Disulfiram for Cocaine Abuse in Methadone - Patients

描述(由申请人提供)：这项竞争性更新进一步检查了多巴胺β-羟基酶(DBH)活性对新型药物疗法双硫兰疗效的影响，该药物用于治疗服用美沙酮的阿片类药物和可卡因依赖患者的可卡因依赖。可卡因的使用在大多数阿片类药物维持方案中仍然很普遍，专门针对可卡因的多巴胺能作用的药物治疗策略在未选定的人群中几乎没有效果。在我们之前的试验中，我们已经表明，DBH活性影响较低剂量(0、62.5、125或250 mg/天)的双硫兰的反应，因此，在DBH活性较低的可卡因依赖、美沙酮稳定的患者中，每天62.5和125 mg的双硫兰分别增加而250 mg/天的双硫兰减少可卡因的使用。在胸径活动正常的人中，双硫兰对可卡因的使用没有影响。因此，我们的目的是在一项为期14周的双盲随机临床试验中，检查胸径活性对高剂量双硫仑治疗160名美沙酮维持可卡因滥用者疗效的影响。由于DPH的活动受到很强的遗传控制，参与者将根据多巴胺β-羟基酶(DBH)基因座的基因型进行分层，以确保在治疗组中受试者的比例相等。美沙酮诱导、基因分型和评估基线可卡因使用将在1-2周内进行。然后，参与者将继续服用美沙酮，按基因等进行分层，并被随机分配到接下来的12周内接受以下剂量的双硫仑之一：0,250,375,500毫克/天。在研究结束时，参与者将不再接受双硫兰治疗，或者转移到常规的美沙酮治疗方案，或者在4到6周的时间里接受美沙酮的戒毒。为了改善结果，所有参与者每周接受1小时的心理治疗(认知行为治疗)，由经验丰富的临床医生接受专门培训来提供治疗，并将接受持续的监督。主要结果将是胸径基因座的基因型和/或DBpH酶活性对减少可卡因使用的影响，通过每周三次的尿液分析进行评估。次要结果将包括留存、减少其他非法药物和酒精的使用、双硫兰副作用概况以及心理社会功能的改善。还将检查其他因素(例如，性别、折扣行为)与预后的相关性。

DESCRIPTION (provided by applicant): This competitive renewal examines further the influence of dopamine beta-hydroxylase (DBH) enzyme activity on the efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in opioid- and cocaine-dependent patients maintained on methadone. Cocaine use remains epidemic among most opioid maintenance programs and pharmacological therapeutic strategies specifically aimed at cocaine's dopaminergic actions have shown little efficacy in unselected populations. In our previous trial, we have shown that DBH activity influences response to disulfiram at lower doses (0, 62.5, 125, or 250 mg/day), such that, disulfiram at 62.5 and 125 mg/day increases and disulfiram at 250 mg/day decreases, respectively, cocaine use relative to placebo in cocaine-dependent, methadone-stabilized patients with low DBH activity. Disulfiram produced no differential effects on cocaine use in those with normal DBH activity. Thus, our aim is to examine the influence of DBH activity on the efficacy of disulfiram at higher doses for treating 160 methadone-maintained cocaine abusers in a 14-wk, double blind, randomized clinical trial. Because DpH activity is under strong genetic control, participants will be stratified on genotype at the dopamine beta- hydroxylase (DBH) locus to ensure equal proportions of subjects across treatment groups. Methadone induction, genotyping, and assessment of baseline cocaine use will occur during weeks 1-2. Then participants will continue on methadone, be stratified by genotype, etc., and be randomly assigned to receive one of the following doses of disulfiram for the next 12 weeks: 0, 250, 375, 500 mg/day. At the end the study, participants will no longer receive disulfiram and either transfer to a regular methadone program or undergo detoxification from methadone over a 4- to 6-wk period. In order to enhance outcome, all participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. The primary outcome will be the influence of genotype at the DBH locus and/or DBpH enzyme activity on reduction cocaine use, as assessed by thrice-weekly urinalyses. Secondary outcomes will include retention, reductions in other illicit drug and alcohol use, disulfiram side-effects profile, and improvements in psychosocial functioning. The prognostic relevance of other factors (e.g., sex, discounting behavior) will also be examined.