Effectiveness of Varenicline vs. Varenicline plus Bupropion for Smoking Cessation

描述(申请人提供)：尼古丁替代疗法、安非他酮和最近的varenicline已经确定了尼古丁依赖的药理治疗效果。在尼古丁依赖的药物治疗方面，绝大多数研究都集中在安慰剂对照试验中对单一药物的评估，根据定义，这代表了一种适用于治疗的“一刀切”的方法。虽然这在治疗评估的初始阶段是合适的，但联合治疗提高疗效水平的潜力往往没有被开发出来。本申请的重点是评估伐伦克林和安非他酮的联合疗效，这两种药物都是FDA批准的戒烟药物。这两种药物在戒烟和治疗尼古丁戒断症状的随机临床试验中都显示出了有效性。安非他酮是一种非典型的抗抑郁药，其特性包括抑制去甲肾上腺素的再摄取，适度的多巴胺再摄取抑制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核中多巴胺的减弱释放。关键试验的结果表明，伐伦克林比单独使用安非他酮更有效。然而，有几条理由表明，这些药物的联合使用可能比单独使用varenicline更有效。这两种药物作用机制的合理差异和作用强度的差异表明，联合使用这两种药物将影响那些被认为对戒烟至关重要的更广泛的生物靶点，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varenicline、varenicline加安非他酮和安慰剂在戒烟、尼古丁戒断、负面影响、渴求和吸烟满意度方面的疗效。我们还将评估治疗结果与认知表现指标之间的关系。我们假设，与单独使用varenicline的吸烟者相比，联合使用这两种药物的吸烟者将显著更频繁地戒烟，需要更长的时间才能复发，并且尼古丁戒断症状、负面影响、渴望和吸烟强化的水平将显著降低。继续开发针对多种生物系统的联合疗法将提高任何一种个人戒烟尝试的成功机会，并有可能为未来针对个人特定特征(即共病病史、遗传学等)量身定做治疗方法的研究提供信息。

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).