Efficacy and Safety of High-Dose Baclofen for Alcohol Dependence

描述(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的治疗正在演变为既包括咨询方法，也包括药物治疗。已经发现了几种对阿尔茨海默病有效的药物，例如纳曲酮、氨基己酸酯。然而，现有药物的总体效果不大，显然需要开发新的药物疗法。根据临床前数据和早期临床试验，GABAB受体激动剂巴氯芬作为治疗AD的潜在新药已引起人们的注意。巴氯芬是FDA批准的药物，具有极好的安全性，即使对肝硬变患者也是如此-这是AD的常见后果。关于巴氯芬的疗效以及更高剂量的巴氯芬是否比之前测试的每天30毫克的剂量安全和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的反应呈正相关。本提案的主要目的是测试30 mg/d和90 mg/d的巴氯芬与安慰剂对照的疗效和安全性，根据饮酒/饮酒日评估依赖的严重程度。一个主要的次要目标是检查巴氯芬的抗焦虑作用。这项研究建议将120名患有阿尔茨海默病的男性和女性纳入一项随机的安慰剂对照试验，包括至少60名AD较严重的患者(男性为E14饮酒/饮酒日；女性为E10饮酒/饮酒日)，随机服用巴氯芬或安慰剂，以平衡这一变量。巴氯芬将在3天内滴定到10毫克，在12天内滴定到30毫克，并维持在该水平12周，然后下降滴定，总研究时间为16周。将提供医疗管理，以鼓励在实现饮酒目标方面取得进展，并提高保留率和遵从性。将评估饮酒模式、焦虑水平、睡眠模式、对酒精的渴望、伽马-谷氨酰转移酶(GGT)和碳水化合物缺乏转移(CDT)。将在第4周对所有患者的R&S-巴氯芬的血药浓度进行评估。总而言之，这项建议是创新的，具有临床意义，因为它将测试和比较标准剂量和大剂量巴氯芬对AD患者的有效性和安全性。该提案有足够的证据来检验基本假设，并提供了很好的证据来评估饮酒/饮酒天数是否预示着巴氯芬的反应。也有足够的能量来检测巴氯芬的抗焦虑作用。确定标准剂量和大剂量巴氯芬的疗效、大量饮酒对巴氯芬反应的预测价值以及巴氯芬的抗焦虑作用是确定巴氯芬在酒依赖患者的临床治疗中是否具有真正价值的重要目标。。

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. .