Disulfiram for Cocaine Abuse in Methadone - Patients

描述（由申请方提供）：本竞争性更新进一步检查了多巴胺β-羟化酶（DBH）酶活性对新型药物疗法双硫仑治疗维持美沙酮的阿片类药物和可卡因依赖患者的可卡因依赖疗效的影响。可卡因的使用在大多数阿片类药物维持治疗中仍然很流行，专门针对可卡因多巴胺能作用的药理学治疗策略在阿片类药物人群中几乎没有效果。在我们之前的试验中，我们已经证明DBH活性影响对低剂量（0、62.5、125或250 mg/天）双硫仑的反应，因此，在DBH活性低的可卡因依赖性美沙酮稳定患者中，与安慰剂相比，62.5和125 mg/天双硫仑分别增加可卡因使用，250 mg/天双硫仑减少可卡因使用。在DBH活动正常的患者中，双硫仑对可卡因使用没有不同的影响。因此，我们的目的是研究DBH活性对双硫仑在较高剂量下治疗160名美沙酮维持可卡因滥用者的疗效的影响，该研究是一项为期14周的双盲随机临床试验。由于DpH活性受强遗传控制，因此将根据多巴胺β-羟化酶（DBH）基因座的基因型对受试者进行分层，以确保治疗组间受试者比例相等。美沙酮诱导、基因分型和基线可卡因使用评估将在第1-2周进行。然后参与者将继续服用美沙酮，按基因型等进行分层，并随机分配接受以下剂量之一的双硫仑，持续12周：0、250、375、500 mg/天。在研究结束时，参与者将不再接受双硫仑，要么转入常规美沙酮计划，要么在4至6周的时间内接受美沙酮解毒。为了提高疗效，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专门培训提供治疗，并接受持续的监督。主要结果将是DBH基因座和/或DBpH酶活性对减少可卡因使用的影响，通过每周三次尿分析进行评估。次要结局将包括保留，减少其他非法药物和酒精的使用，双硫仑副作用概况，并改善心理社会功能。其他因素的预后相关性（例如，性别、折扣行为）也将被审查。

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.