Sustained-Release Naltrexone for Opioid Dependence: Longitudinal Study in Humans

描述(申请人提供)：除了海洛因滥用的持续问题外，处方阿片类药物滥用已经成为一个严重的公共卫生问题。尽管目前存在几种治疗阿片类药物依赖的药物，但与使用这些药物相关的各种问题使得寻找替代形式的药物治疗变得重要。纳曲酮是一种阿片类拮抗剂，目前以口服形式提供，已被批准用于治疗阿片依赖。然而，药物不依从一直是有效治疗的主要障碍。在我们之前的研究中，我们证明了注射用纳曲酮仓库制剂在3-5周内对海洛因的拮抗作用是有效的，这取决于剂量。随后对该药物进行的随机、安慰剂对照临床试验进一步显示，治疗保留率以与剂量相关的方式增加，在2个月的研究期结束时，安慰剂组39%的患者、192毫克纳曲酮组60%的患者和384毫克纳曲酮组68%的患者仍在接受治疗。这些结果支持了这一治疗阿片依赖的策略的安全性和有效性。目前申请中描述的这项研究旨在评估更持久的纳曲酮植入剂的效果。纳曲酮植入物在减少海洛因的止痛、呼吸、主观和行为影响方面的安全性、有效性和持续时间将在人体上进行测量。重要的是，长期阻断阿片受体可能带来的心理和行为变化也将在目前的应用中进行测量。具体地说，在服用纳曲酮植入剂之前和之后，将重复测量冲动行为。纳曲酮的这种制剂的出现为我们提供了一个独特的机会，在一项纵向研究中前瞻性地确定阿片受体本身的阻断是否与冲动行为的减少有关，以及阻断的丧失是否与恢复到基线冲动水平有关。

DESCRIPTION (provided by applicant): In addition to the ongoing problem of heroin abuse, prescription opioid abuse has been emerging as a serious public health concern. Although several medications currently exist for treating opioid dependence, various problems associated with their use make the search for alternative forms of pharmacotherapy important. Naltrexone, an opioid antagonist that is currently available in oral form, is approved for the treatment of opioid dependence. However, medication non-compliance has been a major obstacle to effective treatment. In our previous research, we demonstrated that an injectable depot formulation of naltrexone was effective in antagonizing heroin for 3-5 weeks, depending on dose. A subsequent randomized, placebo-controlled clinical trial of this medication further showed that treatment retention increased in a dose-related fashion, with 39% of patients in the placebo group, 60% of patients in the 192 mg naltrexone group, and 68% of patients in the 384 mg naltrexone group remaining in treatment at the end of the 2-month study period. These results support the safety and effectiveness of this strategy for the treatment of opioid dependence. The study described in the current application is designed to evaluate the effects of an even longer-lasting implantable formulation of naltrexone. The safety, effectiveness, and duration of action of the naltrexone implant in reducing the analgesic, respiratory, subjective, and performance effects of heroin will be measured in humans. Importantly, the psychological and behavioral changes that may accompany long-term blockade of opioid receptors will also be measured in the current application. Specifically, impulsive behavior will be measured before and repeatedly after administration of the naltrexone implant. The availability of this formulation of naltrexone provides us with the unique opportunity to determine prospectively in a longitudinal study whether blockade of opioid receptors per se is associated with reductions in impulsive behavior and whether loss of blockade is associated with a return to baseline levels of impulsivity.