Dronabinol naltrexone treatment for opioid dependence

描述(申请人提供)：阿片类药物滥用和依赖在美国仍然是一个严重的问题；特别是，非医疗使用处方阿片类药物的比率在过去几年里有所增加。主要治疗方法包括脱毒、心理社会治疗或激动剂维持。不幸的是，仅采用戒毒方法的复发率很高，基于激动剂的治疗有几个局限性，仍然存在争议。替代的药理策略，纳曲酮维持，有明显的优势。然而，由于启动治疗的困难和在治疗的头几周耐受性差，它的使用一直受到限制。针对阿片类药物戒断和纳曲酮诱导相关的厌恶症状的药物策略可以显著改善其早期耐受性，允许扩大临床应用，并改善阿片依赖治疗的长期结果。来自临床前和初步临床研究的有力支持表明，大麻样受体激动剂Dronabinol可能有效地改善纳曲酮诱导的耐受性。屈诺比诺可以减轻纳曲酮诱导与急性和残留阿片类药物戒断相一致的体征和症状，如失眠、无痛、痛觉过敏、胃肠道不适、食欲不振、焦虑、易怒、应激反应增强、烦躁不安和快感缺乏。我们的非对照观察表明，在纳曲酮治疗的阿片依赖患者中，适度使用大麻与改善治疗保留有关。这项为期三年的研究的目标是测试屈诺比诺作为纳曲酮维持治疗的辅助药物对阿片类药物依赖者的疗效。我们建议进行一项随机、双盲、安慰剂对照、平行分组、为期8周的阿片类药物依赖者复发预防研究。参与者将被随机分成两种情况之一：(1)纳曲酮+安慰剂和(2)纳曲酮+屈诺比诺20毫克，每日2次(每组40人)。治疗将在门诊进行，但住院戒毒初期除外，为期8天。一种长效的可注射形式的纳曲酮380毫克(Vivitrol)将每月注射一次(总共两次注射)，而屈诺比诺或安慰剂将每天服用。此外，患者将接受心理社会干预，其中包括激励性访谈和认知-行为复发预防治疗。主要的结果衡量标准将是在研究结束时保留治疗。主要目的是测试屈诺比诺在脱毒期间和纳曲酮治疗前两个月减少磨损的效果。 与公共卫生相关：阿片类药物依赖率在过去几年中稳步上升，主要是由于非法使用处方止痛药的增加。现有的治疗方法(以激动剂为基础的或仅以治疗为基础的方法)并不适用于所有患者，且疗效有限。开发一种改进的基于拮抗剂的方法将使其成为更多阿片类药物依赖者的可行治疗选择。

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.