MEDICATIONS FOR COCAINE CESSATION /RELAPSE PREVENTION

可卡因依赖很难治疗。尽管有40多项对照双盲试验，但没有 药物治疗已被证实对可卡因依赖有效。到目前为止，大多数试验在可卡因使用的基线水平和严重程度方面采用了不同的样本。存在这样一种可能性，即某些药物可能或多或少有效，这取决于可卡因的基线使用。我们提出了一种创新的方法，预先指定基线禁欲状态，并测试这个变量是否调节药物治疗和结果之间的关系。在这份修订的申请中，我们选择了三种潜在的药物，对于这些药物，有一个令人信服的理由来检验基线戒断和非戒断条件下的不同治疗效果。根据初步发现，我们假设纳曲酮50毫克和左旋多巴/卡比多巴800/200毫克在可卡因戒断的基线上服用时将比安慰剂显示出显著的疗效，这与“复发预防”机制是一致的。此外，我们假设，莫达非尼400毫克在可卡因非戒断的基线上给药时，与安慰剂相比将显示出显著的疗效，这与“禁欲启动”机制一致。这个为期5年的项目从为期4周的基线阶段开始，涉及激励访谈和激励战略，以启动寻求治疗的可卡因使用者的戒除。这项研究的第二阶段包括一项为期12周的药物试验，比较四种药物治疗条件(安慰剂、纳曲酮50毫克、左旋多巴/卡比多巴800/200毫克和莫达非尼400毫克)，并根据基本禁欲状况(禁欲/非禁欲)分层随机分配。在治疗期间，所有受试者(N=200)都将接受心理治疗和应急管理，旨在 提高服药依从性，每周三次，定期进行尿液筛查。目标和自我报告的药物使用情况将在治疗后(3个月、6个月)继续进行评估。评估小组将收集探索项目次要目标所需的数据，即与实现初步戒毒有关的因素，以及不同药物有助于戒除可卡因或预防复发的可能治疗机制。分级多元回归分析将被用来确定基线状态是否缓和药物治疗对结果的影响。对于显著的交互作用，将绘制每个治疗条件在两个水平的调节因子(禁欲与非禁欲)的回归斜率。该项目将通过确定对治疗最敏感的亚群和基线情况，为我们的P50药物开发研究计划做出贡献，从而为指导未来的治疗决策提供独特的新的、有价值的信息。

Cocaine dependence is difficult to treat. Despite more than 40 controlled double-blind trials, no medication has yet been identified as effective for cocaine dependence. To date, most trials have employed heterogeneous samples in terms of baseline level and severity of cocaine use. The possibility exists that certain medications may be more or less effective depending on baseline cocaine use. We propose an innovative methodology that specifies baseline abstinence status a priori, and tests whether this variable moderates the relationship between pharmacotherapy and outcome. In this revised application we have selected three potential medications for which there exists a compelling rationale for examining differential treatment effects under baseline abstinent and nonabstinent conditions. Based on preliminary findings, we hypothesize that naltrexone 50 mg and levodopa/carbidopa 800/200 mg will show significant efficacy over placebo when administered on a baseline of cocaine abstinence, consistent with a "relapse prevention" mechanism. Further, we hypothesize that modafinil 400 mg will show significant efficacy over placebo when administered on a baseline of cocaine non-abstinence, consistent with an "abstinence initiation" mechanism. This 5-year project begins with a 4-week baseline phase involving motivational interviewing and incentive strategies for initiating abstinence in treatment-seeking cocaine users. The second phase of the study consists of a 12-week medication trial comparing four pharmacotherapy conditions (placebo, naltrexone 50mg, levodopa/carbidopa 800/200 mg, and modafinil 400 mg) with stratified random assignment to condition based on baseline abstinence status (abstinent/non-abstinent). During treatment all subjects (N=200) will receive psychotherapy and contingency management designed to enhance medication compliance, with urine screening conducted on a fixed, thrice-weekly schedule. Objective and self-reported drug use will continue to be measured after treatment (3-, 6-months). The assessment battery will capture data necessary to explore secondary aims of the projects, i.e., factors related to achievement of initial abstinence and possible treatment mechanisms by which different medications facilitate cocaine cessation or relapse prevention. Hierarchical multiple regression analyses will be used to determine whether baseline status moderates the effect of pharmacotherapy on outcome. For significant interactions, regression slopes for each treatment condition at the two levels of the moderator (abstinent vs non-abstinent) will be plotted. This project will contribute to our P50 medication development research program by identifying subpopulations and baseline conditions most responsive to treatment, thus providing unique new and valuable information to guide future treatment decision making.