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

摘要本修订申请建议进行一项随机、双盲、安慰剂对照的实验室和临床结果联合研究，以测试哌唑嗪（PZ）在降低酒精依赖（AD）患者（伴有或不伴有当前焦虑障碍（+Anx/-Anx））的酒精渴求、焦虑、应激失调和酒精使用结果方面的疗效。在以前的研究中，我们已经表明，实验室暴露于压力和酒精线索会增加酒精渴望，焦虑和压力失调，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，已知可降低中枢去甲肾上腺素和CRF上调，在依赖性大鼠和酒精患者的初步研究中，可降低应激诱导的酒精恢复和酒精消耗。然而，PZ可能减少人类饮酒的具体机制尚不清楚。我们的初步数据显示，PZ相对于安慰剂（PL）降低了AD个体中的压力和线索诱导的酒精渴望、焦虑和压力失调，并且这种降低在患有当前焦虑障碍的AD个体中比那些没有这种合并症的AD个体更明显。因此，根据以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（平均分为有和没有AD的患者）。 任何当前的焦虑症）参与随机、双盲、安慰剂对照的12周临床实验室和结果研究。具体目的如下：1）评价PZ的效果（16 mg，tid）在实验室中对伴有和不伴有焦虑障碍的AD患者的应激和线索诱导的酒精渴求和焦虑、应激失调的影响;（2）评价16 mg PZ对酒精渴求的影响。与无焦虑障碍的AD患者相比，存在焦虑障碍的AD患者的焦虑和应激失调;（3）确定12周PZ治疗对主要饮酒结果的有效性，以及次要结果，包括饮酒渴望、负性情绪症状、吸烟和睡眠;（4）评估12周PZ与PL治疗对伴有/不伴有任何当前焦虑障碍的酗酒者的主要酒精使用和次要结局的疗效。(5)检查治疗后一个月随访酒精使用的结果，以获得持久的短期治疗效果。患者的特点和实验室为基础的渴望和压力失调预测酒精治疗结果的作用也将进行探讨。如果所提出的假设得到支持，它将提供证据，哌唑嗪作为一种药物治疗酒精中毒，特别是对那些共病焦虑症的疗效。

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.