therapy. Primary outcome measure will be retention in treatment by the end of the study. The primary aim is to test the efficacy of dronabinol in reducing attrition during detoxification and the first two months of naltrexone treatment. PUBLIC HEALTH RELEVANCE: Rates of opioid dependence have increased steadily over the past several years, mostly due to an increase in illicit use of prescription analgesics. The available treatments (agonist-based or therapy-only approaches) are not suitable for all patients and have limited effectiveness. Development of an improved antagonist based approach would open it up as a viable treatment alternative for a larger population of opioid dependent individuals.