Efficacy of buprenorphine and XR-naltrexone combination for relapse prevention in opioid use disorder

丁丙诺啡和 XR-纳曲酮组合预防阿片类药物使用障碍复发的功效

• 批准号: 9738472
• 负责人: ADAM BISAGA
• 金额: $ 125.84万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9738472
• 关键词: Abstinence; Address; Adherence; Adverse effects; Affect; Agonist; Anxiety; Behavioral; Buprenorphine; Clinical Trials; Clonazepam; Clonidine; Development; Dose; Double-Blind Method; Dropout; Drops; Drug Metabolic Detoxication; Early treatment; Effectiveness; Epidemic; Goals; Individual; Injections; Maintenance; Measures; Methadone; Methods; Monitor; Moods; Morbidity - disease rate; Naltrexone; Opiate Addiction; Opioid; Opioid Antagonist; Opioid agonist; Oral; Outcome; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Pharmacology; Placebos; Population; Preparation; Prevention therapy; Randomized; Recovery; Relapse; Safety; Secure; Severities; Sleep disturbances; Sleeplessness; Symptoms; Testing; Time; Treatment outcome; Withdrawal; Withdrawal Symptom; affective disturbance; anxiety symptoms; arm; base; clinically relevant; craving; delta opioid receptor; depressive symptoms; disorder later incidence prevention; dysphoria; effectiveness testing; experience; high risk; illicit opioid; improved; interest; medication-assisted treatment; mu opioid receptors; novel strategies; opioid abuse; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; outpatient programs; overdose death; pilot trial; placebo controlled trial; premature; primary outcome; protective effect; recruit; relapse risk; zolpidem

Opioid use disorder (OUD) reached epidemic proportions in the US with more than 2.5 million individuals affected and dramatic increase in unintentional opioid-related overdose deaths. While maintenance with buprenorphine is a leading treatment for opioid-dependent individuals, this is not acceptable to some patients, nor is it universally effective as approximately 50% of individuals treated with buprenorphine continue using illicit opioids and/or drop out during the first 6 months of treatment. Naltrexone, a mu-opioid receptor antagonist, given as extended-release (XR) preparation, offers an alternative approach for patients who have failed prior agonist trials or those who are not suitable or agreeable to agonist maintenance. Naltrexone is fitting for individuals seeking recovery without opioid agonists as it offers the promise of securing abstinence and circumventing the high relapse rates currently observed following opioid detoxification. However, at present time only 50% of patients are successfully retained in treatment with XR-naltrexone over long period of time which limits it protective effects and can be a barrier to a widespread dissemination and acceptance of antagonist-based treatment. In the proposed trial, we will test the effectiveness of a new pharmacological approach to increase the proportion of patients successfully retained on XR-naltrexone by combining it with buprenorphine administered daily. Adding buprenorphine after the patient received XR-naltrexone will not produce mu opioid agonist effect but remaining kappa antagonist effects of buprenorphine may provide additional relief of protracted withdrawal, craving, and mood disturbances persisting in patients treated with XR-naltrexone and possibly contributing to premature treatment discontinuation and relapse. The goal of this five-year study is to test whether addition of buprenorphine will improve treatment retention, reduce opioid craving, and improve mood over the subsequent 6-months of treatment during which participants will receive six XR-naltrexone injections and relapse-prevention therapy. We will conduct a placebo-controlled, double-blind, two parallel arm clinical trial with 1:1 randomization to evaluate the safety and the efficacy of buprenorphine 4 mg/d administered concurrently with XR-naltrexone. Individuals with OUD seeking treatment with naltrexone will be detoxified and after they receive XR-naltrexone they will be randomized to treatment with buprenorphine (N = 60), or placebo (N = 60) with 5 additional doses of XR-naltrexone, given every 4 weeks, and weekly therapy. Buprenorphine (4 mg/d) or placebo will be started after the first XR-naltrexone dose and tapered off after the final XR-naltrexone injection. The primary outcome measure will be the proportion of patients successfully retained to receive six consecutive XR-naltrexone injection. Severity of withdrawal symptoms craving, sleep disturbance, and opioid use will be also measured. If found effective, the combined buprenorphine-XR-naltrexone treatment would be a significant advance in treatment of OUD and would have the potential to expand the population of individuals who benefit from XR-naltrexone.

阿片类药物使用障碍 (OUD) 在美国已达到流行病的程度，超过 250 万人 与阿片类药物过量相关的意外死亡受到影响并急剧增加。维护时用 丁丙诺啡是阿片类药物依赖个体的主要治疗方法，这对某些患者来说是不可接受的， 它也不是普遍有效的，因为大约 50% 接受丁丙诺啡治疗的个体继续使用 非法阿片类药物和/或在治疗的前 6 个月内退出。纳曲酮，一种 mu-阿片受体 拮抗剂作为缓释（XR）制剂给药，为患有以下疾病的患者提供了另一种方法： 先前激动剂试验失败或不适合或不同意激动剂维持治疗的人。纳曲酮是 适合寻求在不使用阿片类药物激动剂的情况下康复的个人，因为它提供了确保禁欲的承诺 并避免目前阿片类药物戒毒后观察到的高复发率。然而，在 目前，只有 50% 的患者能够成功地长期接受 XR-纳曲酮治疗。 时间限制了其保护作用，并可能成为广泛传播和接受的障碍 基于拮抗剂的治疗。在拟议的试验中，我们将测试一种新药理学的有效性 通过将 XR-纳曲酮与 每天服用丁丙诺啡。患者接受 XR-纳曲酮治疗后添加丁丙诺啡不会 产生μ阿片类激动剂作用，但丁丙诺啡的剩余κ拮抗剂作用可能提供 进一步缓解接受治疗的患者持续存在的长期戒断、渴望和情绪障碍 XR-纳曲酮可能导致过早治疗终止和复发。 这项为期五年的研究的目标是测试添加丁丙诺啡是否会提高治疗保留率， 在接下来的 6 个月的治疗中，参与者减少对阿片类药物的渴望并改善情绪 将接受六次 XR-纳曲酮注射和预防复发治疗。我们将进行一项安慰剂对照的 双盲、两个平行组临床试验，采用 1:1 随机化，评估安全性和有效性 丁丙诺啡 4 mg/d，与 XR-纳曲酮同时给药。 OUD 患者寻求治疗 使用纳曲酮的患者将被解毒，在接受 XR-纳曲酮治疗后，他们将被随机分配接受治疗 与丁丙诺啡 (N = 60) 或安慰剂 (N = 60) 联合 5 剂 XR-纳曲酮，每 4 次给药 周，每周治疗。丁丙诺啡（4 毫克/天）或安慰剂将在第一次 XR-纳曲酮治疗后开始 剂量并在最后一次 XR-纳曲酮注射后逐渐减少。主要结果指标将是 成功保留接受六次连续 XR-纳曲酮注射的患者比例。严重程度 还将测量戒断症状、渴望、睡眠障碍和阿片类药物的使用。如果发现有效，则 丁丙诺啡-XR-纳曲酮联合治疗将是 OUD 治疗的重大进步 将有可能扩大受益于 XR-纳曲酮的人群数量。