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

• 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
• 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

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.

项目摘要 丁丙诺啡可将过量死亡率降低高达70%，使其成为最关键的干预措施之一， 对抗阿片类药物过量危机随着非法芬太尼的日益流行，使用阿片类药物的患者 尝试开始丁丙诺啡治疗的OUD患者现在经常报告出现突然戒断 尽管要等到戒断症状出现作为回应，临床医生和患者都 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， 施用的剂量显著低于典型的4mg。有了这个策略，突然撤退确实 尽管在戒断症状出现之前给予丁丙诺啡，但不会发生。各种 低剂量诱导方案已被证实-一些使用低剂量（≤ 0.5mg）SL丁丙诺啡，而另一些使用低剂量（≤ 0.5mg）SL丁丙诺啡。 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的初始剂量，缓慢的剂量上调， 丁丙诺啡，并在诱导期间继续使用完全激动剂阿片类药物。然而，这些方法可以 有问题的低剂量SL丁丙诺啡需要削减药物，这往往是禁止在 住院设置;透皮和口腔制剂是昂贵的，往往不是处方集;和他们的使用 违反了美国联邦法律，该法律禁止将其开给寻求治疗OUD的门诊患者。因此，我们认为， 迫切需要研究丁丙诺啡低剂量诱导的策略，以避免不得不削减 药物，或使用禁止和昂贵的配方。为满足这方面的需要，我们建议研究 使用口服（PO）丁丙诺啡的可行性。丁丙诺啡经历了广泛的首过 口服给药时的效果，因此估计生物利用度显著低于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8 mg）可能允许低剂量诱导 而不需要分开用药。然而，关于PO丁丙诺啡的安全性和可行性的研究是 大部分缺席。因此，我们建议分两个阶段进行研究：在第一阶段， 随机交叉试验，健康志愿者接受低剂量SL和PO丁丙诺啡， 测定药代动力学参数。结果将告知成功的低剂量所需的剂量 使用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 OUD患者在受控实验室环境中使用PO丁丙诺啡进行低剂量诱导。鉴于 丁丙诺啡在改善OUD患者临床结局和预防药物过量方面的重要性 因此，迫切需要开展旨在确定开始治疗的安全方法的研究。结果 本研究将为丁丙诺啡启动的安全、可获得和循证方法奠定基础， 为一项随机对照试验奠定基础， 口服丁丙诺啡和标准诱导。