Cocaine Withdrawal and Pharmacotherapy Response

描述（由申请方提供）：尽管尚无有效的可卡因依赖药物疗法，但两种肾上腺素能阻滞剂的研究显示了有希望的结果。在一项人体实验室研究中，卡维地洛，一种α-和β-肾上腺素能阻滞剂，减弱了可卡因诱导的心率和血压升高，并减少了可卡因自我给药行为。此外，在一项开放标签门诊研究中，卡维地洛耐受良好，并减少了可卡因的使用。与这些发现相一致，使用普萘洛尔（一种β-肾上腺素能阻滞剂）的临床试验显示出治疗可卡因依赖的有希望的结果，特别是在那些报告有严重可卡因戒断症状的人中。这些发现，连同临床前和临床研究，可卡因戒断与肾上腺素能活性增加，提供了一个强有力的科学依据，追求肾上腺素能受体阻滞剂作为可卡因成瘾的潜在治疗。在这项研究中，我们将测试卡维地洛的疗效，作为一种治疗可卡因依赖的随机14周的临床试验。我们选择卡维地洛而不是其他肾上腺素能受体阻滞剂是因为其良好的安全性，每日一次给药方案，以及其在可卡因成瘾中的有效性的有希望的初步发现。共120例阿片类药物和可卡因依赖受试者，稳定丁丙诺啡，将随机分配至25或50 mg/天卡维地洛或安慰剂组。为了确定卡维地洛的疗效是否受戒断严重程度的调节，将3个治疗组的可卡因戒断严重程度进行匹配，使用可卡因选择性严重程度评估（CSSA）进行测量。主要结局指标为可卡因尿液结果，在研究期间每周采集3次。我们假设卡维地洛在减少可卡因使用方面比安慰剂更有效。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，因此高基线戒断严重程度将预测更好的治疗反应。通过测试卡维地洛的疗效并研究戒断严重程度对卡维地洛疗效的影响，这一建议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.