Efficacy and Safety of High-Dose Baclofen for Alcohol Dependence

高剂量巴氯芬治疗酒精依赖的功效和安全性

• 批准号: 9112811
• 负责人: James C. Garbutt
• 金额: $ 30.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112811
• 关键词: Abstinence; Accounting; Adverse event; Agonist; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Anti-Anxiety Agents; Anxiety; Area; Attention; Baclofen; Blood; Carbohydrates; Case Study; Cells; Clinical; Clinical Management; Clinical Trials; Counseling; Data; Data Analyses; Dependence; Development; Dose; Enrollment; Equilibrium; FDA approved; Gamma-glutamyl transferase; Goals; Health; Heavy Drinking; Individual; Intervention; Knowledge; Lead; Left; Liver Cirrhosis; Measures; Medical; Methods; Modality; Naltrexone; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Population; Predictive Value; Publishing; Randomized; Recording of previous events; Relapse; Reporting; Research; Safety; Severities; Sleep; Symptoms; Testing; Time; Uncertainty; Woman; acamprosate; addiction; alcohol craving; alcohol use disorder; anxiety management; anxiety states; base; carbohydrate-deficient transferrin; clinical care; clinically significant; double-blind placebo controlled trial; drinking; efficacy testing; high standard; improved; innovation; men; pilot trial; pre-clinical; randomized placebo controlled trial; receptor; response; screening; spasticity

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a common problem with significant health consequences. Treatment of AD is evolving to include both counseling methods and medications. Several medications have been discovered, that show efficacy in AD, e.g. naltrexone, acamprosate. However, the overall effect of existing medications is modest leaving a clear need for the development of new pharmacotherapies. The GABAB receptor agonist baclofen has attracted attention as a potential new medication for AD based on preclinical data and early clinical trials. Baclofen is an FDA approved medication with an excellent safety profile even for patients with liver cirrhosis-a not uncommon consequence of AD. Questions have arisen with regards to the efficacy of baclofen and whether higher doses of baclofen are safe and more effective than the prior tested dose of 30 mg/ day. There is emerging evidence that severity of dependence is positively associated with baclofen response. The main goal of the present proposal is to test the efficacy and safety of 30 mg/d and 90 mg/d of baclofen compared to placebo controlling for severity of dependence as assessed by drinks/drinking day. A primary secondary goal will examine for an anxiolytic effect of baclofen. The study proposes to enroll 120 men and women with AD in a randomized, placebo-controlled trial to include at least 60 individuals with more severe AD (e14 drinks/drinking day for men; e10 drinks/drinking day for women) with randomization to baclofen or placebo balanced for this variable. Baclofen will be titrated to 10 mg t.i.d over 3 days and to 30 mg t.i.d over 12 days and maintained at that level for 12 weeks and then down- titrated for a total study time of 16 weeks. Medical Management will be provided to encourage progress towards drinking goals and to enhance retention and compliance. Drinking patterns, anxiety levels, sleep patterns, craving for alcohol, gamma-glutamyl transferase (GGT) and carbohydrate deficient transferring (CDT) will be assessed. Trough blood levels of R & S-baclofen will be assessed in all individuals at week 4. In summary, the present proposal is innovative and of clinical significance as it will test and compare standard and high-dose baclofen for efficacy and safety in individuals with AD. The proposal is adequately powered to test the primary hypothesis and provides good power to assess whether drinks/drinking day is predictive of baclofen response. Adequate power is also present to examine the anxiolytic effect of baclofen. Ascertaining the effects of standard and high-dose baclofen, the predictive value of heavy drinking on baclofen response and the anxiolytic effect of baclofen are important goals towards determining whether baclofen has true value for the clinical management of the patient with alcohol dependence. .

描述（由申请人提供）：酒精依赖（AD）是一种常见的问题，对健康有重大影响。AD的治疗正在发展，包括咨询方法和药物治疗。已经发现了几种在AD中显示出功效的药物，例如纳洛酮、阿坎酸。然而，现有药物的总体效果是适度的，因此显然需要开发新的药物疗法。基于临床前数据和早期临床试验，GABAB受体激动剂巴氯芬作为一种潜在的治疗AD的新药引起了人们的注意。巴氯芬是一种FDA批准的药物，即使对于肝硬化患者也具有良好的安全性-这是AD的一种常见后果。关于巴氯芬的疗效以及更高剂量的巴氯芬是否比先前测试的30 mg/天的剂量更安全和更有效的问题已经出现。有新的证据表明，依赖的严重程度与巴氯芬反应呈正相关。本提案的主要目的是测试30 mg/d和90 mg/d巴氯芬与安慰剂相比的疗效和安全性，以控制依赖性的严重程度，通过饮酒/饮酒日进行评估。一个主要的次要目标是检查巴氯芬的抗焦虑作用。该研究计划在一项随机、安慰剂对照试验中招募120名AD男性和女性患者，其中包括至少60名更严重的AD患者（男性e14饮酒/饮酒日;女性e10饮酒/饮酒日），随机分配至巴氯芬或安慰剂平衡该变量。巴氯芬将在3天内滴定至10 mg t.i.d，在12天内滴定至30 mg t.i.d，并维持该水平12周，然后在总研究时间16周内下调剂量。将提供医疗管理，以鼓励实现饮酒目标的进展，并加强保留和遵守。将评估饮酒模式、焦虑水平、睡眠模式、对酒精的渴望、γ-谷氨酰转移酶（GGT）和碳水化合物缺乏转移（CDT）。将在第4周评估所有个体中R & S-巴氯芬的血液谷水平。总之，本提案具有创新性和临床意义，因为它将测试和比较标准和高剂量巴氯芬在AD患者中的疗效和安全性。该建议有足够的把握度来检验主要假设，并提供良好的把握度来评估饮酒/饮酒日是否可预测巴氯芬反应。也有足够的力量来检查巴氯芬的抗焦虑作用。确定标准和高剂量巴氯芬的效果，大量饮酒对巴氯芬反应的预测价值和巴氯芬的抗焦虑作用是确定巴氯芬是否对酒精依赖患者的临床管理具有真正价值的重要目标。.

项目成果

Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial.

• DOI: 10.1038/s41386-021-01055-w
• 发表时间: 2021-12
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Garbutt JC;Kampov-Polevoy AB;Pedersen C;Stansbury M;Jordan R;Willing L;Gallop RJ
• 通讯作者: Gallop RJ