Pharmacotherapy and Mechanisms of Sleep Disturbance in Alcohol Dependence

酒精依赖睡眠障碍的药物治疗和机制

• 批准号: 7208285
• 负责人: KIRK J BROWER
• 金额: $ 42.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-20 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208285
• 关键词: Abstinence; Acute; Adult; Affect; Age; Alcohol dependence; Alcohol or Other Drugs use; Alcohol withdrawal syndrome; Alcoholism; Biological; Brain; Cessation of life; Characteristics; Chronic Disease; Circadian Rhythms; Clinical; Data; Depth; Diagnosis; Double-Blind Method; Electroencephalography; Functional disorder; Gender; Hour; Hyperactive behavior; Laboratories; Measures; Melatonin; Monitor; Neuraxis; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebos; Psyche structure; Public Health; Randomized; Recording of previous events; Regulation; Relapse; Research; Research Personnel; Risk; Risk Factors; Science; Score; Screening procedure; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Time; Trazodone; Visit; Wakefulness; Week; actigraphy; base; cost; day; design; drinking; follow-up; gabapentin; impaired driving performance; improved; indexing; insight; problem drinker; programs; response; sex; sleep abnormalities

DESCRIPTION (provided by applicant): Insomnia and other sleep abnormalities are common, persistent, and, as a key component of protracted alcohol withdrawal, associated with relapse in alcohol-dependent patients. Both subjective and objective sleep measures can predict relapse; however, objective measures provide additional insight into the potential mechanisms underlying disrupted sleep. The overall, long-term objectives of the proposed research are to investigate the neurophysiologic mechanisms of sleep disturbance that are associated with relapse in patients with alcohol dependence, and to target those mechanisms with medication in order to reduce relapse risk. The specific research aims are 1) to investigate three potential mechanisms of sleep disturbance in alcoholic patients with insomnia: impaired homeostatic drive, impaired circadian regulation, and brain hyperactivation; 2) to investigate short-term effects of medication on sleep and its regulatory mechanisms in alcoholics; and 3) to investigate the short-term clinical course of alcoholism as a function of baseline sleep parameters. Three study phases are proposed. In Phase I (Screening & Stabilization; 10 days), subjects are characterized clinically to diagnose insomnia and alcohol dependence; determine baseline values for drinking and sleeping; and rule out confounding sleep-impairing causes such as acute alcohol withdrawal, other substance use, and/or physical, mental, and other sleep disorders, e.g., sleep apnea. Phase II (Medication; 10 days), is a randomized, double-blind parallel design of 3 medication groups (placebo, gabapentin, trazodone). Phases I & II each have 7 days of monitoring with sleep logs and actigraphy, followed by 3 nights in the sleep laboratory: an adaptation night, a baseline sleep night, and a challenge night in which sleep is recorded after a 3-hour extension of prior wakefulness. Dim-light melatonin onset (DLMO), a measure of circadian phase is also assessed. Power spectral analysis is used to quantify all night EEG activity. On each challenge night, homeostatic sleep drive is assessed by evaluating the time course and distribution of delta power in NREM sleep after delay, compared to baseline levels. Phase III (Follow-up) consists of one visit after 12 weeks to assess course of drinking. In summary, sleep disturbance in alcoholic patients reflects neurophysiologic dysfunction; increases risk of relapse, and may be amenable to pharmacotherapy. Targeting treatment to the specific sleep regulatory disturbance is likely to improve alcoholism outcomes. Relevance: Alcoholism is a devastating chronic disorder that in any one year affects 10% of adults, costs over $185 billion, and causes more than 100,000 deaths in the U.S. Despite treatment, most alcoholic patients achieve only short-term abstinence, and medically based treatment improvements are needed that target biological risk factors for relapse. Overall public health will be improved by developing science-based treatments that can augment existing, but only partially effective, treatment approaches.

描述(申请人提供)：失眠和其他睡眠异常是常见的、持续的，作为长期戒酒的关键组成部分，与酒精依赖患者的复发有关。主观和客观的睡眠测量都可以预测复发；然而，客观的测量提供了对睡眠中断潜在机制的额外洞察。这项拟议研究的总体、长期目标是调查与酒精依赖患者复发有关的睡眠障碍的神经生理学机制，并针对这些机制进行药物治疗，以降低复发风险。本研究的具体目的是：1)探讨酒精性失眠症患者睡眠障碍的三种可能机制：稳态驱动力受损、昼夜节律受损和脑过度激活；2)研究药物对酒精者睡眠的短期影响及其调节机制；3)探讨酒精中毒的短期临床病程与基线睡眠参数的关系。提出了三个研究阶段。在第一阶段(筛查和稳定；10天)，受试者的临床特征是诊断失眠和酒精依赖；确定饮酒和睡眠的基线值；并排除混杂的睡眠障碍原因，如急性酒精戒断、其他物质使用和/或身体、精神和其他睡眠障碍，如睡眠呼吸暂停。第二阶段(服药；10天)，为随机双盲平行设计，分为3组(安慰剂、加巴喷丁、曲唑酮)。 第一阶段和第二阶段每个阶段都有7天的睡眠记录和活动记录监测，然后是睡眠实验室的3个晚上：适应之夜、基线睡眠之夜和挑战之夜，在此夜晚，在先前的清醒状态延长3小时后记录睡眠。暗光褪黑素发作(DLMO)，一种衡量昼夜节律的指标也被评估。功率谱分析用于量化整夜的脑电活动。在每个挑战之夜，通过评估延迟后NREM睡眠中与基线水平相比较的时间进程和增量功率分布来评估动态平衡睡眠驱动力。第三阶段(随访)包括12周后的一次访问，以评估饮酒过程。综上所述，酒精中毒患者的睡眠障碍反映了神经生理功能障碍，增加了复发的风险，并可能接受药物治疗。针对特定睡眠调节障碍的治疗可能会改善酒精中毒的结果。相关性：酒精中毒是一种毁灭性的慢性疾病，在美国任何一年都会影响10%的成年人，造成超过1850亿美元的损失，并导致超过10万人死亡。尽管接受了治疗，但大多数酒精中毒患者只能实现短期戒酒，需要改进基于医学的治疗，针对复发的生物风险因素。通过开发以科学为基础的治疗方法，可以加强现有的、但只能部分有效的治疗方法，整体公共健康将得到改善。