Cocaine Withdrawal and Pharmacotherapy Response

描述(由申请人提供)：尽管目前尚无有效的可卡因依赖药物疗法，但对两种肾上腺素能阻滞剂的研究显示出了令人振奋的发现。在一项人体实验室研究中，卡维地洛是一种α和β肾上腺素能阻滞剂，可以减缓可卡因诱导的心率和血压增加，并减少可卡因的自我给药行为。此外，在一项开放标签的门诊研究中，卡维地洛耐受性良好，减少了可卡因的使用。与这些发现一致的是，使用β-肾上腺素能阻滞剂心得安的临床试验显示，在治疗可卡因依赖方面有很好的结果，特别是在那些报告有严重可卡因戒断症状的人。这些发现，以及将可卡因戒断与肾上腺素能活动增加联系起来的临床前和临床研究，为寻求肾上腺素能阻滞剂作为可卡因成瘾的潜在治疗方法提供了强有力的科学依据。在这项研究中，我们将在一项为期14周的随机临床试验中测试卡维地洛作为治疗可卡因依赖的疗效。我们选择卡维地洛而不是其他肾上腺素能阻滞剂，是因为它具有良好的安全性，每天给药一次，而且有希望初步发现其对可卡因成瘾的疗效。总共120名依赖阿片和可卡因的受试者，在丁丙诺啡的稳定下，将被随机分配到卡维地洛或安慰剂，每天25或50毫克。为了确定卡维地洛的疗效是否受到戒断严重程度的影响，3个治疗组将根据可卡因选择性严重程度评估(CSSA)测量的可卡因戒断严重程度进行匹配。主要的结果测量将是可卡因的尿液结果，将在研究期间每周获得3次。我们假设卡维地洛在减少可卡因使用方面将比安慰剂更有效。我们还假设，卡维地洛的疗效将受到可卡因使用严重程度的影响，因此较高的基线戒断严重程度将预测更好的治疗反应。这项建议通过测试卡维地洛的疗效并调查戒断严重程度对卡维地洛疗效的影响，可能会导致开发更有效的可卡因成瘾治疗方法。

Description (provided by the applicant): Although there are no effective pharmacotherapies for cocaine dependence, studies with two adrenergic blockers showed promising findings. In a human laboratory study, carvedilol, a combined alpha- and beta-adrenergic blocker, attenuated cocaine-induced heart rate and blood pressure increases and reduced cocaine self-administration behavior. Further, in an open label outpatient study, carvedilol was well-tolerated and reduced cocaine use. Consistent with these findings, clinical trials using propranolol, a beta-adrenergic blocker, showed promising results for the treatment of cocaine dependence, especially in those who report severe cocaine withdrawal symptoms. These findings, together with preclinical and clinical studies linking cocaine withdrawal with increased adrenergic activity, provide a strong scientific rationale for pursuing adrenergic blockers as potential treatments for cocaine addiction. In this study, we will test the efficacy of carvedilol, as a treatment for cocaine dependence in a randomized 14-week clinical trial. We chose carvedilol over other adrenergic blockers due to its favorable safety profile, once-daily dosing schedule, and promising preliminary finding for its efficacy in cocaine addiction. A total of 120 opioid and cocaine dependent subjects, stabilized on buprenorphine, will be randomly assigned to 25 or 50 mg/day carvedilol or placebo. To determine if the efficacy of carvedilol is moderated by withdrawal severity, the 3 treatment groups will be matched for the severity of cocaine withdrawal measured with the Cocaine Selective Severity Assessment (CSSA). The main outcome measure will be cocaine urine results, which will be obtained 3 times per week during the study. We hypothesize that carvedilol will be more effective than placebo in reducing cocaine use. We also hypothesize that the efficacy of carvedilol will be moderated by the severity of cocaine use, such that high baseline withdrawal severity will predict better treatment response. This proposal, by testing the efficacy of carvedilol and investigating the influence of withdrawal severity on carvedilol's efficacy, may result in development of more effective treatments for cocaine addiction.