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

项目摘要摘要 丁丙诺啡将过量死亡率降低高达70%，使其成为治疗 应对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 尝试启动丁丙诺啡的精神障碍(OUD)现在经常报告经历突然戒断 尽管等待戒断症状首次出现。作为回应，临床医生和患者都 越来越多的人推荐一种称为“微剂量”或“低剂量”丁丙诺啡诱导的新策略，其中 剂量明显低于典型的4毫克。在这一策略下，仓促撤资确实 即使丁丙诺啡在戒断症状出现之前服用，也不会发生。各种各样的 已经报道了低剂量的诱导方案-一些使用低剂量(≤0.5 mg)SL丁丙诺啡，而另一些使用 最初使用透皮(BuTrans®)或口腔(BelBulca®)配方。无论采用哪种具体方法， 成功的低剂量诱导的要求似乎是低初始剂量，缓慢的滴定 丁丙诺啡，并在诱导期间继续使用全激动剂阿片类药物。然而，这些方法可以 有问题--小剂量的SL丁丙诺啡需要切断药物，这通常是在 住院环境；透皮和口腔制剂价格昂贵，而且往往不在处方中；及其使用 违反了美国联邦法律，禁止将其开给寻求OUD治疗的门诊患者。因此， 迫切需要研究丁丙诺啡低剂量诱导的策略，以避免不得不切断 药物，或使用违禁和昂贵的配方。为配合这方面的需要，我们建议研究 丁丙诺啡口服给药的可行性。丁丙诺啡经历广泛的首次通过 在服用PO时的效果，因此生物利用度估计明显低于SL路线的30-50%。 因此，通过口服途径使用现有的SL剂量配方(例如8 mg)可允许低剂量诱导 而不需要分开服药。然而，对PO丁丙诺啡的安全性和可行性的研究是 基本上是缺席的。因此，我们建议分两阶段进行研究：在第一阶段，我们会进行 健康志愿者接受小剂量SL和PO丁丙诺啡治疗的随机交叉试验 测定药动学参数。结果将告知成功的低剂量治疗所需的剂量。 用PO丁丙诺啡诱导。在第二阶段，我们将在个人中进行试点可行性试验 在受控的实验室环境下，使用PO丁丙诺啡进行低剂量的诱导。给定 丁丙诺啡在改善OUD患者临床结局和预防过量用药中的重要性 为了减少死亡，迫切需要开展研究，以确定开始治疗的安全方法。结果来自 这项研究将为丁丙诺啡启动的安全、可及和循证的方法奠定基础。 为比较低剂量诱导策略的有效性的随机对照试验奠定了基础 丁丙诺啡标准诱导剂。

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.