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

描述（由申请人提供）：除了海洛因滥用的持续问题外，处方阿片类药物滥用已成为一个严重的公共卫生问题。虽然目前存在几种药物用于治疗阿片类药物依赖，但与其使用相关的各种问题使得寻找替代形式的药物治疗很重要。纳洛酮是一种目前以口服形式可用的阿片类拮抗剂，被批准用于治疗阿片类药物依赖。然而，不遵守药物治疗一直是有效治疗的主要障碍。在我们以前的研究中，我们证明了纳洛酮的注射贮库制剂在拮抗海洛因3-5周内是有效的，这取决于剂量。随后的一项随机、安慰剂对照临床试验进一步表明，治疗保留率以剂量相关的方式增加，安慰剂组39%的患者，192 mg纳洛酮组60%的患者，384 mg纳洛酮组68%的患者在2个月研究期结束时仍在治疗中。这些结果支持该策略用于治疗阿片类药物依赖的安全性和有效性。本申请中描述的研究旨在评估纳洛酮的甚至更持久的可植入制剂的效果。将在人体中测量纳洛酮植入物在减少海洛因的镇痛、呼吸、主观和性能影响方面的安全性、有效性和作用持续时间。重要的是，可能伴随阿片受体长期阻断的心理和行为变化也将在当前应用中测量。具体而言，将在纳洛酮植入物给药前和给药后重复测量冲动行为。这种纳洛酮制剂的可用性为我们提供了独特的机会，可以在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冲动性恢复到基线水平有关。

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.