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

描述(申请人提供)：背景：酒精依赖(AD)是一种基于生物、遗传的疾病，但大多数临床接受的治疗方法都是基于行为或心理的。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头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，去甲肾上腺素系统参与了与AD相关的大脑过程，如唤醒、强化和应激反应。然而，到目前为止，几乎没有任何工作试图将这种知识转化为临床有效的生物学干预措施。我们采用了一种新颖的、有希望的策略，通过非选择性的A1拮抗剂哌唑嗪来阻断去甲肾上腺素与突触后A1受体的结合，从而降低肾上腺素能活性。临床前研究表明，哌唑嗪可减少酒精消费的恢复，初步临床试验数据表明，哌唑嗪减少了阿尔茨海默病患者的酒精使用。FDA批准用于治疗高血压的哌唑嗪，通常副作用很少，而且价格低廉。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)，有明确的戒酒目标，没有创伤后应激障碍。干预：或者按照研究方案滴定哌唑嗪，或者在联合研究程序的基础上，将安慰剂与医疗管理(MM)相匹配，为期12周，并在停药一个月后进行最终研究访问。测量：主要结果是在研究的12周用药阶段期间饮酒，以及在同一时间段内的渴望报告。每天，将在研究的12周用药阶段进行提示交互式语音应答(IVR)电话监测，以评估主要结果，并提供有关影响和用药依从性的信息。这种每日监测比标准的回溯性结果测量提供了更准确的酒精使用报告。此外，由于 酒精渴求和饮酒可能会突然发生，之前的事情很快就会被遗忘，每天 监测将加强评估这些现象之间关系的能力。分析：分层线性建模，以测试随着时间的推移，哌唑嗪+MM与安慰剂+MM对酒精渴求和使用的主要影响，并评估渴求的降低是否中介了哌唑嗪的效果。

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.