Effectiveness of Varenicline vs. Varenicline plus Bupropion for Smoking Cessation

描述（由申请人提供）：尼古丁替代疗法安非他酮和最近的伐尼克兰对尼古丁依赖的药理治疗效果已经确立。绝大多数关于尼古丁依赖的药物治疗的研究都集中在安慰剂对照试验中单一药物的评估上，根据定义，这代表了一种“一刀切”的治疗应用方法。虽然这在治疗评估的初始阶段是适当的，但联合治疗提高疗效水平的潜力往往未被探索。本申请的重点是评估伐尼克兰和安非他酮的联合作用，这两种药物都是FDA批准的戒烟药物。在戒烟和治疗尼古丁戒断症状的随机临床试验中，这两种药物都显示出了有效性。安非他酮是一种非典型抗抑郁药，其特性包括抑制去甲肾上腺素再摄取，适度抑制多巴胺再摄取和尼古丁拮抗剂的作用。Varenicline主要作为VTA中1422尼古丁胆碱能受体的部分激动剂，并提供相对于尼古丁的伏隔核多巴胺的减弱释放。关键试验的结果表明，伐尼克兰比单独使用安非他酮更有效。然而，有几条推理线表明，这些药物的组合可能比单独使用伐尼克兰更有效。两种药物作用机制的差异和作用强度的差异表明，联合使用这些药物将影响更广泛的生物靶标，特别是可能影响和增强多巴胺能通路的反应。本研究是一项随机、双盲临床试验，旨在评估伐尼克兰的疗效。伐尼克兰加安非他酮和安慰剂对戒烟、尼古丁戒断、负面影响、渴望和吸烟满意度的影响。我们还将评估治疗结果与认知表现测量之间的关系。我们假设，与单独使用伐尼克兰的吸烟者相比，联合使用这两种药物的吸烟者戒烟的次数会明显增加，复发的时间会更长，并且尼古丁戒断症状、负面影响、渴望和吸烟强化的程度会明显降低。继续开发针对多种生物系统的联合疗法将提高任何个体戒烟尝试的成功机会，并有可能为未来针对个体特定特征（即共病史、遗传学等）定制治疗的研究提供信息。公共卫生相关性：本研究将测试联合使用伐尼克兰和安非他酮两种药物戒烟的有效性。我们还将评估这种组合在治疗有害情绪和认知变化方面的效果，这些变化被认为会影响戒烟的成功。这项研究很重要，因为任何一种戒烟方法都不可能对所有吸烟者都有效，通过继续开发新的治疗方法，使更广泛的吸烟者受益，我们可以对公众健康产生有利的影响。

DESCRIPTION (provided by applicant): The efficacy for the pharmacological treatment of nicotine dependence has been established for nicotine replacement therapies, bupropion and most recently, varenicline. The vast majority of research in the pharmacological treatment of nicotine dependence has focused on the evaluation of single medications in placebo controlled trials, which by definition represents a "one-size fits all" approach to the application of the treatment. While this is appropriate in the initial stages of treatment evaluation, the potential for combined treatments to raise the level of efficacy above individual treatments alone is often unexplored. The focus of this application is on the evaluation of the combined effects of varenicline and bupropion, both in their own right FDA approved medications for smoking cessation. Both have shown effectiveness in randomized clinical trials for smoking cessation and the treatment of nicotine withdrawal symptoms. Bupropion is an atypical antidepressant whose properties include inhibition of norepinephrine re-uptake, modest dopamine re-uptake inhibition and nicotine antagonist affects. Varenicline acts primarily as a partial agonist of the 1422 nicotine cholinergic receptor in the VTA and provides an attenuated release of dopamine in the nucleus accumbens, relative to nicotine. The results from the pivotal trials of varenicline showed it to be more effective than bupropion alone. However, there are several lines of reasoning to suggest that the combination of these drugs might be more effective than varenicline alone. Plausible differences in the mechanisms of action of the two drugs and differences in their intensity of action suggest that combining these medications, will affect a broader range of the biological targets among those identified as being important for smoking cessation, and in particular may effect and enhanced response in the dopaminergic pathways The present study is a randomized, double-blinded clinical trial designed to evaluate the efficacy of varenicline, varenicline plus bupropion and placebo on smoking cessation, nicotine withdrawal, negative affect, craving, and smoking satisfaction. We will also evaluate the relationship between treatment outcomes and measures of cognitive performance. We hypothesize that smokers treated with the combination of the two medications will be abstinent significantly more often, will take a longer time to relapse, and will report significantly lower levels of nicotine withdrawal symptoms, negative affect, craving and smoking reinforcement, than those treated with varenicline alone. Continuing to develop combination therapies that target multiple biological systems will improve the chances of success on any one individual smoking cessation attempt and has the potential to inform future research on tailoring treatments to particular characteristics of the individual (i.e. comorbid history, genetics, etc). PUBLIC HEALTH RELEVANCE: This study will test the effectiveness of combining two medications, varenicline and bupropion for smoking cessation. We will also evaluate how effective this combination is for the treatment of deleterious mood and cognitive changes thought to affect success at quitting smoking. This study is important because it is unlikely that any one approach to quitting will work for all smokers and by continuing to develop new treatments that reach a broader range of smokers we can have a favorable impact on public health.