Prevention of Relapse in Addiction

预防成瘾复吸

• 批准号: 8336482
• 负责人: Kenzie Preston
• 金额: $ 129.38万
• 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/8336482
• 关键词: Adrenergic Agonists; Attenuated; Behavior; Behavioral; Boredom; Buprenorphine; Clinical; Clinical Trials; Clonidine; Cocaine; Cocaine Users; Complex; Cues; Data; Devices; Dose; Drug Exposure; Drug usage; Electronics; Environment; Experimental Models; Exposure to; Extinction (Psychology); Goals; Handheld Computers; Happiness; Heroin; Heroin Abuse; Hour; Human; Individual; Intervention; Laboratory Animals; Laboratory Study; Lead; Maintenance; Measurement; Methadone; Modeling; Moods; Natural History; Opioid; Outcome; Outpatients; Participant; Pathway interactions; Pharmaceutical Preparations; Physiological; Rattus; Relapse; Relaxation; Reporting; Role; Self Administration; Shock; Stress; Testing; Thinking; Time; Tobacco; addiction; alpha 2 agonist; cocaine use; craving; disorder later incidence prevention; drug abuser; drug of abuse; experience; foot; irritation; negative mood; pre-clinical; prevent; prospective; trend

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.

研究表明，压力会导致实验动物重新开始寻求药物。实验模型是在先前获得的药物自我给药消失后恢复操作行为。电击足部形式的身体压力已被一致证明会导致大鼠恢复对海洛因和可卡因的寻求（Shaham 和 Stewart，1995 年；Erb 等人，1996 年；Shaham，1996 年）。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）。 α-2激动剂可能作用于压力诱发的复发的一些最终共同途径，与多种药物滥用相关。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的压力和提示引起的渴望的影响，发现 0.1 和 0.2 毫克可乐定显着减弱了对压力脚本的反应；仅当可乐定剂量较高（0.2 mg）时，对药物提示脚本的反应才显着减弱。因此，可乐定可以减少药物滥用者对可卡因的渴望和一些生理反应，这些药物滥用者正在经历压力情况或提醒他们吸毒的情况。 为了测试这一发现的临床实用性，我们正在进行一项可乐定的临床试验，用于预防丁丙诺啡维持治疗中个体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压力暴露和提示暴露相关的失误方面是否有差异有效。 我们还在自然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所经历的压力的定量实时数据。我们评估了使用美沙酮维持可卡因和海洛因滥用的门诊患者中与渴望、情绪、复发触发暴露和可卡因使用相关的压力的发生情况，这些患者在手持电脑上提供了生态瞬时评估（EMA）数据。在随机提示的条目中以及参与者发起可卡因使用报告之前 5 小时内，将压力评级与渴望和情绪以及过去一小时接触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、海洛因和烟草的渴望评级以及疲劳、无聊和烦躁的评级有显着的正相关关系，与幸福和放松的评级有显着的负相关关系。在参与者还报告过去一小时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。在可卡因使用事件之前的五个小时内，压力的线性增加并不显着，尽管在使用事件之前存在这种增加的趋势，参与者将其归因于发生时的压力状态。研究结果表明压力在成瘾中发挥着复杂的作用。在自然环境中实时报告的压力显示出与渴望、情绪和药物使用触发因素的强烈横截面瞬时关系。然而，压力评级与可卡因使用事件之间的前瞻性关联充其量也很弱。 这种预期和意外发现的结合说明了收集实时、现场行为数据的价值，这些数据可以量化和汇总以进行分析。