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（即重新开始吸毒）的主要诱因之一是压力。例如，电击一直被证明会导致大鼠恢复对海洛因和可卡因的寻求（Shaham 和 Stewart，1995；Erb 等，1996；Shaham，1996）。这种应激诱导的恢复被α-2肾上腺素受体激动剂可乐定阻断（Erb等人，2000；Shaham等人，2000；Highfield等人，2001）。由于可乐定和其他 α-2 激动剂可防止多种药物滥用的恢复，因此它们可能作用于压力诱发的复发的某些最终常见途径，与许多或所有成瘾相关。 为了测试我们实验室发现的临床实用性和普遍性，我们正在继续进行可乐定的临床试验，以预防丁丙诺啡维持治疗中个体非法阿片类药物的复发。试验设计具有创新性。大多数药物滥用试验都是在持续吸毒的患者中进行的。很少有研究被设计为真正的复发预防试验。这是解释性的一个主要障碍，因为临床前研究表明，停止持续使用在生物学和行为上与预防复发有很大不同。在我们的临床试验中，应急管理促进了戒断的开始，这是我们实验室广泛研究的一种治疗方法。我们正在使用手持电子设备进行实时现场监测（这是我们在这一人群中首创的方法），因此我们可以前瞻性地评估可乐定对预防复发的影响将通过改变日常环境中的应激反应而不是提示反应来发挥作用的假设。 该试验已接近其目标可评估样本量 120 个。积极的结果将提供一种立即的治疗替代方案，医生可以在标签外开处方，因为可乐定已获得 FDA 批准并上市。这将是成瘾治疗方面的真正创新：尽管可乐定是一种熟悉的药物（目前用作阿片类药物逐渐减量的短期佐剂），但将其用作预防复发的维持药物将是全新的。迄今为止，我们的诊所经验表明，尽管我们尚未打破盲法，但可乐定具有良好的耐受性，并且在用于预防复发时也不易被滥用。此外，我们只是将可乐定作为同类药物的原型进行了测试。如果它可以防止复发，那么其他 α-2 激动剂也应该起到同样的作用。 我们很早就在一项类似设计的非典型精神安定药阿立哌唑预防可卡因成瘾复发的试验中打破了盲法。 该试验的招募进展缓慢，因为达到随机化研究条件的初始可卡因戒断标准的参与者太少，而且其他研究正在争夺同一组参与者。 我们对结果的初步分析表明，阿立哌唑可能会延缓可卡因成瘾的复发，但效果太小，无法达到统计显着性，至少在我们能够招募的小样本中是这样。 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，其中压力源暴露的实时现场监测与通过 GPS 进行的连续位置跟踪相结合。初步分析表明，邻里环境与自我报告的压力之间存在一些意想不到的关系。随着我们收集更多数据，我们应该能够确定环境压力源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流动评估，将其转变为移动干预措施。