Prevention of Relapse in Addiction

戒毒吸毒者在戒断症状消退后很长一段时间内仍有复发的风险。人们对其中的原因知之甚少。对实验室动物的研究提供了一条线索：对药物相关线索的反应不仅持续存在，而且随着戒断时间的延长而增加。如果这种被称为渴求潜伏期的现象也在人类身上发生，可能会导致长期复发的风险。我们使用对照实验方法，在一项翻译研究中研究了这种可能性。门诊吸烟者被分配到三种不同的经过验证的强化戒烟持续时间中的一种：7、14或35天。三组受试者在一个单独的禁欲间隔内测试线索反应性，第四组受试者在所有三个间隔期都接受测试，以调查反复接触线索是否会随着时间的推移抑制对线索的反应。我们假设，在单次和多次暴露于线索后，吸烟线索的反应性会随着戒烟持续时间的延长而增加。 这项研究是芝加哥大学(Harriet de Wit博士，PI)和NIDA IRP进行的一项多点试验的合作努力。吸烟者(健康的、不寻求治疗的、每天至少抽10支香烟的成年人)被随机分为四组，并支付戒烟费，戒烟7天(第1组)、14天(第2组)或35天(第3组、第4组)。对禁欲进行了生化验证，并在禁欲期间每天访问实验室时收集了戒断和情绪问卷。在最后一次戒烟日(第1、2和3组)，或在第7、14和35天(第4组)，参与者接受了2小时的暗示会议，在此期间，他们随机地接触到吸烟和中性线索。线索包括视觉、嗅觉和触觉刺激。86名参与者完成了这项研究，并被纳入分析。正如预期的那样，吸烟后的渴望比中性暗示增加得更多。在组内和组内的分析中，线索诱导的渴望作为禁欲持续时间的函数而增加。第三组(戒烟35天)的参与者报告说，吸烟线索引发的渴望显著高于第一组参与者(戒烟7天)。第四组(重复提示)的参与者报告说，在35天比14天(未显示)时，线索引发的渴望更强烈。条件性渴望的时间依赖性增加是在基线(无刺激的)渴望和戒断症状逐渐减少的背景下发生的。这是人类吸毒者在线索诱导的渴望中出现孵化样变化的第一个证据。这些发现表明，即使日常背景渴望和尼古丁戒断症状缓解，由线索引发的渴望也会随着禁欲的增加而增加，这对治疗具有重要意义。我们的发现表明，临床医生和使用者应该意识到，即使戒断症状消退，由线索诱导的渴望引发的复发风险也可能随着戒断而增加。戒毒吸毒者在长期离开正常环境后，例如在接受住院治疗后，当他们回到充满线索的环境时，他们可能面临更大的复发风险。 在这个项目的其他方面，我们将重点放在压力上，这已经被证明会导致实验动物重新开始寻找药物。以脚部电击为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。这种应激诱导的恢复可被α-2肾上腺素能受体激动剂可乐定阻断。在某种意义上，α-2激动剂的疗效只针对一种类型的复发：可乐定阻止应激诱导的恢复，但不能阻止由药物相关线索或注射药物诱导的恢复。然而，在另一种意义上，α-2激动剂可能具有广泛的疗效：海洛因和可卡因都证明了它们可以阻断应激诱导的恢复。因此，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。我们假设α-2激动剂将有助于防止人类复发。在一项实验室研究中，我们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。健康的、未寻求治疗的可卡因使用者(n=59)在双盲条件下被随机分为三组，分别口服可乐定0、0.1和0.2 mg。在一个单独的测试过程中，每个参与者在3小时后接受研究药物，然后暴露于两对标准化的听觉-图像脚本(中性/应激和中性/药物)。在基线和剧本配对之前和之后收集渴望和唾液样本的主观测量。毒品和压力剧本显著增加了渴望的程度。在0.2和0.1毫克组中，对应激脚本的反应性显著减弱；仅在0.2毫克组中，对药物提示脚本的反应性显著减弱。可乐定还阻止了与药物脚本相关的唾液α-淀粉酶增加的趋势。因此，可乐定可能会减少吸毒者在经历压力或(在较小程度上)遇到提醒他们吸毒的线索时的可卡因渴望和一些生理反应。 我们目前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。我们正在使用手持电子设备来改进结果测量。我们已经证明了这种形式的数据收集在我们的人群中的可行性，并正在利用它来确定克隆尼丁预防复发的效果是否针对复发亚型。

Abstinent drug users remain at risk for relapse for long periods of time, well after their withdrawal symptoms subside. The reasons are poorly understood. Studies with laboratory animals offer a clue: responses to drug-related cues not only persist, but increase with abstinence duration. If this phenomenon, termed incubation of craving, also occurs in humans, it may contribute to prolonged relapse risk. We investigated this possibility in a translational study using a controlled experimental approach. Outpatient cigarette smokers were assigned to one of three different durations of verified, reinforced abstinence: 7, 14, or 35 days. Three groups were tested for cue reactivity at a single abstinence interval, and a fourth group was tested at all three intervals to investigate whether repeated exposure to cues would dampen responses to the cues over time. We hypothesized that smoking cue reactivity would increase with duration of abstinence after both single and repeated exposure to cues. The study was a collaborative effort conducted as a multisite trial at the University of Chicago (Dr. Harriet de Wit, PI) and the NIDA IRP. Smokers (healthy, non-treatment-seeking, adults who smoked at least 10 cigarettes daily, were randomized to four groups and paid to abstain for 7 (Group 1), 14 (Group 2), or 35 (Groups 3, 4) days. Abstinence was biochemically verified and withdrawal and mood questionnaires were collected in daily visits to the lab during the abstinence period. On the final abstinence day (Groups 1, 2, and 3), or on Days 7, 14 and 35 (Group 4), participants underwent a 2-hour cue session, during which they were exposed to smoking and neutral cues, in random order. Cues included visual, olfactory, and tactile stimuli. Eighty-six participants completed the study and were included in the analyses. As expected, craving increased more after the smoking than neutral cues. In both between- and within- groups analyses, cue-induced craving increased as a function of abstinence duration. Participants in Group 3 (35-day abstinence) reported significantly greater smoking-cue-elicited craving than did Group 1 participants (7-day abstinence). Participants in Group 4 (repeated cues) reported greater cue-elicited craving at 35 days than at 14 days (not shown). Time-dependent increases in conditioned craving occurred in the context of progressively decreasing baseline (non-provoked) craving and withdrawal symptoms. This is the first evidence of incubation-like changes in cue-induced craving in human drug users. These findings, which suggest that craving elicited by cues increase with abstinence even as daily background craving and nicotine withdrawal symptoms subside, have significant implications for treatment. Our findings indicate that clinicians and users should be aware that risk of relapse precipitated by cue-induced craving may increase with abstinence, even as withdrawal symptoms subside. Abstinent drug users may be at greater relapse risk when they return to the cue-laden environments after long absences from their normal environments such as after inpatient treatments. In other aspects of this project, we are focusing on stress, which has been shown to induce resumption of drug seeking in laboratory animals. Physical stress in the form of electric foot-shock has been consistently shown to lead to reinstatement of heroin and cocaine seeking in rats. This stress-induced reinstatement is blocked by the alpha-2 adrenergic receptor agonist clonidine. In one sense, the efficacy of alpha-2 agonists is specific to just one type of relapse: clonidine blocks stress-induced reinstatement, but not reinstatement induced by a drug-associated cue or a priming injection of drug. In another sense, however, the alpha-2 agonists may have a broad spectrum of efficacy: their blockade of stress-induced reinstatement has been demonstrated with heroin as well as cocaine. Thus, the alpha-2 agonists may act upon some final common pathway of stress-induced relapse, relevant to multiple drugs of abuse. We hypothesized that alpha-2 agonists would help prevent relapse in humans. We tested the effect of clonidine on stress- and cue-induced craving in human cocaine users in a laboratory study. Healthy, non-treatment-seeking cocaine users (n = 59) were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg, orally, under double-blind conditions. In a single test session, each participants received study drug followed 3 hrs later by exposure to two pairs of standardized auditory-imagery scripts (neutral/stress and neutral/drug). Subjective measures of craving and saliva samples were collected at baseline and before and after script pairs. Drug and stress scripts significantly increased craving ratings. Responsivity to stress scripts was significantly attenuated in the 0.2 and 0.1 mg groups; responsivity to drug-cue scripts was significantly attenuated in the 0.2 mg group only. Clonidine also prevented a trend toward increases in salivary alpha-amylase associated with the drug script. Thus, clonidine may reduce cocaine craving and some physiological reactivity in drug abusers when they experience stress or (to a lesser degree) when they encounter cues that remind them of drug use. We are currently 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 to improve outcome measurement. We have demonstrated the feasibility of this form of data collection in our population and are using it to determine whether clonidines relapse-prevention effect is specific to subtypes of relapse.