A Combination of Scheduled Reduced Smoking with Varenicline to Enhance Cessation

描述（由申请人提供）：吸烟仍然是一个不容妥协的公共卫生问题。有充分的证据表明，非药物因素，如环境触发因素（如香烟的视觉或气味），可引起强烈的经典条件反射性吸烟冲动（称为“线索反应性”[CR]），暴露于吸烟线索可能导致戒烟失败。一种有希望解决CR的干预措施是有计划的逐渐减少吸烟（SGR）。在SGR下，个人只在固定的时间间隔吸烟，并在几周内系统地减少每天的卷烟消费量。该方法的设想是：1)提供“练习”应对环境引发的烟瘾，这种烟瘾会在两次吸烟的间隔期间出现，从而提高戒烟的自我效能；2)削弱线索与吸烟之间的联系。越来越多的证据也表明，戒烟药物伐尼克兰（varenicline， VN）能显著改善烟瘾，增强戒烟效果，明显优于其他药物。有趣的是，最近的动物研究表明，VN可能至少部分地通过抑制条件性药物渴望来起作用。因此，由SGR+VN组成的联合治疗可能会显著增强戒烟效果，同时使用药物和非药物方法来攻击烟瘾。由于SGR和VN的有益作用可能至少部分归因于对条件渴望的加强管理，因此它们可能对CR水平高的吸烟者特别有效。在本R34应用中，我们使用实验室实验技术和前瞻性干预设计，我们建议提供初步数据：1)验证SGR+VN联合使用将促进戒烟的假设；2)探索SGR和VN联合使用对CR水平较高的吸烟者可能特别有效的可能性；3)探索治疗效果的潜在机制。这项研究的结果将为SGR单独或与VN联合进行更大规模的疗效和有效性试验奠定基础，并努力将SGR和/或VN瞄准最受益的亚群（例如，高CR水平的吸烟者，特定吸烟相关基因型的携带者）。目的1：通过评估戒烟和戒烟后2个时间点（戒烟后4周和12周）的吸烟水平，提供SGR+VN联合戒烟疗效的初步数据。吸烟者将被随机（n=48/组）分为：SGR+VN、SGR+安慰剂药物、基本建议+VN或基本建议+安慰剂药物，采用2 × 2的因子设计。目的2：探索SGR+VN在研究开始时评估的具有较高背景CR水平的吸烟者中特别有效的可能性，使用经典的实验性吸烟CR范式。CR将在统计分析中作为治疗效果的预测因子进行探讨。目标3：

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.