A dose ranging study of modafinil for methamphetamine dependence

描述（由申请人提供）：对甲基苯丙胺（MA）的依赖在美国许多地区普遍存在。该病的重要后遗症包括认知障碍、乙型和丙型肝炎以及艾滋病毒感染。认知障碍和戒断症状，如嗜睡、疲劳和渴望，可能使使用者有复发的危险。目前还没有针对MA依赖的既定药物治疗方法。莫达非尼是一种新型的促进清醒的药物，可以缓解疲劳，增强认知功能，耐受性好，滥用风险低。莫达非尼减弱了可卡因的主观效应，减少了门诊患者可卡因的使用，我们小组最近完成的工作表明，与静脉注射MA合用是安全的。将进行一项为期8周的剂量范围研究，以评估莫达非尼治疗MA依赖的效应大小。MA依赖性受试者将被随机分配接受每天200或400毫克的莫达非尼或安慰剂。评估将包括尿检MA、MA使用自我报告、成瘾严重程度指数、艾滋病行为风险、神经认知测试、安非他明戒断问卷、血浆莫达非尼水平、血液化学和不良事件报告。采用自我报告和尿毒理学综合测量的广义估计方程模型来评估莫达非尼剂量对MA使用的影响。药代动力学/药效学（PK/PD）模型将用于确定莫达非尼血浆浓度与结果之间的关系。我们假设1)莫达非尼是安全且耐受性良好的，2)服用400mg莫达非尼的人比服用安慰剂的人使用更少的MA， 3) PK/PD模型将揭示莫达非尼水平与a)认知功能，b)戒断症状和c) MA使用之间的浓度效应关系。

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is prevalent in many regions of the United States. Important sequelae of this illness include cognitive impairment, hepatitis B and C, and HIV infection. Cognitive impairment and withdrawal symptoms, e.g., somnolence, fatigue, and craving, may put users at risk for relapse. There is no established pharmacotherapy for MA dependence. Modafinil is a novel wake-promoting agent that relieves fatigue, enhances cognitive function, is well tolerated, and has low abuse liability. Modafinil blunts the subjective effects of cocaine, reduces cocaine use in outpatients, and recently completed work by our group indicates that it is safe when co-administered with intravenous MA. An 8-week dose ranging study will be conducted to assess the effect size of modafinil for treatment of MA dependence. MA dependent subjects will be randomly assigned to receive either 200 or 400 mg per day of modafinil or placebo. Assessments will include urinalysis for MA, self-report of MA use, the Addiction Severity Index, the Risk for AIDS Behaviors, a neurocognitive test battery, the Amphetamine Withdrawal Questionnaire, plasma modafinil levels, blood chemistries, and adverse event reports. A generalized estimating equation model of a composite measure of self-report and urine toxicology be used to assess the effect of modafinil dose on MA use. Pharmacokinetic/pharmacodynamic (PK/PD) modeling will used to determine the relationship between modafinil plasma concentration and outcomes. We hypothesize that 1) modafinil will be safe and well tolerated, 2) persons given 400 mg modafinil will use less MA than those given placebo, and 3) PK/PD modeling will reveal concentration-effect relationships between modafinil levels and a) cognitive function, b) withdrawal symptoms, and c) MA use.