Balanced Placebo Design with Varenicline: Pharmacological and Expectancy Effects on Medication Adherence

在美国，吸烟仍然是可预防的死亡的首要原因，占1/4 每年有五人死亡。伐伦克林(Chantix)是一种部分尼古丁能激动剂，是目前世界上最 有效的单一疗法成功戒烟；然而，长期戒烟 Varenicline的范围只有20%-40%。造成这种低效率的一个因素可能是 由于非特定副作用导致的药物依从性差(即 药物的药理学，但可能是由于负面的药物预期或尼古丁 被错误地归因于药物使用的戒断症状)。非特异性副作用有 与不坚持、停止有效治疗等负面后果有关，以及 试图用额外的药物来治疗这些症状。目前的提案将利用 双盲平衡安慰剂设计区分期望值与药理学 对寻求治疗的吸烟者实施为期两周的伐伦尼克林的作用机制。双打- 盲法平衡安慰剂设计包括交叉平衡给药(主动 药物VS安慰剂)和指导性设置(说真话VS欺骗)导致四组 寻求治疗的吸烟者：(1)告知治疗剂量(TD)药物+接受TD药物治疗；(2) 告知TD药物+接受安慰剂；(3)告知低剂量(LD)药物+接受TD剂量 用药；(4)告知LD用药+服用安慰剂。中国的生态瞬时评估(EMA) 通过智能手机交付的Daily Dairies表格将评估实时副作用、停药 症状、吸烟、用药情况和不坚持用药的原因。这个 这项提案的具体目标将审查教学设置和 药理学对用药依从性的影响(目标1和目标2)和评价药理学调节因子 以及预期对服药依从性的影响(探索性目标)。评估期望值和 对varenicline用药依从性的生理障碍(即非特异性副作用)将确定 目标是提高服药依从性并开发可以修改和 重新定义负面的预期和经历。该项目的具体目标将于#年完成。 结合由Karen Cropsey博士、Peter Hendricks博士、Dr Karen Cropsey赞助的正式培训计划， 迈克尔·布西内尔、理查德·谢尔顿博士和西尔维·穆格博士。本培训计划包括：1) 药理研究进展，2)EMA方法学，3)先进的纵向数据 分析，以及4)研究传播和指导。

Smoking continues to be the leading cause of preventable death in the U.S., accounting for one in five deaths each year. Varenicline (Chantix) is a partial nicotinergic agonist and is the most efficacious monotherapy for successful smoking cessation; however, long-term abstinence with varenicline only ranges from 20% – 40%. One contributing factor to this low effectiveness may be poor medication adherence due to nonspecific side effects (i.e., side effects not explained by the pharmacology of the medication, but possibly due to negative medication expectancies or nicotine withdrawal symptoms that are mistakenly attributed to medication use). Nonspecific side effects have been linked to negative outcomes such as nonadherence, discontinuing effective treatment, and attempts to treat these symptoms with additional medications. The current proposal will utilize the double-blind balanced placebo design to differentiate expectancies versus pharmacologic mechanisms of varenicline administered for two weeks to smokers seeking treatment. The double- blind balanced placebo design includes a cross-balanced medication administration (active medication v. placebo) and instructional set (told truth v. deception) resulting in four groups of smokers seeking treatment: (1) told therapeutic dose (TD) medication + received TD medication; (2) told TD medication + received placebo; (3) told low dose (LD) medication+ received TD dose medication; (4) told LD medication + received placebo. Ecological momentary assessments (EMA) in the form of Daily Dairies delivered via smartphone will assess real-time side effects, withdrawal symptoms, cigarettes smoked, medication use, and reasons for medication non-adherence. The specific aims for this proposal will examine the main effects and interaction of instructional set and pharmacology on medication adherence (Aims 1 and 2) and evaluate moderators of pharmacology and expectancy effects on medication adherence (Exploratory Aim). Assessing expectancies and physiological barriers (i.e., non-specific side effects) to varenicline medication adherence will identify targets to improve medication adherence and to develop behavioral interventions that can modify and reframe negative expectancies and experiences. The specific aims of this project will be completed in conjunction with a formal training plan, sponsored by Dr. Karen Cropsey, Dr. Peter Hendricks, Dr. Michael Businelle, Dr. Richard Shelton, and Dr. Sylvie Mrug. This training plan includes: 1) pharmacological research development, 2) EMA methodology, 3) advanced longitudinal data analysis, and 4) research dissemination and mentorship.