Combining Pregabalin with Lofexidine: Can it Increase the Success of Transition to Naltrexone?

普瑞巴林与洛非西定联合使用：能否提高纳曲酮过渡的成功率？

• 批准号: 10832720
• 负责人: KYLE Matthew KAMPMAN
• 金额: $ 288.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10832720
• 关键词: Combining; Pregabalin; Lofexidine; Increase; Success

Extended-release naltrexone (XR-NTX) reduces overdose risk and is filling a niche for opioid addicted patients that do not want agonist maintenance or cannot access it. However transitioning to naltrexone requires detoxification, which is a major hurdle. Methadone or buprenorphine tapers are effective but require a 7 to 14-day opioid-free interval before starting naltrexone, leaving ample time to relapse. Non-opioid detoxification with an alpha-2 adrenergic receptor agonist may shorten the time, and lofexidine was recently approved for this indication. It is safer than clonidine however like clonidine, it does not reduce the subjective effects of withdrawal and patients do not like it. A medication that better targets these symptoms may improve outcomes and increase the proportion that transition to XR-NTX. Pregabalin may be such a medication. It potentiates the activity of glutamic acid decarboxylase, inhibits calcium influx and release of excitatory neurotransmitters, raises GABA levels, and is approved for neuropathic pain, fibromyalgia, adjunctive therapy for adults with partial onset seizures and in Europe, for anxiety. It was not controlled in Russia for several years but was placed on their equivalent of our Schedule V due to reports that opioid addicted persons were using it to reduce withdrawal and abuse. Based on this information, Krupitsky and colleagues randomized 34 consenting, heroin-addicted inpatients under double-blind conditions to pregabalin or clonidine-based detoxification protocols. More pregabalin than clonidine patients completed detoxification (p = 0.01) and pregabalin patients had better retention than clonidine patients (p = 0.001) with no differences in adverse events. Here we propose to see if pregabalin can be combined with lofexidine to better reduce the subjective effects of opioid withdrawal than lofexidine, and increase the proportion that transition to XR-NTX. Such a dosing combination could lower the detoxification hurdle for patients who are interested in antagonist treatment or who are in settings where it is unavailable or difficult to access. This work will require two phases, and both fit into the UG3/UH3 announcement. In UG3 we will study pregabalin/lofexidine combinations to identify one that reduces withdrawal-related subjective effects without generating more serious adverse events than lofexidine alone. In UH3 we will test that combination in an adequately powered trial to determine if it increases the number of patients that complete detoxification and transition to XR-NTX. Hypotheses are that we will identify a dosing combination that is safe and reduces opioid withdrawal to a greater degree than lofexidine alone, and that this lofexidine/pregabalin combination will result in more patients completing detoxification and transitioning to XR-NTX. The ultimate goal is to generate data to support new or modified indications(s) and/or inclusion of new recommendations in product prescribing information to improve detoxification outcome and increase the proportion that transition to XR-NTX

扩展释放的纳曲酮（XR-NTX）降低了过量的风险，并且正在填补阿片类药物的利基市场 不需要激动剂维护或无法访问的患者。但是过渡到纳曲酮 需要排毒，这是一个主要障碍。美沙酮或丁丙诺啡锥有效，但需要 在开始纳曲酮之前，7至14天无阿片类型间隔，留出充足的复发时间。非阿片类药物 用α-2肾上腺素能受体激动剂的排毒可能会缩短时间，而lofexidine最近是 批准了此指示。它比可乐定更安全，但是喜欢可乐定，它不会减少主观 戒断的影响和患者不喜欢它。更好地靶向这些症状的药物可能会改善 结果并增加过渡到XR-NTX的比例。 gababalin可能是一种药物。它 增强谷氨酸脱羧酶的活性，抑制钙的流入和兴奋的释放 神经递质，提高GABA水平，并被批准用于神经性疼痛，纤维肌痛，辅助治疗 对于患有部分发作性发作和欧洲的成年人而言，焦虑。它在俄罗斯没有控制几个 多年，但由于报道说阿片类药物上瘾的人是 使用它来减少戒断和滥用。基于此信息，Krupitsky及其同事随机分组34 同意，在双盲条件下，在基于gababalin或可乐定的双盲条件下，海洛因的住院患者 解毒方案。比可乐定患者完成排毒（p = 0.01）和 gababalin患者的保留率比可乐定患者（p = 0.001）更好 事件。 在这里，我们建议查看pregabalin是否可以与Lofexidine合并，以更好地降低主观 阿片类药物戒断的作用比洛芬丁胺增加了，并增加了过渡到XR-NTX的比例。这样的 剂量组合可以降低对拮抗剂治疗感兴趣的患者的排毒障碍 或者在不可用或难以访问的设置中。这项工作将需要两个阶段，两者都需要 适合UG3/UH3公告。在UG3中，我们将研究gabalin/lofexidine组合以识别一种 这可以减少与戒断相关的主观效果，而不会产生比 单独使用洛己胺。在UH3中，我们将在足够动力的试验中测试该组合，以确定是否是否 增加了完全排毒并过渡到XR-NTX的患者数量。假设就是这样 我们将确定一种安全的剂量组合，并将阿片类药物撤离的程度比 仅Lofexidine，这种Lofexidine/pregabalin组合将导致更多患者完成 解毒和过渡到XR-NTX。最终目标是生成数据以支持新的或修改 指示和/或在产品处方中包含新建议以改进 排毒结果并增加过渡到XR-NTX的比例