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（由申请人提供）：失眠和其他睡眠异常是常见的，持久的，并且作为旷日持久的酒精戒断的关键组成部分，与酒精依赖性患者的复发有关。主观睡眠和客观睡眠措施都可以预测复发。但是，客观措施为睡眠破坏的潜在机制提供了更多的了解。拟议的研究的总体长期目标是研究与酒精依赖患者复发有关的睡眠障碍的神经生理机制，并使用药物靶向这些机制，以降低复发风险。具体研究的目的是1）研究失眠症患者的三种潜在睡眠障碍机制：稳态驱动受损，昼夜节律调节受损和大脑过度激活； 2）研究药物对睡眠及其在酗酒者中的调节机制的短期影响； 3）研究酒精中毒的短期临床过程是基线睡眠参数的函数。提出了三个研究阶段。在第一阶段（筛查和稳定； 10天）中，受试者在临床上的特征是诊断失眠和酒精依赖。确定饮酒和睡眠的基线值；并排除混淆睡眠不适的原因，例如急性戒酒，其他药物使用和/或身体，精神和其他睡眠障碍，例如睡眠呼吸暂停。 II期（药物； 10天）是3种药物组的随机，双盲平行设计（安慰剂，加巴喷丁，曲唑酮）。 第I＆II阶段每个人都有7天的睡眠日志和精美的监视，然后在睡眠实验室中进行3晚：改编之夜，基准睡眠之夜和一个挑战之夜，在先前唤醒3小时后，记录了睡眠。还评估了昏暗的褪黑激素发作（DLMO），还评估了昼夜节相的度量。功率谱分析用于量化整夜的脑电图活性。在每个挑战之夜，与基线水平相比，延迟后NREM睡眠中的时间课程和分布来评估体内睡眠驱动器。第三阶段（随访）由12周后的一次访问组成，以评估饮酒课程。总而言之，酒精患者的睡眠障碍反映了神经生理功能障碍。增加复发的风险，并且可能适合药物治疗。针对特定睡眠调节性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，在任何一年中，都会影响10％的成年人，成本超过1,850亿美元，尽管治疗了，但在美国导致超过100,000人死亡，大多数酒精患者仅实现短期弃权，并且需要基于医学的治疗改善，而需要对生物学危险的靶向生物学危险因素。通过开发可以增加现有但只有部分有效治疗方法的科学治疗方法，将改善公共卫生的整体公共卫生。