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

肾上腺素a-1拮抗剂哌唑嗪治疗酒精依赖的临床试验

• 批准号: 8071038
• 负责人: TRACY L. SIMPSON
• 金额: $ 26.61万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071038
• 关键词: Abstinence; Adopted; Adrenergic Agents; Adrenergic Antagonists; Adverse effects; Affect; Affective; Alcohol consumption; Alcohol dependence; Alcohols; Antihypertensive Agents; Arousal; Behavior; Behavior Therapy; Benign Prostatic Hypertrophy; Binding; Biological; Brain; Breeding; Clinical; Clinical Trials; Cognitive; Complement; Controlled Clinical Trials; Data; Dependence; Development; Disease; Disulfiram; Double-Blind Method; Ethanol; Ethanol dependence; Event; FDA approved; Goals; Health Care Costs; Hour; Human; Hypertension; Individual; Injectable; Intervention; Knowledge; Lead; Light; Linear Models; Measures; Mediating; Mediation; Medical; Modeling; Monitor; Morbidity - disease rate; Naltrexone; Neuraxis; Neurobiology; Neuropharmacology; Nightmare; Norepinephrine; Oral; Outcome; Outcome Measure; Participant; Patients; Personal Communication; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Placebo Control; Placebos; Population; Post-Traumatic Stress Disorders; Prazosin; Procedures; Process; Protocols documentation; Psychological reinforcement; Randomized; Rattus; Relapse; Relative (related person); Reporting; Research; Risk; Role; Sampling; Stress; Study Section; Substance Addiction; Synapses; System; Telephone; Testing; Time; Translating; Treatment outcome; Variant; Veterans; Visit; Voice; Woman; Work; acamprosate; addiction; adrenergic; alcohol abstinence; alcohol craving; base; combat; cost; craving; dependence relapse; design; double-blind placebo controlled trial; drinking; follow-up; forgetting; improved; medication compliance; mortality; noradrenergic; novel; placebo controlled study; pre-clinical; preclinical study; primary outcome; receptor; reduced alcohol use; response; success; treatment response

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.

背景：酒精依赖（AD）是一种基于生物学和基因的疾病，然而大多数临床接受的治疗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：临床前证据显示，去甲肾上腺素能系统参与与AD相关的大脑过程，如觉醒、强化和应激反应。然而，迄今为止，几乎没有工作试图将这些知识转化为临床有效的生物干预措施。我们采用了一种新颖的、有前途的策略，通过非选择性的a1拮抗剂吡唑嗪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，哌唑嗪可减少AD患者的酒精使用。美国食品药品监督管理局（FDA）批准用于治疗高血压的普唑嗪，通常没有什么副作用，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），明确目标为戒酒且无创伤后应激障碍。干预：根据联合研究程序，在医学管理（MM）下，根据研究方案滴定吡嗪或匹配安慰剂12周，并在停药一个月后进行最后一次研究访问。测量方法：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在同一时期的渴望报告。在为期12周的药物治疗阶段，每天都会进行交互式语音应答（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