Biobehavioral Studies of Opioid Seeking: Effects of Buprenorphine/Naloxone Dose on Experimental Stress Reactivity and Opioid Abstinence

摘要 阿片类药物滥用/滥用仍然处于前所未有的水平，是一个主要的公共卫生负担。应激反应 干扰阿片类药物的戒断，增加复发和不良后果的风险。我们已经证明了 药物应激源育亨宾+氢化可的松(YOH/CORT)增加丁丙诺啡中阿片类药物的寻找 (BUP)-稳定的志愿者。先前的研究表明，美沙酮(MTD)和BUP的维持可以减弱 应激反应，但这些研究有几个局限性。BUP通过阿片类药物替代(戒断)有效 抑制)和交叉容忍(封锁)；另一个重要但知之甚少的机制是BUP 可能负担得起压力保护。在我们的研究中，对YOH/CORT的反应性(它共同激活去甲肾上腺素和 糖皮质激素系统)在一些措施中被发现，但在另一些措施中没有；这表明中等剂量的BUP有 部分阻断对应激反应的影响。尽管压力在毒品寻觅/复发中起作用，但一项研究 差距在于，还没有研究证实BUP(或MTD)是否剂量依赖性地减弱应激反应 阿片类药物使用障碍的受试者。改善治疗结果需要我们识别阿片类药物滥用 复发风险升高的患者应解决其易感性问题。然而，很少有研究研究是否 慢性应激生物标志物水平或急性应激反应可预测慢性应激障碍患者的复发和后果 阿片类药物使用障碍。在这个项目中，我们将确定不同丁丙诺啡/纳洛酮的维持 (BUP/NAL)剂量降低YOH/CORT剂量相关的反应性(阶段1：受试者内交叉)，然后使用 这些数据用于预测标准化门诊BUP/NAL剂量缩减期间阿片类药物的复发和后果 配对阿片类药物戒断应急强化，并在1、2和3个月随访(阶段2：意向- 招待)。我们预测：(1A)YOH/CORT将增加阿片类药物的价格不弹性(更大的经济需求)， 急性应激生物标志物(如血压、血浆去甲肾上腺素、唾液皮质醇、负面情绪)和新奇 根据非阿片类药物研究预测的敏感指数(例如，血液中BDNF和促炎因子的水平 细胞因子；唾液α-淀粉酶)；(1b)BUP/NAL将剂量依赖地阻断YOH/CORT应激反应；(2a) 低剂量BUP/NAL的应激反应将预测更多的阿片类药物使用和不良后果 在BUP/NAL剂量逐渐减少后；以及慢性应激指标(例如头发皮质醇水平、问卷回答)将 调节YOH/Cort反应性(1c)和复发(2b)。该项目的影响将是异常的，因为：阿片类药物 使用问题仍然处于关键水平，与应激相关的阿片类药物使用情况知之甚少，这构成了一个主要的 临床挑战；BUP提供压力保护的高度创新的想法将通过严格的 方法(安慰剂对照，剂量-反应-药物相互作用设计)采用已建立的和新的生物标志物， 应激反应的中介物/调节物将被用来预测复发潜力，以弥合大的 翻译鸿沟。该项目提供了一种新的模板来检验应激源对药物寻求和 复发的生物标志物，并开发治疗方法，以减少应激增强的药物使用。

ABSTRACT Opioid misuse/abuse remains at unprecedented levels and is a major public health burden. Stress-reactivity interferes with opioid abstinence and increase risks of relapse and adverse outcomes. We have shown that the pharmacological stressor yohimbine + hydrocortisone (YOH/CORT) increases opioid seeking in buprenorphine (BUP)-stabilized volunteers. Prior studies suggest maintenance on methadone (MTD) and BUP can attenuate stress-reactivity, but those studies have several limitations. BUP is effective via opioid substitution (withdrawal suppression) and cross-tolerance (blockade); another important but poorly understood mechanism is that BUP might afford stress-protection. In our studies, reactivity to YOH/CORT (which co-activates noradrenaline and glucocorticoid systems) was found for some measures but not others; this suggests moderate-dose BUP has a partial blocking effect on stress reactivity. Although stress plays a role in drug seeking/relapse, one research gap is that no studies have examined whether BUP (or MTD) dose-dependently attenuates stress reactivity in subjects with opioid use disorder. Improving treatment outcomes requires that we identify opioid-abusing patients with elevated relapse risk to address their susceptibility. Yet, few studies have examined whether chronic stress biomarker levels or acute stress-reactivity predicts relapse and consequences in subjects with opioid use disorder. In this project, we will determine whether maintenance on varying buprenorphine/naloxone (BUP/NAL) doses reduces YOH/CORT dose-related reactivity (phase 1: within-subject crossover), then use these data to predict opioid relapse and consequences during a standardized outpatient BUP/NAL dose taper paired with opioid abstinence-contingent reinforcement, and at 1, 2 and 3 months follow up (phase 2: intent-to- treat). We predict: (1a) YOH/CORT will increase opioid price-inelasticity (greater economic demand), elevate acute stress biomarkers (e.g. blood pressure, plasma noradrenaline, saliva cortisol, negative mood) and novel indices predicted to be sensitive based on non-opioid studies (e.g. blood levels of BDNF and pro-inflammatory cytokines; saliva α-amylase); (1b) BUP/NAL will dose-dependently block YOH/CORT stress-reactivity; (2a) stress-reactivity at lower-dose BUP/NAL will predict more opioid use and adverse consequences during and after BUP/NAL dose tapering; and chronic stress indices (e.g. hair cortisol level, questionnaire responses) will modulate YOH/CORT reactivity (1c) and relapse (2b). Impact of this project will be exceptional because: opioid use problems remain at critical levels and stress-related opioid use is poorly understood, posing a major clinical challenge; the highly innovative idea that BUP affords stress protection will be tested using rigorous methods (placebo controlled, dose-response drug-interaction design) with established and novel biomarkers, and mediators/moderators of stress-reactivity will be used to predict relapse potential to bridge a large translational gap. This project offers a novel template to examine effects of stressors on drug seeking and relapse biomarkers, and to develop treatment approaches to reduce stress-potentiated drug use.