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

缓释纳曲酮（XR-NTX）可降低用药过量风险，并填补阿片类药物成瘾者的空白 不想维持激动剂或无法获得激动剂的患者。然而过渡到纳曲酮 需要排毒，这是一个主要障碍。美沙酮或丁丙诺啡逐渐减量是有效的，但需要 在开始使用纳曲酮之前，间隔 7 至 14 天不使用阿片类药物，为复发留出充足的时间。非阿片类药物 用α2肾上腺素能受体激动剂解毒可能会缩短时间，洛非西定最近被用于 批准用于该适应症。它比可乐定更安全，但与可乐定一样，它不会降低主观 戒断效应，患者不喜欢。更好地针对这些症状的药物可能会有所改善 结果并增加过渡到 XR-NTX 的比例。普瑞巴林可能就是这样的药物。它 增强谷氨酸脱羧酶的活性，抑制钙内流和兴奋性物质的释放 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 用于治疗部分性癫痫发作的成人，以及在欧洲用于治疗焦虑症。它在俄罗斯有好几年没有受到控制 年，但由于有报告称阿片类药物成瘾者被列入我们的附表 V 的同等内容 用它来减少戒断和滥用。根据这些信息，Krupitsky 和同事随机抽取了 34 在双盲条件下同意海洛因成瘾的住院患者使用普瑞巴林或可乐定 解毒方案。完成戒毒的普瑞巴林患者多于可乐定患者 (p = 0.01) 普瑞巴林患者比可乐定患者有更好的保留率 (p = 0.001)，不良反应没有差异 事件。 这里我们建议看看普瑞巴林是否可以与洛非西丁联合使用，以更好地降低主观 阿片类药物戒断效果优于洛非西定，并增加转向 XR-NTX 的比例。这样一个 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 或者处于不可用或难以访问的环境中的人。这项工作需要两个阶段 适合 UG3/UH3 公告。在 UG3 中，我们将研究普瑞巴林/洛非西丁组合以确定一种 减少与戒断相关的主观影响，而不会产生比 单独使用洛非西定。在 UH3 中，我们将在动力充足的试验中测试该组合，以确定它是否 增加完成戒毒并过渡到 XR-NTX 的患者数量。假设是 我们将确定一种安全的剂量组合，并能更大程度地减少阿片类药物戒断 单独使用洛非西定，以及洛非西定/普瑞巴林组合将导致更多患者完成 解毒并过渡到 XR-NTX。最终目标是生成数据来支持新的或修改的 适应症和/或在产品处方信息中纳入新建议以改进 解毒结果并增加过渡到 XR-NTX 的比例