Effect of Prazosin on Alcohol Craving, Stress Dysregulation and Alcohol Relapse

摘要这项修订后的申请建议进行随机、双盲、安慰剂对照的联合实验室和临床结果研究，以测试哌唑嗪(PZ)在治疗患有和不患有当前焦虑症(ANX/-ANX)的酒精依赖(AD)患者中减少酒精渴求、焦虑、压力调节障碍和酒精使用结果的有效性。在之前的研究中，我们已经证明，实验室暴露在压力和酒精线索下会增加酒精渴望、焦虑和压力调节失调，这反过来又预示着随后的酒精复发结果。哌唑嗪是一种α-1肾上腺素能拮抗剂，已知可以减少中枢去甲肾上腺素和CRF的上调，在依赖大鼠和在酒精患者的初步研究中，它可以减少应激诱导的酒精恢复和酒精消耗。然而，PZ可能减少人类酒精摄入量的具体机制尚不清楚。我们的初步数据显示，相对于安慰剂(PL)，PZ可以减少AD患者的压力和线索诱导的酒精渴求、焦虑和压力调节失调，并且这种减少在患有当前焦虑障碍的AD患者中比那些没有这种共病的人更明显。因此，根据之前的研究和我们的初步发现，我们建议进行一项为期5年的研究，招募150名AD患者(由患有和不患有AD的人平均分配 任何目前的焦虑症)参加一项随机、双盲、安慰剂对照的为期12周的临床实验室和结果研究。具体目标如下：1)评价PZ(16 mg，tid)对伴有和不伴有当前焦虑症的AD患者的应激和线索诱发的酒精渴求和焦虑以及实验室应激失调的影响；(2)与非焦虑症患者相比，评价16 mg PZ对阿尔茨海默病患者的酒精渴求、焦虑和应激失调的影响；(3)确定PZ治疗12周对初次酒精使用结果和包括酒精渴望、消极情绪症状、吸烟和睡眠在内的次要结果的疗效；(4)评价PZ与PL治疗12周对有无焦虑症的酒精者的初次饮酒和二次结局的疗效。(5)观察治疗后1个月随访的饮酒结果，观察持续的短期治疗效果。还将探讨患者特征和基于实验室的渴求和压力失调在预测酒精治疗结果中的作用。如果提议的假设得到支持，将为哌唑嗪作为治疗酒精中毒的药物的有效性提供证据，特别是对那些患有共病焦虑症的人。

ABSTRACT This revised application proposes to conduct a randomized, double blind, placebo-controlled combined laboratory and clinical outcome study to test the efficacy of Prazosin (PZ) in decreasing alcohol craving, anxiety, stress dysregulation and alcohol use outcomes in treatment seeking alcohol dependent (AD) individuals with and without current anxiety disorders (+Anx/-Anx). In previous research we've shown that laboratory exposure to stress and alcohol cues increases alcohol craving, anxiety and stress dysregulation, which in turn, are predictive of subsequent alcohol relapse outcomes. Prazosin, an alpha-1 adrenergic antagonist, known to decrease central norepinephrine and CRF upregulation, decreases stress-induced alcohol reinstatement and alcohol consumption in both dependent rats and in a preliminary study with alcoholic patients. However, the specific mechanisms by which PZ may be decreasing alcohol consumption in humans is not understood. Our preliminary data show that PZ relative to Placebo (PL) decreases stress and cue- induced alcohol craving, anxiety and stress dysregulation in AD individuals, and that such decreases are more pronounced in AD individuals with current anxiety disorders than those without such comorbidity. Thus, in light of previous research and our preliminary findings, we propose a 5-year study that will recruit 150 AD individuals (evenly split by those with and without any current anxiety disorders) to participate in a randomized, double blind, placebo-controlled 12-week clinical laboratory and outcome study. The following specific aims will be addressed: 1) To evaluate the effects of PZ (16 mg, tid) on stress and cue-induced alcohol craving and anxiety, stress dysregulation in the laboratory in AD patients with and without current anxiety disorders; (2)To evaluate the effects of 16mg PZ on alcohol craving, anxiety and stress dysregulation in AD patients with current anxiety disorders as compared to those without anxiety disorders; (3) To determine the efficacy of 12- week PZ treatment on primary alcohol use outcomes, and secondary outcomes including alcohol craving, negative mood symptoms, smoking and sleep; (4) To assess the efficacy of 12-week PZ versus PL treatment on primary alcohol use and secondary outcomes in alcoholics with/without any current anxiety disorders. (5) To examine one-month post-treatment follow-up alcohol use outcomes for enduring short term treatment effects. The role of patient characteristics and laboratory-based craving and stress dysregulation in predicting alcohol treatment outcome will also be explored. If the proposed hypotheses are supported, it will provide evidence for efficacy of Prazosin as a medication for alcoholism, particularly for those with co-morbid anxiety disorders.