Repurposing Melatonin Receptor Agonists as Adjunct Treatments for Smoking Cessation

 描述(由申请人提供)：即使使用FDA批准的戒烟药物疗法，大多数吸烟者在戒烟尝试后的头几天内仍会复发。因此，有必要确定新的方法来优化治疗，以帮助更多的吸烟者在这一关键时期保持戒烟。有证据表明，尼古丁戒断期间的睡眠障碍可能是一个重要的、但被忽视的戒烟治疗目标。这一点尤其重要，因为现有的治疗方法并不能缓解与戒断相关的睡眠障碍。关键的是，睡眠困难预示着吸烟复发。在这项概念验证研究中，我们假设FDA批准的褪黑素受体激动剂Ramelteon与经皮尼古丁替代疗法(TN)相结合，将通过减少尼古丁戒断期间的睡眠障碍来促进戒烟。使用一个经过充分验证的药物筛选范例，我们提出了一个受试者内、安慰剂对照的交叉设计，受试者内有一个短期用药因素(Ramelteon vs.安慰剂)。50名寻求治疗的吸烟者将完成这项为期6周的研究，该研究包括两个为期两周的阶段，中间隔着两周的戒烟时间。每个阶段包括一周的随意吸烟(基线)和一周的药物治疗(8毫克拉梅尔酮或安慰剂)加上试图戒烟的TN(戒烟评估)。吸烟者将获得通过生化手段确认的戒烟的小额金钱奖励。Ramelteon的独特特性减少了第二天残留效应、反弹失眠和身体依赖症状的可能性，这些症状使其他安眠药成为问题。我们之所以选择TN，是因为它对解决身体尼古丁戒断症状(如头痛、便秘)非常重要，而且它是美国使用最广泛的治疗方法。在研究期间，受试者将被要求记录睡眠日记，并在睡觉时佩戴臂章，以提供睡眠持续时间和质量的客观指数(SensewearPro)。研究完成后，所有受试者都将获得标准的TN。主要结果将是通过一氧化碳呼气样本确认的戒酒总天数(总共五天)。这一指标对长期戒烟成功具有很高的预测性。中间结果将包括入睡延迟(自我报告)和睡眠效率(SensewearPro臂章)。这一创新的研究将首次改变褪黑素受体激动剂(Ramelteon)的用途，以评估其对寻求治疗的吸烟者与戒烟有关的睡眠障碍和短期戒烟成功的影响。对已“降低风险”的药物进行再利用，消除了药物开发的一个关键障碍(即安全信号)，增加了药物上市的可能性。关键的是，我们的研究设计允许探索治疗效果背后的假定机制。如果我们的假设得到支持，这些数据将为更大规模的II期临床试验奠定基础，并将这种辅助药物治疗扩展到其他戒烟治疗。

 DESCRIPTION (provided by applicant): Even with the use of FDA-approved pharmacotherapies for smoking cessation, most smokers relapse within the first few days following a quit attempt. Thus, there is a need to identify novel approaches to optimize treatment to help more smokers maintain abstinence during this critical period. Evidence indicates that sleep disturbance during nicotine withdrawal may be an important, yet overlooked smoking cessation treatment target. This is particularly important since existing treatments do not mitigate withdrawal-related sleep disturbance. Critically, difficulty sleeping is predictive of smoking relapse. In this proof-of-concept study, we hypothesize that the FDA-approved melatonin receptor agonist, ramelteon, in combination with transdermal nicotine replacement therapy (TN), will promote smoking cessation by attenuating sleep disturbance during nicotine withdrawal. Using a well-validated medication screening paradigm, we propose a within-subject, placebo-controlled crossover design with one within-subjects factor of short-term medication (ramelteon vs. placebo). Fifty treatment-seeking smokers will complete this 6-week study, which consists of two 2-week phases separated by a 2-week washout. Each phase includes 1 week of ad libitum smoking (baseline) and 1 week of medication (8mg ramelteon or placebo) plus TN while trying to abstain (quit assessment). Smokers will be provided small monetary incentives for biochemically-confirmed abstinence. Ramelteon's unique properties reduce the likelihood of next-day residual effects, rebound insomnia, and symptoms of physical dependence which render other sleep medications problematic. We have chosen TN because it will be important to address physical nicotine withdrawal symptoms (e.g., headaches, constipation) and it is the most widely used treatment in the U.S. For the duration of the study, subjects will be asked to keep sleep diaries and wear an armband while sleeping which provides objective indices of sleep duration and quality (SensewearPro). All subjects will receive standard TN following completion of the study. The primary outcome will be the total number of days abstinent (out of five), confirmed by carbon monoxide breath sample. This measure is highly predictive of longer-term quit success. Intermediate outcomes will include sleep onset latency (self-report) and sleep efficiency (SensewearPro armband). This innovative line of research will be the first to repurpose a melatonin receptor agonist (ramelteon) to evaluate its effects on withdrawal-related sleep disturbance and short-term quitting success in treatment-seeking smokers. Repurposing medications that have been "de-risked" removes a key barrier to drug development (i.e., safety signals), increasing the likelihood that the drug will be brought to market. Critically, our study design permits exploration of putative mechanisms that underlie the treatment effect. If our hypotheses are supported, these data will lay the foundation for a larger Stage II clinical trial and to extend this adjunct pharmacological treatment to other treatments for smoking cessation.