Prevention of Relapse in Addiction

在实验动物中，应激已被证明会导致重新开始寻找药物。实验模型是在先前获得的药物自我给药灭绝后恢复操作行为。足部电击形式的身体应激一直被证明会导致大鼠恢复海洛因和可卡因寻找(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)。α-2激动剂可能作用于与多种药物滥用有关的应激诱导复发的最终共同途径。我们在一项实验室研究中测试了可乐定对人类可卡因使用者压力和线索诱导的渴求的影响，发现可乐定0.1和0.2 mg显著减弱了对应激脚本的反应性；仅在较高剂量(0.2 mg)时，对药物线索脚本的反应性显著减弱。因此，可乐定可能会减少吸毒者在经历压力或提醒他们吸毒的情况下对可卡因的渴望和一些生理反应。 为了测试这一发现的临床效用，我们正在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。我们使用手持电子设备作为结果测量的一部分，因此我们应该能够确定可乐定在预防与应激暴露和线索暴露相关的失误方面是否具有不同的有效性。 我们还在自然历史研究中评估压力在复发中的作用，在这些研究中，我们收集了药物滥用者在日常生活中经历的压力的实时定量数据。我们评估了在手持计算机上提供生态瞬时评估(EMA)数据的美沙酮维持可卡因和海洛因滥用门诊患者中与渴望、情绪、复发触发暴露和可卡因使用有关的压力的发生。在随机提示的条目中，以及在参与者发起的可卡因使用报告之前的5个小时内，将压力评级与渴望、情绪和过去一小时暴露于假定的药物使用触发因素的评级进行比较。压力与当前对可卡因、海洛因和烟草的渴求程度以及疲倦、无聊和烦躁的程度呈显著正相关，与幸福和放松的程度呈显著负相关。在参与者报告过去一小时内暴露于负面情绪触发因素、大多数药物暴露触发因素或任何涉及药物想法的触发因素(例如，突然受到诱惑)的条目中，压力明显更大。在个别可卡因使用之前的五个小时内，压力的线性增加并不显著，尽管在使用可卡因之前有这样一种增加的趋势，参与者将其归因于发生时的压力状态。这些发现表明，压力在成瘾中扮演着复杂的角色。在自然环境中实时报告的压力显示出与渴望、情绪和暴露于药物使用触发因素之间的强烈的横向瞬时关系。然而，压力等级和可卡因使用事件之间的预期关联充其量也是微弱的。这一预期和意外发现的组合说明了收集实时、现场行为数据的价值，这些数据可以量化和汇总以供分析。

Stress has been shown to induce resumption of drug seeking in laboratory animals. The experimental model is reinstatement of operant behavior following extinction of previously acquired drug self-administration. Physical stress in the form of electric foot-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). The alpha-2 agonists may act upon some final common pathway of stress-induced relapse, relevant to multiple drugs of abuse. We tested the effect of clonidine on stress- and cue-induced craving in human cocaine users in a laboratory study and found that responsivity to stress scripts was significantly attenuated by clonidine 0.1 and 0.2 mg; responsivity to drug-cue scripts was significantly attenuated at the higher clonidine dose (0.2 mg) only. Thus, clonidine may reduce cocaine craving and some physiological reactivity in drug abusers experiencing stressful situations or situations that remind them of drug use. To test the clinical utility of this finding, we are conducting a clinical trial of clonidine for the prevention of relapse to illicit opioid use in individuals in buprenorphine maintenance. We are using handheld electronic devices as part of our outcome measurement, so we should be able to determine whether clonidine is differentiallty effective in preventing lapses associated with stress exposure versus cue exposure. We are also evaluating the role of stress in relapse in natural-history studies in which we collect quantitative real-time data on the stress experienced by drug misusers in their daily lives. We evaluated the occurrence of stress in relation to craving, mood, relapse-trigger exposure, and cocaine use in methadone-maintained cocaine- and heroin-abusing outpatients who provided ecological momentary assessment (EMA) data on handheld computers. Ratings of stress were compared to those of craving and mood and past-hour exposure to putative drug-use triggers in randomly prompted entries, and in the 5 hours prior to participant-initiated cocaine use reports. Stress had significant positive relationships with current ratings of craving for cocaine, heroin, and tobacco and with ratings of tiredness, boredom, and irritation, and had significant negative relationships with ratings of happiness and relaxation. Stress was significantly greater in entries in which participants also reported past-hour exposure to negative-mood triggers, most of the drug-exposure triggers, or any trigger involving thoughts about drugs (e.g., tempted out of the blue). The linear increase in stress during the five hours preceding individual episodes of cocaine use was not significant, though there was a trend for such an increase before the use episodes that participants attributed to stressful states when they occurred. The findings suggest a complex role of stress in addiction. Stress reported in real time in the natural environment showed strong cross-sectional momentary relationships with craving, mood, and exposure to drug-use trigger. However, the prospective association between stress ratings and cocaine-use episodes was, at best, weak. This combination of expected and unexpected findings illustrates the value of collecting real-time, in-the-field behavioral data that can be quantified and aggregated for analysis.