Clinical Trials of the Adrenergic a-1 Antagonist Prazosin for Alcohol Dependence

描述（由申请人提供）：背景：酒精依赖（AD）是一种生物学和遗传学基础疾病，但大多数临床接受的治疗方法是基于行为或心理社会的。尽管这些治疗最初取得了成功，但40-70%的患者在开始治疗后的前12个月内复发。酒精和哌唑嗪的神经药理学：新出现的临床前证据表明，去甲肾上腺素能系统参与与AD相关的脑过程，如唤醒，强化和应激反应。然而，迄今为止，几乎没有任何工作试图将这些知识转化为临床有效的生物干预措施。我们采用了一种新的、有希望的策略，通过非选择性的α 1受体拮抗剂哌唑嗪阻断去甲肾上腺素与突触后α 1受体的结合，从而降低肾上腺素能活性。临床前研究表明，哌唑嗪减少酒精消耗的恢复，初步临床试验数据表明，哌唑嗪减少AD患者的酒精使用。哌唑嗪，FDA批准用于治疗高血压，通常副作用很少，而且价格便宜。设计：随机双盲安慰剂对照临床试验。参与者：120名AD患者（25%为女性），其目标是戒酒，无创伤后应激障碍。干预措施：根据研究方案滴定哌唑嗪或匹配安慰剂，持续12周，并根据联合收割机研究程序进行医学管理（MM），停药后1个月进行最终研究访视。测量：主要结果是在研究的12周药物治疗阶段的酒精使用情况和同一时期的渴望报告。在整个研究的12周给药期内，将进行每日提示交互式语音应答（IVR）电话监测，以评估主要结局并提供有关影响和药物依从性的信息。这种日常监测提供了比标准回顾性结果测量更准确的酒精使用报告。此外，由于 酒精的渴望和使用可能会突然发生，而先前的事件会立即被遗忘，每天 监测将提高评估这些现象之间关系的能力。分析：分层线性建模，以检验哌唑嗪+MM与安慰剂+MM随时间推移对酒精渴求和使用的主要影响，并评价渴求的减少是否介导哌唑嗪的影响。

DESCRIPTION (provided by applicant): Background: Alcohol dependence (AD) is a biologically, genetically based disease, yet the majority of clinically accepted treatments are behaviorally or psychosocially based. Despite the initial success of these treatments, 40-70% of patients relapse within the first 12 months after initiating treatment. Neuropharmacology of alcohol and prazosin: Emerging pre-clinical evidence shows that noradrenergic systems are involved in brain processes relevant to AD, such as arousal, reinforcement, and stress responsivity. However, virtually no work to date has attempted to translate this knowledge into clinically effective biological interventions. We have adopted the novel, promising strategy of reducing adrenergic activity by blocking noradrenaline binding to post-synaptic a1 receptors via the non-selective, a1 antagonist, prazosin. Preclinical studies have demonstrated that prazosin decreases reinstatement of alcohol consumption, and preliminary clinical pilot data suggest that prazosin reduces alcohol use in humans with AD. Prazosin, FDA approved to treat hypertension, typically has few side effects, and is inexpensive. Design: Randomized double-blind placebo-controlled clinical trial. Participants: 120 AD individuals (25%women) with stated goal to abstain from alcohol use and without PTSD. Intervention: Either prazosin titrated per study protocol or matched placebo for 12 weeks with Medical Management (MM) based on the COMBINE Study procedures and a final study visit one month after medication discontinuation. Measures: The primary outcomes are alcohol use during the 12-week medication phase of the study and reports of craving during the same time period. Daily, prompted Interactive Voice Response (IVR) telephone monitoring will be done throughout the 12-week medication phase of the study to assess the primary outcomes and to provide information on affect and medication adherence. Such daily monitoring provides more accurate reports of alcohol use than standard retrospective outcome measures. Furthermore, since alcohol craving and use can occur precipitously with antecedent events promptly forgotten, daily monitoring will enhance the capacity to evaluate the relationship between these phenomena. Analyses: Hierarchical linear modeling to test for main effects of prazosin+MM vs placebo+MM on alcohol craving and use over time, and to evaluate whether reductions in craving mediate the effect of prazosin.