Prevention of Relapse in Addiction

在实验动物中，压力是导致复发的主要原因之一，也就是重新开始寻找药物。例如，电击一直被证明会导致大鼠恢复海洛因和可卡因的寻找(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)。由于可乐定和其他α-2激动剂可防止多种药物滥用恢复，它们可能作用于与许多或所有成瘾有关的应激诱导复发的最终共同途径。 为了测试我们实验室发现的临床实用性和普适性，我们正在继续进行可乐定的临床试验，以防止丁丙诺啡维持过程中个人对非法阿片类药物的复发。试验的设计是创新的。大多数药物滥用的药物试验都是在持续使用药物的患者身上进行的。很少有研究被设计成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，停止正在进行的使用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的实时现场监测(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克隆定预防复发的作用是通过改变应激反应而不是日常环境中的提示反应来实现的。 这项试验正在接近120个可评估样本的目标规模。阳性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出处方，因为可乐定已经获得FDA批准并上市。这将是成瘾治疗方面的一项真正的创新：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少的短期佐剂)，但将其用作预防复发的维持药物将是全新的。到目前为止，我们的临床经验表明，尽管我们还没有打破失明，但可乐定耐受性很好，在开出预防复发的处方时也不容易误用。此外，我们只是将可乐定作为同类药物中的一种典型药物进行测试；如果它能防止复发，那么其他阿尔法-2激动剂也应该起到同样的作用。 我们已经在类似设计的非典型抗精神病药物阿立哌唑的早期试验中打破了盲目，以防止对可卡因成瘾的复发。该试验的登记速度很慢，因为只有太少的参与者达到了随机进入研究条件的初始可卡因戒断标准，而且其他研究也在争夺相同的参与者群体。我们对结果的初步分析表明，阿立哌唑可能倾向于推迟可卡因成瘾的复发，但效果太小，无法达到统计学意义，至少在我们能够登记的小样本中是这样。 我们还在一项大型自然历史研究中评估应激在复发中的作用，在该研究中，应激源暴露的实时现场监测与通过GPS进行的持续位置跟踪相结合。初步分析表明，社区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应激源暴露的模式如何预测复发。我们的目标之一是用现场反馈补充我们的动态评估，将其转化为移动干预。

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.