Improving Buprenorphine Detoxification Outcomes with Isradipine

描述（由申请人提供）：阿片类药物依赖仍然是一个严重的公共卫生问题，特别是随着处方阿片类药物滥用的急剧增加。传统的阿片类药物解毒方法，包括逐渐停用阿片类药物激动剂美沙酮或丁丙诺啡（BUP），以及使用α 2-肾上腺素能受体激动剂对症状进行支持性治疗，由于复发率高和/或缺乏缓解主观症状的疗效而受到限制。此外，从美沙酮过渡到BUP维持的个体受到限制，因为美沙酮维持个体在转换到BUP维持之前需要急剧减少美沙酮维持剂量，这可能导致阿片类药物戒断和复发。本应用采用一种新颖的方法来解决阿片类药物戒断问题，通过检查l型钙通道阻滞剂（CCB） isradipine作为BUP解毒的辅助药物的效用。l型CCBs已被证明可减轻阿片类药物治疗的非人类的阿片类戒断症状，在人类解毒试验中安全有效地减轻戒断症状，并且具有低滥用潜力。此外，isradipine是几种CCBs测试中最有效的，并且在阻断纳洛酮诱导的行为效应方面比α 2-肾上腺素能激动剂可乐定更有效，而不会产生与高滥用可能性相关的自我报告效应。因此，这个项目将解决

DESCRIPTION (provided by applicant): Opioid dependence continues to be a serious public health problem, particularly with the dramatic rise in prescription opioid abuse. Traditional methods of detoxification from opioids, including tapering off the opioid agonist methadone or buprenorphine (BUP) and supportive treatment of symptomatology with the alpha2- adrenergic receptor agonists are limited by the high relapse rate and/or lack of efficacy in relieving subjective symptoms. In addition, transitioning individuals from methadone to BUP maintenance has been limited by the need to drastically taper the methadone maintenance dose of methadone-maintained individuals prior to switching to BUP maintenance, which can precipitate opiate withdrawal and relapse. This application takes a novel approach to address the problem of opioid withdrawal by examining the utility of the L-type calcium channel blocker (CCB) isradipine as an adjunct to BUP detoxification. L-type CCBs have been shown to alleviate opioid withdrawal in opioid-treated nonhumans, to be safe and effective in alleviating withdrawal symptoms in human detoxification trials, and to have low abuse potential. Moreover, isradipine was the most effective of several CCBs tested and was more effective than the alpha2-adrenergic agonist clonidine in blocking naloxone-induced behavioral effects without producing self-reported effects associated with high potential for abuse. Thus, this project will address the need for improved detoxification strategies by assessing the tolerability and preliminary efficacy of adjunct isradipine during a BUP detoxification in opioid-dependent participants. The aim of this 8-week randomized, placebo-controlled pilot clinical trial is to determine the potential utiliy of the L-type CCB isradipine to improve treatment outcomes in up to 60 opioid-dependent individuals undergoing a BUP detoxification procedure. The specific aims are to (Aim 1) determine the efficacy of isradipine to reduce withdrawal symptoms, craving, and illicit use of opioids in opioid-dependent individuals undergoing BUP detoxification and (Aim 2) determine the tolerability and safety of controlled-release isradipine (10 mg/day) in opioid-dependent individuals undergoing BUP detoxification. Currently, the only FDA-approved medications for opioid withdrawal are the opioid agonist's methadone and BUP, both of which have abuse liability. Our findings, if positive, will support a larger phase II clinical trial. Ultimately, ths work could impact the addiction field by providing another pharmacological tool that is efficacious for treating opioid withdrawal while having minimal abuse liability. This would shift clinical practice establishing an effective adjunct regimen for BUP detoxification as well as having the potential to enhance transition to naltrexone therapy.