Prevention of Relapse in Addiction

预防成瘾复吸

• 批准号: 8736757
• 负责人: Kenzie Preston
• 金额: $ 113.28万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736757
• 关键词: Abstinence; Adrenergic Agonists; Antipsychotic Agents; Buprenorphine; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Clonidine; Cocaine; Cocaine Dependence; Cues; Data; Devices; Drug usage; Electronics; Enrollment; Environment; Evaluable Disease; Exposure to; FDA approved; Feedback; Goals; Heroin; Human; Individual; Intervention; Label; Laboratories; Laboratory Animals; Laboratory Finding; Lead; Location; Maintenance; Marketing; Methods; Modeling; Monitor; Natural History; Neighborhoods; Opioid; Participant; Pathway interactions; Patient Self-Report; Patients; Pattern; Pharmaceutical Preparations; Physicians; Population; Randomized; Rattus; Relapse; Role; Sample Size; Sampling; Shock; Spottings; Stress; Substance abuse problem; Testing; Time; addiction; alpha 2 agonist; alternative treatment; aripiprazole; blind; contingency management; craving; cue reactivity; design; disorder later incidence prevention; drug of abuse; environmental stressor; experience; innovation; pre-clinical; pre-clinical research; prevent; stressor

In laboratory animals, one of the major precipitants of relapsethat is, resumption of drug seekingis stress. For example, electric shock has been consistently shown to lead to reinstatement of heroin and cocaine seeking in rats (Shaham and Stewart, 1995; Erb et al., 1996; Shaham, 1996). This stress-induced reinstatement is blocked by the alpha-2 adrenergic receptor agonist clonidine (Erb et al., 2000; Shaham et al., 2000; Highfield et al., 2001). Because clonidine and other alpha-2 agonists prevent reinstatement for multiple drugs of abuse, they may be acting upon some final common pathway of stress-induced relapse, relevant to many or all addictions. To test the clinical utility and generalizability of our laboratory finding, we are continuing our clinical trial of clonidine for prevention of relapse to illicit opioid use in individuals in buprenorphine maintenance. The design of the trial is innovative. Most medication trials for substance abuse are conducted in patients who have ongoing drug use. Few studies have been designed as true relapse-prevention trials. This has been a major barrier to interpretability, because preclinical research suggests that cessation of ongoing use is very different biologically and behaviorally from prevention of relapse. In our clinical trial, abstinence initiation is facilitated with contingency management, a treatment method studied extensively in our laboratory. We are using real-time field monitoring with handheld electronic devices (a method we pioneered in this population) so we can prospectively evaluate the hypothesis that clonidines effects on relapse prevention will be through alteration of stress reactivity rather than cue reactivity in the daily environment. The trial is nearing its targeted evaluable sample size of 120. Positive results will provide an immediate treatment alternative that physicians can prescribe off-label, because clonidine is already FDA-approved and marketed. This would be a real innovation in addiction treatment: although clonidine is a familiar drug (currently used as a short-term adjuvent to opioid tapers), its use as a maintenance medication for relapse prevention would be entirely new. Our clinics experience so far, although we have not broken the blind, suggests that clonidine is well tolerated and is also not prone to misuse when prescribed for relapse prevention. Also, we tested clonidine simply as a prototypical drug of its class; if it prevents relapse, then other alpha-2 agonists should do the same. We have broken the blind early on a similarly designed trial of the atypical neuroleptic aripiprazole for prevention of relapse to cocaine addiction. Enrollment into that trial was slow because too few participants were achieving the initial cocaine-abstinence criterion for randomization to a study condition and because other studies were competing for the same pool of participants. Our preliminary analysis of the results suggests that aripiprazole might tend to delay relapse to cocaine addiction, but that the effect is too small to reach statistical significance, at least in the small sample we were able to enroll. We are also evaluating the role of stress in relapse in a large natural-history study in which real-time field monitoring of stressor exposure is combined with continuous location tracking via GPS. Preliminary analyses suggest some unexpected relationships between neighborhood environment and self-reported stress. As we collect more data, we should be able to determine how patterns of environmental-stressor exposure predict relapse. One of our goals is to supplement our ambulatory assessments with on-the-spot feedback, turning them into mobile interventions.

在实验动物中，复发的主要降水物之一是恢复探索药物的压力。例如，始终显示出电击导致恢复海洛因和可卡因在大鼠中寻求的恢复（Shaham and Stewart，1995; Erb等，1996; Shaham，1996）。这种应力诱导的恢复原状被α-2肾上腺素能受体激动剂可乐定阻断（Erb等，2000； Shaham等，2000； Highfield等，2001）。由于可乐定和其他α-2激动剂阻止恢复多种滥用药物，因此它们可能会采取与许多或所有成瘾有关的压力引起的复发的最终共同途径。 为了测试实验室发现的临床效用和普遍性，我们正在继续对可乐定的临床试验预防丁丙诺啡维持中个人中非法阿片类药物的复发。试验的设计是创新的。大多数滥用药物的药物试验都是在持续使用药物的患者中进行的。很少有研究被设计为真正预防复发试验。这一直是解释性的主要障碍，因为临床前研究表明，持续使用的停止在生物学和行为上与预防复发截然不同。在我们的临床试验中，通过应急管理促进了禁欲的启动，这是一种在我们的实验室中广泛研究的治疗方法。我们正在使用手持电子设备（我们在该人群中开创的方法）使用实时场监测，因此我们可以预期评估以下假设：克罗奈德斯对预防复发的影响将是通过改变压力反应性而不是在日常环境中的提示反应性。 该试验接近其针对性的可评估样本量为120。阳性结果将为医生可以开出标签的立即治疗方法，因为可乐定已经经过FDA批准和销售。这将是成瘾治疗中的真正创新：尽管可乐定是一种熟悉的药物（目前用作阿片类药物锥度的短期辅助药物），但它用作预防复发的维护药物将是全新的。到目前为止，我们的诊所经验，尽管我们尚未破坏盲人，但表明可乐定的耐受性很好，并且在预防复发时也不容易滥用。另外，我们仅将可乐定作为其类别的原型药物进行测试。如果防止复发，那么其他alpha-2激动剂也应该这样做。 我们已经在非典型神经疗法阿ipiprazole的类似设计的试验中破坏了盲人，以预防可卡因成瘾。 参加该试验的入学率很慢，因为很少有参与者达到了最初的可卡因侵入性标准，即随机分配到研究条件，并且其他研究正在争夺同一参与者。 我们对结果的初步分析表明，Aripiprazole可能倾向于延迟可卡因成瘾的复发，但是效果太小而无法达到统计学意义，至少在小样本中，我们能够招募。 我们还在一项大型自然历史研究中评估压力在复发中的作用，在大型自然历史研究中，对压力源暴露的实时野外监测与通过GPS的连续位置跟踪结合在一起。初步分析表明，邻里环境与自我报告的压力之间有一些意外的关系。当我们收集更多数据时，我们应该能够确定环境压力暴露模式如何预测复发。我们的目标之一是通过现场反馈来补充我们的门诊评估，将其转化为移动干预措施。