Prevention of Relapse in Addiction

在实验动物中，应激是导致复发的主要因素之一，也就是重新开始寻找药物。例如，电击一直显示导致大鼠中海洛因和可卡因寻求的恢复（Shaham和Stewart，1995; Erb等人，1996; Shaham，1996）。这种应激诱导的恢复被α-2肾上腺素能受体激动剂可乐定阻断（Erb等人，2000; Shaham等人，2000; Highfield等人，2001年）。由于可乐定和其他α-2激动剂可防止多种滥用药物的复吸，因此它们可能作用于与许多或所有成瘾相关的应激诱导复吸的最终共同途径。 为了测试我们实验室发现的临床效用和普遍性，我们正在继续我们的可乐定预防丁丙诺啡维持治疗个体复发非法阿片类药物使用的临床试验。试验设计具有创新性。大多数药物滥用的药物试验都是在正在使用药物的患者中进行的。很少有研究被设计为真正的复发预防试验。这一直是可解释性的主要障碍，因为临床前研究表明，停止正在使用的药物在生物学和行为学上与预防复发有很大不同。在我们的临床试验中，通过应急管理促进禁欲启动，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（这是我们在该人群中首创的方法），因此我们可以前瞻性地评估可乐定对复发预防的影响将通过改变压力反应性而不是日常环境中的提示反应性来实现的假设。 该试验接近其目标可评估样本量120。积极的结果将提供一个立即的治疗选择，医生可以处方标签外，因为可乐定已经FDA批准和上市。这将是成瘾治疗领域的一项真实的创新：尽管可乐定是一种常见的药物（目前用作阿片类药物的短期辅助剂），但将其用作预防复发的维持药物将是全新的。我们的临床经验，到目前为止，虽然我们还没有打破盲，表明可乐定是耐受性良好，也不容易误用时，规定为预防复发。此外，我们只是将可乐定作为同类药物的原型进行了测试;如果它能预防复发，那么其他α-2激动剂也应该能做到这一点。 我们已经在一项类似设计的非典型精神抑制剂阿立哌唑预防可卡因成瘾复发的试验中早期破盲。 该试验的招募速度很慢，因为太少的参与者达到了随机分配到研究条件的初始可卡因戒断标准，并且因为其他研究正在争夺相同的参与者。 我们对结果的初步分析表明，阿立哌唑可能倾向于延迟可卡因成瘾的复发，但效果太小，无法达到统计学显著性，至少在我们能够招募的小样本中是如此。 我们还在一项大型自然史研究中评估了压力在复发中的作用，在这项研究中，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，邻里环境和自我报告的压力之间存在一些意想不到的关系。随着我们收集更多的数据，我们应该能够确定环境压力暴露模式如何预测复发。我们的目标之一是用现场反馈补充我们的门诊评估，将其转变为移动的干预。

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.