Improving Buprenorphine Detoxification Outcomes with Isradipine

描述(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上升。传统的阿片类药物戒毒方法，包括逐步停用阿片激动剂美沙酮或丁丙诺啡(BUP)，以及使用α2-肾上腺素能受体激动剂对症状进行支持性治疗，都受到复发率高和/或在缓解主观症状方面缺乏有效性的限制。此外，从美沙酮转向BUP维持的个人受到限制，因为在转向BUP维持之前，需要大幅减少美沙酮维持者的美沙酮维持剂量，这可能导致鸦片类药物戒断和复发。这项申请采用了一种新的方法来解决阿片类药物戒断的问题，通过检查L类型的钙通道阻滞剂(CCB)伊拉地平作为BUP戒毒的辅助药物的效用。L类CCB已被证明可以缓解阿片类药物治疗的非人类阿片类药物戒断，在人类戒毒试验中安全有效地缓解戒断症状，并具有较低的滥用潜力。此外，在测试的几种CCB中，伊拉地平是最有效的，在阻断纳洛酮诱导的行为效应方面，伊拉地平比α2肾上腺素能激动剂可乐定更有效，而不会产生与滥用可能性高相关的自我报告效应。因此，该项目将解决 需要通过评估辅助剂伊拉地平在阿片依赖者BUP戒毒期间的耐受性和初步疗效来改进戒毒策略。这项为期8周的随机、安慰剂对照试点临床试验的目的是确定L类型的CCB伊拉地平在多达60名接受BUP戒毒程序的阿片依赖患者中改善治疗结果的潜在用途。其具体目的是(目的1)确定伊拉地平在阿片依赖患者接受BUP脱毒时减少戒断症状、渴求和非法使用阿片类药物的有效性，(目标2)确定控释伊拉地平(10 mg/d)在接受BUP脱毒治疗的阿片依赖患者中的耐受性和安全性。目前，FDA批准的唯一用于阿片类药物戒断的药物是阿片激动剂的美沙酮和BUP，这两种药物都有滥用倾向。我们的发现，如果呈阳性，将支持更大的II期临床试验。最终，这项工作可能会通过提供另一种有效治疗阿片类药物戒断的药理学工具来影响成瘾领域，同时将滥用责任降至最低。这将改变临床实践，为BUP解毒建立有效的辅助方案，并有可能加强向纳曲酮治疗的过渡。

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.