A Combination of Scheduled Reduced Smoking with Varenicline to Enhance Cessation

描述(申请人提供)：吸烟仍然是一个不可妥协的公共健康问题。有充分的证据表明，非药理学因素，如环境诱因(例如，看到或闻到香烟)，可以引起强烈的古典条件下吸烟的急促反应(称为‘线索反应性’[CR])，暴露在吸烟线索中可能导致戒烟失败。一种可能解决CR的有希望的干预措施是计划吸烟并逐渐减少(SGR)。在SGR下，个人只按固定的时间间隔吸烟，并在几周内系统地减少每天的香烟消费量。这种方法被认为是为了：1)提供应对吸烟间歇期间环境引发的渴望的“练习”，产生更高的戒烟自我效能；2)削弱暗示与吸烟之间的联系。越来越多的证据还表明，戒烟药物varenicline(VN)大大缓解了烟瘾，促进了戒烟，显著优于其他药物。有趣的是，最近的动物研究表明，VN可能至少部分通过抑制条件性药物的渴望来发挥作用。因此，由SGR+VN组成的联合疗法可能会显著增强戒烟作用，同时使用药理学和非药理学方法打击食欲。因为SGR和VN的有益效果可能至少部分是由于加强了对条件性渴望的管理，所以它们可能对CR水平高的吸烟者特别有效。在这项R34应用中，我们建议使用实验室实验技术和前瞻性干预设计来提供初始数据：1)测试SGR+VN组合将促进戒烟的假设；2)探索SGR和VN在CR水平较高的吸烟者中可能特别有效的可能性；3)探索潜在的治疗效果机制。这项研究的结果将为SGR单独和与VN联合进行更大的疗效和有效性试验，以及针对将受益最大的亚组(例如，CR水平高的吸烟者、特定吸烟相关基因类型的携带者)的SGR和/或VN的努力奠定基础。目的1：通过对戒烟后2个时间点(戒烟后4周和12周)的戒烟率和吸烟水平的评估，为联合应用SGR+VN戒烟的效果提供初步数据。吸烟者将按2×2析因设计随机分为SGR+VN、SGR+安慰剂、基本建议+VN或基本建议+安慰剂。目的2：使用经典的实验性吸烟CR范式，探讨SGR+VN在背景CR水平较高的吸烟者中特别有效的可能性，如研究开始时评估的那样。在统计分析中，将探讨CR作为治疗效果的预测因子。目标3：实现 通过评估治疗效果的潜在中介因素(即自我效能、线索诱导的渴求)，探索SGR+VN效果潜在的可能机制。

DESCRIPTION (provided by applicant): Smoking remains an intransigent public health concern. There is ample evidence that non-pharmacological factors, such as environmental triggers (e.g., sight or smell of a cigarette), can give rise to strong classically-conditioned urgs to smoke (termed 'cue-reactivity' [CR]), and that exposure to smoking cues can contribute to cessation failure. One promising intervention that may address CR is scheduled smoking with gradual reduction (SGR). Under SGR, individuals smoke only at fixed intervals, and over several weeks, systematically decrease their cigarettes consumed each day. The approach is postulated to: 1) provide 'practice' coping with environmentally-triggered cravings that occur during the inter-cigarette intervals, yielding increased self-efficacy to quit, and 2) weaken the associations between cues and smoking. Accumulating evidence has also shown that the smoking cessation drug, varenicline (VN), substantially ameliorates cravings and enhances cessation, significantly outperforming other drugs. Interestingly, recent animal research suggests that VN may operate at least partially by dampening conditioned drug cravings. A combination therapy consisting of SGR+VN might thus lead to significantly enhanced cessation, simultaneously attacking cravings using both pharmacological and non-pharmacological approaches. Because the beneficial effects of SGR and VN may be at least partially due to enhanced management of conditioned cravings, it is possible that that they will be particularly efficacious for smokers with high levels of CR. Using both laboratory experimental techniques and a prospective intervention design in this R34 application, we propose to provide initial data to: 1) test the hypothesis that a combination of SGR+VN will enhance cessation, 2) explore the possibility that SGR and VN might be particularly efficacious among smokers with higher levels of CR, and 3) explore potential mechanisms underlying treatment effects. Findings from this study would set the stage for larger efficacy and effectiveness trials of SGR alone and in conjunction with VN, as well as efforts to target SGR and/or VN toward the subgroups that would benefit the most (e.g., smokers with high levels of CR, carriers of specific smoking-related genotypes). Aim 1: To provide initial data on the efficacy of combined SGR+VN for smoking cessation, by assessing abstinence and levels of smoking at 2 time points (4 and 12 weeks post quit). Smokers will be randomized (n=48/group) to either: SGR+VN, SGR+Placebo Drug, Basic Advice+VN, or Basic Advice+Placebo Drug, in a 2 x 2 factorial design. Aim 2: To explore the possibility that SGR+VN will be particularly efficacious among smokers with higher background levels of CR, as assessed at the start of the study, using a classic experimental smoking CR paradigm. CR will be explored as a predictor of treatment effect in statistical analyses. Aim 3: To explore possible mechanisms underlying the effects of SGR+VN, by assessing potential mediators (i.e., self-efficacy, cue-induced cravings) of treatment effects.