Gabapentin for Relapse Prevention: Alc. Withdrawal-Brain GABA/Glutamate Effects

加巴喷丁预防复发：Alc。

• 批准号: 9315600
• 负责人: RAYMOND F ANTON
• 金额: $ 51.24万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315600
• 关键词: Abstinence; Acute; Aftercare; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Alleles; Anticonvulsants; Attention; Basic Science; Biological; Biology; Brain; Characteristics; Clinical; Clinical Trials; Code; Conduct Clinical Trials; DSM-IV; DSM-V; Data; Development; Evaluation; FDA approved; Future; GABA Receptor; Generic Drugs; Genes; Genetic; Genotype; Glutamate Receptor; Glutamates; Goals; Heavy Drinking; Imaging technology; Individual; Investigation; Lead; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Mediator of activation protein; Medical; Medicine; Naltrexone; Neurotransmitters; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Placebos; Population; Prevention; Prevention approach; Publishing; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recording of previous events; Relapse; Reporting; Risk; Signs and Symptoms; Single Nucleotide Polymorphism; Subgroup; System; Testing; Translational Research; Treatment outcome; Variant; Withdrawal; Withdrawal Symptom; Work; acamprosate; alcohol abuse therapy; alcohol relapse; alcohol use disorder; alcoholism therapy; base; control trial; disorder later incidence prevention; drinking; effective therapy; experience; gabapentin; gamma-Aminobutyric Acid; genetic variant; improved; interest; meetings; neurochemistry; novel; personalized approach; personalized medicine; prevent; problem drinker; prospective; prospective test; public health relevance; receptor; relapse prediction; relapse risk; response; sound; topiramate; treatment response; week trial

DESCRIPTION (provided by applicant): Pharmacotherapy of alcohol dependence is limited and the medications with proven efficacy clearly do not work for everyone. In the field of medicine, there is a great desire, and need, for more personalized treatment approaches. To achieve this laudable goal, there needs to be better matching of novel medications that are safe, affordable, and efficacious to clinical and/or biological subgroups of alcoholics. One understudied alcohol use disorder subgroup are those that experience alcohol withdrawal (AW) syndrome, a well-defined constellation of signs and symptoms present in a significant number of those who abruptly stop drinking. We have found in two completed and published clinical trials that gabapentin (a well-studied and ubiquitously prescribed generic medication), that had previously shown efficacy in treatment of acute AW, might also be efficacious in preventing relapse over a more prolonged period in those with a "history of AW". Since gabapentin was combined with other medications in those studies and given for a relatively short duration (six weeks), a longer prospective controlled trial is necessary to prove its efficacy when given alone, in those with an AW history. Basic science investigation postulates that dysregulation in two prominent neurochemical systems, the glutamate and GABA systems, underlies the expression of AW and may be modified by gabapentin. By using advanced magnetic resonance imaging technology (1H-MRS) to measure brain levels of glutamate and GABA, and by genotyping functional variants in certain glutamate and GABA receptors, we have the opportunity to explore the involvement of these systems in predicting relapse and in the mechanism of gabapentin action - providing an important translational science component to a well-conducted clinical trial. To that end, 190 individuals with alcohol use disorder will be screened, and after 3-7 days of abstinence 90 individuals, who meet DSM-5 criteria for a history of AW, will be randomized to a 16-week trial of gabapentin or placebo. All subjects will undergo 1H-MRS prior to treatment randomization and again between days 17-24 of treatment and all subjects will be genotyped for specific variation in glutamate 8 receptor and GABA2A genes. Subjects will be evaluated over 16 weeks (and post-treatment at weeks 20 and 28) for drinking and other salient outcome variables. The main outcome variable will be "percent of subjects relapsing to a heavy drinking day". Change in brain glutamate and/or GABA levels and genetic variants will be evaluated as mediators or moderators respectively of treatment-response. Positive results would provide another medication option, while advancing a more personalized approach to pharmacotherapy of alcohol use disorder. Also, providing new information on brain and genetic mechanisms underlying AW risk and treatment adds scientific value. As such, advancement in understanding the biology and treatment of individuals with alcohol dependence would be greatly enhanced.

描述（由申请人提供）：酒精依赖的药物疗法有限，具有可靠疗效的药物显然对所有人都无效。在医学领域，人们对更个性化的治疗方法有着巨大的渴望和需求。为了实现这一值得称赞的目标，需要更好地匹配新型药物，这些药物安全，负担得起且对酒精中毒的临床和/或生物亚组有效。一个正在研究的酒精使用障碍子组是那些经历戒酒（AW）综合征的人，这是一个明确定义的体征和症状，其中大量突然停止饮酒的人中存在。我们在两项完整和发表的临床试验中发现，加巴喷丁（一种经过良好研究且普遍开处方的普通药物）先前在治疗急性AW的治疗方面也可能有效，也可能有效地防止在患有更延长的时期的复发中“ AW的历史”。由于加巴喷丁在这些研究中与其他药物合并并给予持续时间相对较短（六周），因此在具有AW病史的患者中，必须进行更长的前瞻性对照试验，以证明其在单独赋予其功效。基础科学调查假设，在两个突出的神经化学系统（谷氨酸和GABA系统）中的失调是AW的表达的基础，可以通过加巴喷丁进行修饰。通过使用先进的磁共振成像技术（1H-MRS）来测量谷氨酸和GABA的大脑水平，以及通过在某些谷氨酸和GABA受体中的基因分型功能变异，我们有机会探索这些系统参与这些系统参与预测复发和预测复发和加巴喷丁作用的机制 - 为良好的临床试验提供了重要的转化科学组成部分。 为此，将筛选190名饮酒障碍的人，在戒酒3-7天后，符合DSM-5标准的AW史的90人将被随机分为16周的Gabapentin或安慰剂试验。 。所有受试者将在治疗随机分组前进行1H-MR，并且在治疗的第17-24天之间，所有受试者均将对谷氨酸8受体和GABA2A基因的特异性变异进行基因分型。将在16周内评估受试者（以及第20周和第28周的治疗后）进行饮酒和其他显着结果变量。主要的结果变量将是“重复饮酒日的受试者的百分比”。脑谷氨酸和/或GABA水平以及遗传变异的变化将分别评估为治疗反应的介体或主持人。积极的结果将提供另一种药物选择，同时推进对酒精使用障碍药物治疗的更个性化的方法。此外，提供有关AW风险和治疗基础的大脑和遗传机制的新信息还增加了科学价值。因此，了解酒精依赖人的生物学和治疗的进步将大大增强。