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忽视的公共卫生问题。有充分的证据表明，非药理学因素，如环境触发因素（例如，香烟的视觉或气味），可以引起强烈的经典条件反射性吸烟冲动（称为“线索反应”[CR]），暴露于吸烟线索可能导致戒烟失败。一个有希望的干预措施，可能解决CR是计划逐步减少吸烟（SGR）。在SGR下，个人只在固定的时间间隔内吸烟，并在几周内系统地减少每天的吸烟量。该方法假定：1）提供“实践”应对在吸烟间隔期间发生的环境触发的渴望，产生戒烟的自我效能增加，以及2）削弱线索和吸烟之间的关联。越来越多的证据也表明，戒烟药物伐尼克兰（VN），大大改善了渴望和促进戒烟，显着优于其他药物。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运作。因此，由SGR+VN组成的联合治疗可能导致显著增强的戒烟，同时使用药理学和非药理学方法攻击渴望。由于SGR和VN的有益效果可能至少部分是由于对条件性渴望的增强管理，因此它们可能对具有高水平CR的吸烟者特别有效。在R34申请中使用实验室实验技术和前瞻性干预设计，我们建议提供初始数据：1）检验SGR+VN组合将促进戒烟的假设，2）探索SGR和VN在具有较高CR水平的吸烟者中特别有效的可能性，3）探索潜在的治疗作用机制。这项研究的发现将为单独SGR和与VN联合使用的更大的疗效和有效性试验奠定基础，并努力将SGR和/或VN靶向受益最大的亚组（例如，高CR水平的吸烟者，特定吸烟相关基因型的携带者）。目标1：通过评估2个时间点（戒烟后4周和12周）的戒烟率和吸烟水平，提供SGR+VN组合戒烟疗效的初始数据。吸烟者将在2 x 2析因设计中随机（n=48/组）接受：SGR+VN、SGR+安慰剂药物、基本建议+VN或基本建议+安慰剂药物。目标二：探索SGR+VN在具有较高背景CR水平的吸烟者中特别有效的可能性，如在研究开始时所评估的，使用经典的实验性吸烟CR范例。CR将在统计分析中作为治疗效果的预测因子进行探索。目标3： 通过评估潜在的介质（即，自我效能、线索诱导的渴望）的治疗效果。

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.