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

缓释纳洛酮（XR-NTX）降低了过量的风险，并填补了阿片类药物成瘾的利基 不需要激动剂维持或无法获得激动剂的患者。 需要解毒，这是一个主要的障碍。美沙酮或丁丙诺啡逐渐减量是有效的，但需要 在开始使用纳洛酮之前，有7至14天的无阿片类药物间隔，留出充足的时间复发。非阿片 用α-2肾上腺素能受体激动剂解毒可能会缩短时间， 批准用于该适应症。它比可乐定更安全，但与可乐定一样，它不会减少主观 戒断反应和患者不喜欢它。更好地针对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。Pregabalin可能就是这样一种药物。它 增强谷氨酸脱羧酶的活性，抑制钙内流和兴奋性 神经递质，提高GABA水平，并被批准用于神经性疼痛，纤维肌痛， 在欧洲，部分性癫痫发作的成年人，焦虑症。它在俄罗斯几年内没有受到控制， 年，但由于有报告称阿片类药物成瘾者 用它来减少戒断和滥用。根据这些信息，Krupitsky和同事随机选择了34名 同意，海洛因成瘾住院患者在双盲条件下普瑞巴林或可乐定为基础的 解毒方案完成脱毒治疗的普瑞巴林患者多于可乐定患者（p = 0.01）， 普瑞巴林组的尿潴留好于可乐定组（p = 0.001）， 事件 在这里，我们建议看看普瑞巴林是否可以与洛非西定联合使用，以更好地减少主观性 阿片类戒断作用优于洛非西定，并增加转换为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解毒障碍 或者处于无法获得或难以访问的环境中的人。这项工作将需要两个阶段， UG3/UH3的公告。在UG3中，我们将研究普瑞巴林/洛非西定组合，以确定一种 减少与停药相关的主观影响，而不会产生比 洛非西定单独给药。在UH3中，我们将在充分把握度的试验中测试该组合，以确定其是否 增加完成解毒并过渡到XR-NTX的患者数量。假设是， 我们将确定一种安全的剂量组合，并在更大程度上减少阿片类药物戒断， 洛非西定单独给药，并且这种洛非西定/普瑞巴林组合将导致更多的患者完成 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的 适应症和/或在产品处方信息中纳入新的建议，以改善 提高向XR-NTX过渡的比例