Development of Guanfacine to decrease drug craving, anxiety and cocaine relapse r

描述（由申请方提供）：本申请拟进行一项随机、双盲、安慰剂对照的实验室研究，以检查胍法辛（GUA）是否能降低可卡因依赖、尼古丁吸烟（CD）个体的可卡因和尼古丁渴求、焦虑和压力相关唤醒。在以前的研究中，我们已经表明，实验室暴露于压力和药物线索增加药物渴望和压力相关的觉醒，这两种措施预测可卡因复发的结果。α-2-肾上腺素能激动剂，如洛非西定和胍法辛减弱可卡因经验的实验室动物的可卡因寻求行为的应激诱导的恢复。在以前的试点研究中，我们已经表明，洛非西定减少压力和线索诱导的阿片类药物和可卡因的渴望，并减少负面影响和生理唤醒阿片类药物依赖的个人与纳洛酮治疗。还发现它可以提高阿片类药物戒断率和每日纳洛酮方案的依从性。GUA 2 mg和3 mg每日给药与安慰剂（PLA）相比的初步研究显示，在药物线索诱导和压力诱导的药物渴求、焦虑和压力相关唤醒方面，结果是积极的。因此，根据之前的临床前研究和我们的临床发现，我们提出了一项为期3年的研究，将招募60名CD患者参加一项随机、双盲、安慰剂对照、为期4周的住院实验室研究。将解决以下具体目标：（1）评估CD个体中每日2 mg和3 mg胍法辛的安全性/耐受性;（2）确定胍法辛对基础可卡因和尼古丁渴求、抑郁症状和住院期间每周评估中的感知压力评分的剂量依赖性效应;（3）研究胍法辛对应激、药物线索和应激+药物线索情景下可卡因渴求、尼古丁渴求和情绪的剂量依赖效应;和（4）确定胍法辛对暴露于应激、药物线索和应激+药物线索组合情景后的心血管和儿茶酚胺（去甲肾上腺素和肾上腺素）反应的剂量依赖性作用。这项研究的结果将提供重要的信息，α-2肾上腺素能化合物，如胍法辛是否显示出减少药物渴望，焦虑和压力的承诺，因素显示预测高可卡因复吸的结果。如果所提出的假设得到支持，它也将提供证据，进一步开发胍法辛作为药物的可卡因复吸预防。 公共卫生相关性：药物渴求和相关的高可卡因复发率是可卡因依赖治疗中的主要临床挑战，药物渴求、焦虑和与压力相关的觉醒是增加可卡因复发风险的重要因素。拟议的研究将测试胍法辛作为一种潜在的治疗策略，以减少这些药物渴望，焦虑和痛苦的症状和可卡因复发风险，结果将对开发新的药物以减少可卡因渴望和预防可卡因依赖复发具有重要的临床意义。

DESCRIPTION (provided by applicant): This application proposes to conduct a randomized, double blind, placebo-controlled laboratory study to examine whether guanfacine (GUA) decreases cocaine and nicotine craving, anxiety and stress related arousal in cocaine dependent, nicotine smoking (CD) individuals. In previous research we've shown that laboratory exposure to stress and drug cues increases drug craving and stress related arousal and both measures predict cocaine relapse outcomes. Alpha-2-adrenergic agonists such as lofexidine and guanfacine attenuate stress-induced reinstatement of cocaine-seeking behavior in cocaine experienced laboratory animals. In previous pilot studies, we've shown that lofexidine decreases stress and cue-induced opiate and cocaine craving and reduces negative affect and physiological arousal in opiate dependent individuals treated with naltrexone. It was also found to improve opiate abstinence rates and compliance with daily naltrexone regimen. Preliminary work with GUA 2 mg and 3 mg daily dosing versus placebo (PLA) showed positive results with respect to drug cue-induced and stress- induced drug craving, anxiety and stress-related arousal. Thus, in light of previous preclinical research and our clinical findings, we propose a 3-year study that will recruit 60 CD individuals to participate in a randomized, double blind, placebo-controlled 4-week inpatient laboratory study. The following specific aims will be addressed: (1) to evaluate the safety/tolerability of 2mg and 3mg daily of guanfacine in CD individuals; (2) to determine the dose-dependent effects of guanfacine on basal cocaine and nicotine craving, depressive symptoms and perceived stress scores in weekly assessments during the inpatient stay; (3) To determine the dose-dependent effects of guanfacine on cocaine craving, nicotine craving and mood following guided imagery exposure to stress, drug cue and combined stress+drug cue scenarios; and (4) to determine the dose-dependent effects of guanfacine on cardiovascular and catecholamine (norepinephrine and epinephrine) response following exposure to stress, drug cue and combined stress+drug cue scenarios. Findings from this study will provide important information on whether alpha-2adrenergic compounds such as guanfacine show promise in decreasing drug craving, anxiety and stress, factors shown to predict high cocaine relapse outcomes. If the proposed hypotheses are supported, it will also provide evidence for further development of guanfacine as a medication for cocaine relapse prevention. PUBLIC HEALTH RELEVANCE: Drug craving and associated high cocaine relapse rates are major clinical challenges in the treatment of cocaine dependence, and drug craving, anxiety and stress-related arousal are significant factors that increase cocaine relapse risk. The proposed study will test guanfacine as a potential therapeutic strategy to decrease these symptoms of drug craving, anxiety and distress and cocaine relapse risk and the results will have significant clinical implications for the development of new medications to decrease cocaine craving and prevent relapse in cocaine dependence.