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

哌唑嗪对酒精渴望、压力失调和酒精复吸的影响

• 批准号: 8901730
• 负责人: Helen Cecilia Fox
• 金额: $ 57.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901730
• 关键词: Address; Adrenal Glands; Adrenergic Antagonists; Aftercare; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; American; Anxiety; Anxiety Disorders; Basic Science; Blood Pressure; Cessation of life; Characteristics; Chronic; Clinical; Clinical Research; Comorbidity; Corticotropin; Cues; Data; Disease; Double-Blind Method; Drug usage; Exposure to; FDA approved; Family history of; Gender; Health Care Costs; Heavy Drinking; Hospitals; Human; Hydrocortisone; Imagery; Individual; Laboratories; Laboratory Study; Light; Measures; Methods; Modeling; Norepinephrine; Outcome; Outcome Measure; Outcome Study; Pathway interactions; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Play; Prazosin; Randomized; Rattus; Recruitment Activity; Relative (related person); Research; Risk; Role; Sleep; Smoking; Stress; Surgeon; Symptoms; Treatment outcome; Up-Regulation; Woman; Work; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol misuse; alcohol relapse; alcohol seeking behavior; alcoholism therapy; anxiety symptoms; base; craving; efficacy testing; executive function; follow-up; hypothalamic-pituitary-adrenal axis; improved; men; negative mood; noradrenergic; problem drinker; reduced alcohol use; secondary outcome; stress disorder; treatment effect

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.

摘要：本修订后的申请拟进行一项随机、双盲、安慰剂对照的实验室和临床结果相结合的研究，以测试哌唑嗪 (PZ) 在减少酒精渴望、焦虑、压力失调和酒精使用结果方面的功效，以治疗患有或不患有焦虑症 (+Anx/-Anx) 的酒精依赖 (AD) 个体。在之前的研究中，我们已经表明，实验室暴露于压力和酒精暗示会增加对酒精的渴望、焦虑和压力失调，这反过来又可以预测随后的酒精复发结果。 Prazosin 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，在依赖大鼠和酗酒患者的初步研究中，可减少应激诱导的酒精恢复和饮酒量。然而，PZ 减少人类酒精消耗的具体机制尚不清楚。我们的初步数据表明，相对于安慰剂（PL），PZ 可以降低 AD 个体的压力和提示诱发的酒精渴望、焦虑和压力失调，并且这种降低在患有当前焦虑症的 AD 个体中比没有此类合并症的个体更为明显。因此，根据之前的研究和我们的初步发现，我们提出了一项为期 5 年的研究，将招募 150 名 AD 个体（按患有和未患有 AD 的人各占一半） 任何当前的焦虑症）参加一项随机、双盲、安慰剂对照的 12 周临床实验室和结果研究。将解决以下具体目标： 1) 在实验室中评估 PZ（16 mg，tid）对患有或不患有焦虑症的 AD 患者的压力和提示诱发的酒精渴望和焦虑、压力失调的影响； (2)评估16mg PZ对当前患有焦虑症的AD患者与没有焦虑症的患者相比对酒精渴望、焦虑和压力失调的影响； (3) 确定 12 周 PZ 治疗对主要饮酒结果和次要结果（包括酒精渴望、负面情绪症状、吸烟和睡眠）的功效； (4) 评估 12 周 PZ 与 PL 治疗对患有/不患有任何当前焦虑症的酗酒者的主要酒精使用和次要结果的疗效。 (5) 检查治疗后一个月的后续饮酒结果，以获得持久的短期治疗效果。还将探讨患者特征以及基于实验室的渴望和压力失调在预测酒精治疗结果中的作用。如果所提出的假设得到支持，它将为哌唑嗪作为酒精中毒药物的功效提供证据，特别是对于那些患有共病焦虑症的患者。