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

描述(申请人提供)：这项申请建议进行一项随机、双盲、安慰剂对照的实验室研究，以检验瓜那法辛(GUA)是否能减少可卡因依赖、尼古丁吸烟(CD)个人的可卡因和尼古丁渴望、焦虑和压力相关的唤醒。在之前的研究中，我们已经证明，实验室暴露在压力和药物线索下会增加对药物的渴望和与压力相关的唤起，这两个指标都可以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，减轻了应激诱导的可卡因寻找行为的恢复，在经历可卡因的实验动物中。在之前的试点研究中，我们已经表明，洛非西定减少了压力和线索诱导的鸦片和可卡因渴望，并减少了纳曲酮治疗的阿片依赖患者的负面情绪和生理唤醒。它还被发现可以提高阿片类药物的戒断率和对纳曲酮每日疗法的依从性。初步研究表明，每天服用2毫克和3毫克GUA与安慰剂(PLA)相比，在药物线索诱导和压力诱导的药物渴望、焦虑和与压力相关的唤醒方面都有积极的结果。因此，根据之前的临床前研究和我们的临床研究结果，我们建议进行一项为期3年的研究，招募60名CD患者参加随机、双盲、安慰剂对照的为期4周的住院患者实验室研究。将针对以下具体目标：(1)评估CD患者每日服用2 mg和3 mg瓜那法辛的安全性/耐受性；(2)在住院期间的每周评估中，确定瓜那法辛对基础可卡因和尼古丁渴求、抑郁症状和感觉应激评分的剂量依赖性影响；(3)确定瓜那法辛对暴露于应激、药物线索和压力+药物线索情景下的可卡因渴求、尼古丁渴求和情绪的剂量依赖性影响；以及(4)确定在应激、药物线索和联合应激+药物线索情景下，瓜那法辛对心血管和儿茶酚胺(去甲肾上腺素和肾上腺素)反应的剂量依赖性影响。这项研究的发现将为α-2肾上腺素能化合物，如鸟嘌呤，是否在减少药物渴求、焦虑和压力方面显示出希望提供重要信息，这些因素被证明是预测高可卡因复发结果的因素。如果所提出的假设得到支持，也将为进一步将金刚烷作为预防可卡因复发的药物提供证据。 公共卫生相关性：药物渴望和相关的高可卡因复发率是治疗可卡因依赖的主要临床挑战，药物渴望、焦虑和应激相关的唤醒是增加可卡因复发风险的重要因素。这项拟议的研究将测试金刚烷作为一种潜在的治疗策略，以减少这些药物渴望、焦虑和痛苦的症状以及可卡因复发的风险，结果将对开发减少可卡因渴望和防止可卡因依赖复发的新药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.