Repurposing Melatonin Receptor Agonists as Adjunct Treatments for Smoking Cessation

重新利用褪黑激素受体激动剂作为戒烟的辅助治疗

• 批准号: 9144346
• 负责人: Rebecca Ashare
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144346
• 关键词: Abstinence; Address; Agonist; Attenuated; Carbon Monoxide; Clinical Trials; Constipation; Coupled; Crossover Design; Data; Development; FDA approved; Female; Foundations; Future; Headache; Health; Human; Incentives; Individual; Individual Differences; Intervention; Laboratories; Lead; Marketing; Measures; Melatonin Receptors; Mental Depression; Modeling; Moods; Nicotine Dependence; Nicotine Withdrawal; Outcome; Patient Self-Report; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Physical Dependence; Placebo Control; Placebos; Population; Procedures; Property; Rebound Insomnia; Recording of previous events; Relapse; Research; Research Design; Residual state; Risk; Safety; Sampling; Signal Transduction; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Smoker; Smoking; Staging; Study Subject; Symptoms; Testing; Therapeutic; Withdrawal; Withdrawal Symptom; Withholding Treatment; base; critical period; diaries; drug development; experience; falls; gender difference; improved; indexing; innovation; negative mood; nicotine patch; nicotine replacement; novel; novel strategies; primary outcome; screening; sleep onset; smoking cessation; smoking relapse; success; therapeutic target; treatment effect; varenicline

 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.