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: 7750598
• 负责人: KIRK J BROWER
• 金额: $ 43.81万
• 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/7750598
• 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; 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; Screening procedure; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Time; Visit; Wakefulness; actigraphy; base; cost; design; drinking; effective therapy; follow-up; gabapentin; impaired driving performance; improved; indexing; insight; phase 1 study; problem drinker; programs; response; sex; sleep abnormalities

Project Summary: 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 ~ofsleep 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. In Study Phases I & II (Screening & Baseline; 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 III (Medication; 10 days), is a randomized, double-blind parallel design comparison of gabapentin vs. placebo. Phases II & III 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 IV is a 2-day med taper, & Phase V (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.

项目摘要：失眠和其他睡眠异常是常见的，持久的，并且作为关键 旷日持久的酒精戒断的成分，与酒精依赖性患者复发有关。两个都 主观和客观的睡眠措施可以预测复发；但是，客观措施提供 对睡眠中断的潜在机制的更多洞察力。总体长期目标 拟议的研究是研究神经生理机制〜Sleep扰动 与酒精依赖患者的复发有关，并用 药物以减少复发风险。具体研究目的是1）研究三个潜力 失眠症患者的睡眠障碍机制：稳态驱动受损，受损 昼夜节律调节和大脑过度激活； 2）研究药物对睡眠的短期影响 及其在酗酒者中的调节机制； 3）调查酒精中毒的短期临床过程 作为基线睡眠参数的函数。在研究阶段I和II（筛选和基线； 10天以上）中， 受试者在临床上的特征是诊断失眠和酒精依赖。确定基线 喝酒和睡觉的价值；并排除混淆睡眠不足的原因，例如急性酒精 提取，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。 III期（药物； 10天）是Gabapentin vs的随机，双盲平行设计比较。 安慰剂。第II和III阶段分别有7天的睡眠日志和精美的监测，然后进行3晚 在睡眠实验室中：改编之夜，一个基线睡眠之夜和一个挑战之夜，睡眠是 在先前的清醒延伸3小时后记录。昏暗的褪黑激素发作（DLMO），量度 还评估了昼夜节律阶段。功率谱分析用于量化通宵的脑电图活性。每个 挑战之夜，通过评估三角洲的时间课程和分布来评估体内稳态睡眠驱动器 与基线水平相比，延迟后NREM睡眠的功率。第四阶段是2天的MED锥度，＆阶段V （随访）由12周后的一次访问组成，以评估饮酒课程。总之，睡眠障碍 酒精性患者反映神经生理功能障碍，增加复发风险，可能是可正常的 进行药物治疗。针对特定睡眠调节性障碍的靶向治疗可能会改善 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，任何一年都会影响 成年人中有-10％，成本超过1,850亿美元，尽管治疗治疗，但在美国造成100,000多人死亡 大多数酒精患者仅获得短期禁欲和基于医学的治疗改善 需要目标生物危险因素以复发。通过开发将改善公共卫生的总体健康 基于科学的治疗方法可以增加现有但只有部分有效的治疗方法。