Oral buprenorphine as a novel low-dose induction strategy for individuals with opioid use disorder

口服丁丙诺啡作为阿片类药物使用障碍患者的新型低剂量诱导策略

基本信息

批准号：
10574877
负责人：
Joji Suzuki
金额：
$ 23.52万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10574877
关键词：
Admission activity Area Biological Availability Buprenorphine Clinical Cross-Over Trials Dose Drug Kinetics Ensure Fentanyl Formularies Formulation Goals Heroin Hospitals Hour Human Volunteers Incidence Individual Inpatients Intervention Intravenous Laboratories Laws Measures Methods Monitor Naltrexone Opiate Addiction Opioid Opioid agonist Oral Oral Administration Outcome Outpatients Overdose Overdose reduction Oxycodone Participant Patients Pharmaceutical Preparations Phase Physiological Plasma Prevalence Property Protocols documentation Randomized Randomized, Controlled Trials Recommendation Reporting Research Route Safety Titrations United States Visit Withdrawal Withdrawal Symptom Work bioaccumulation buprenorphine treatment combat comparative efficacy cost craving design evidence base experience feasibility trial healthy volunteer improved innovation lipophilicity mortality novel novel strategies open label opioid overdose opioid use disorder opioid withdrawal overdose death prevent primary outcome public health priorities response safety and feasibility safety study secondary outcome side effect

项目摘要

Project Summary Abstract Buprenorphine reduces overdose mortality by up to 70%, making it one of the most critical interventions to combat the opioid overdose crisis. With the increasing prevalence of illicit fentanyl, patients with opioid use disorder (OUD) attempting to initiate buprenorphine now routinely report experiencing precipitated withdrawal despite waiting for withdrawal symptoms to first emerge. In response, clinicians and patients alike are increasingly recommending a novel strategy called “micro-dosing” or “low-dose” buprenorphine induction, where a dose significantly lower than the typical 4mg is administered. With this strategy, precipitated withdrawal does not occur despite buprenorphine is administered before the emergence of withdrawal symptoms. A variety of low-dose induction protocols have been reported—some use low dose (≤0.5mg) SL buprenorphine, while others initially use transdermal (Butrans®) or buccal (Belbulca®) formulations. Regardless of the specific approach, the requirements for a successful low-dose induction appear to be the low initial dose, the slow up-titration of the buprenorphine, and continuation of the full agonist opioid during the induction. However, these approaches can be problematic—low-dose SL buprenorphine requires the medication to be cut which is often prohibited in inpatient settings; transdermal and buccal formulations are costly and often not on formulary; and their use violates US federal laws that prohibit them to be prescribed to outpatients seeking treatment for OUD. Therefore, there is an urgent need to research strategies for buprenorphine low-dose inductions that avoid having to cut the medication, or use prohibited and costly formulations. To meet this need, we propose to study the safety and feasibility of utilizing orally (PO) administered buprenorphine. Buprenorphine undergoes extensive first-pass effect when taken PO, hence the bioavailability is estimated to be significantly less than the SL route of 30-50%. As such, using the existing SL dose formulations (e.g. 8mg) via the oral route may allow low-dose induction without having to split the medication. However, research on the safety and feasibility of PO buprenorphine is largely absent. We therefore propose to conduct a two-phased study: in the first phase, we will conduct a randomized cross-over trial with healthy human volunteers to receive low-dose SL and PO buprenorphine to determine the pharmacokinetic parameters. The results will inform the dose needed for a successful low-dose induction using PO buprenorphine. In the second phase, we will conduct a pilot feasibility trial among individuals with OUD to undergo a low-dose induction using PO buprenorphine in a controlled laboratory setting. Given the importance of buprenorphine in improving clinical outcomes for individuals with OUD and preventing overdose deaths, research that aims to identify safe approaches to treatment initiation are urgently needed. Results from this study will be the basis for a safe, accessible, and evidence-based approach to buprenorphine initiation, and lay the groundwork for a randomized controlled trial comparing the efficacy of low-dose induction strategies using PO buprenorphine with standard inductions.

项目概要摘要丁丙诺啡可将过量用药死亡率降低高达 70%，使其成为最重要的干预措施之一对抗阿片类药物过量危机随着非法芬太尼的流行，阿片类药物的使用患者越来越多。尝试启动丁丙诺啡的障碍（OUD）现在经常报告经历突然戒断尽管当地人和患者都在等待戒断症状的出现。越来越多地推荐一种称为“微剂量”或“低剂量”丁丙诺啡诱导的新策略，其中采用这种策略时，服用的剂量明显低于通常的 4 毫克，可以促进戒断。尽管在出现各种戒断症状之前给予丁丙诺啡，但不会发生。低剂量诱导方案已有报道——一些使用低剂量（≤0.5mg）SL丁丙诺啡，而另一些使用最初使用透皮 (Butrans®) 或口腔 (Belbulca®) 制剂，无论具体方法如何。成功的低剂量诱导的要求似乎是低初始剂量、缓慢的滴定然而，这些方法可以在诱导期间继续使用完全激动剂阿片类药物。是有问题的——低剂量 SL 丁丙诺啡需要停药，这在许多国家是被禁止的住院环境；透皮和含服制剂价格昂贵，且通常不符合处方规定；违反了禁止向寻求 OUD 治疗的门诊患者开处方的美国联邦法律。迫切需要研究丁丙诺啡低剂量诱导策略，以避免必须削减为了满足这一需求，我们建议研究其安全性和有效性。使用口服（PO）丁丙诺啡的可行性经历了广泛的首过。 PO 服用时的效果，因此估计生物利用度显着低于 SL 途径的 30-50%。因此，通过口服途径使用现有的 SL 剂量制剂（例如 8mg）可以实现低剂量诱导然而，PO 丁丙诺啡的安全性和可行性的研究正在进行中。因此，我们建议进行两阶段的研究：在第一阶段，我们将进行一项研究。健康人类志愿者接受低剂量 SL 和 PO 丁丙诺啡的随机交叉试验确定药代动力学参数，结果将告知成功低剂量所需的剂量。在第二阶段，我们将在个人中进行试点可行性试验。与 OUD 在受控实验室环境中使用 PO 丁丙诺啡进行低剂量诱导。丁丙诺啡在改善 OUD 患者临床结果和预防过量用药方面的重要性死亡，迫切需要旨在确定开始治疗的安全方法的研究结果。这项研究将成为安全、易于使用且基于证据的丁丙诺啡起始治疗方法的基础，以及为一项随机对照试验奠定基础，该试验比较低剂量诱导策略的功效 PO 丁丙诺啡，采用标准诱导。