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.

在美国，阿片类药物使用障碍（OUD）达到了超过250万人的流行比例 无意阿片类药物相关的过量死亡的影响和急剧增加。同时维护 丁丙诺啡是针对阿片类药物依赖性个体的领先治疗方法，这对某些患者是不可接受的， 它也不是普遍有效的，因为用丁丙诺啡治疗的个体中约有50％继续使用 在治疗的前6个月中，非法阿片类药物和/或退出。纳曲酮，一种mu阿片受体 对抗者，作为扩展释放（XR）准备，为患者提供了另一种方法 失败的先前激动剂试验或不适合或不适合动力学的人。纳曲酮是 适合寻求康复的人，而无需阿片类药物激动剂，因为它提供了确保禁欲的承诺 并规避阿片类药物排毒后目前观察到的高复发率。但是，在 目前，只有50％的患者在长期以来成功保留在XR-NELTREXONE治疗中 限制其保护作用的时间，可能是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，我们将测试新药理的有效性 通过将其与XR-NELTREXONE成功保留在XR-NELTREXONE上的患者的比例的方法 丁丙诺啡每天给药。患者接受XR-NELTREXONE后，添加丁丙诺啡将不会 产生MU阿片类动力学作用，但丁丙诺啡的剩余Kappa拮抗作用可能会提供 治疗患者的持久持续的旷日持久的戒断，渴望和情绪障碍的额外缓解 XR-NELTREXONE，可能导致过早的治疗中断和复发。 这项五年研究的目的是测试添加丁丙诺啡是否会改善治疗保留率， 减少阿片类药物的渴望，并改善随后的6个月治疗的情绪 将接受六次XR纳曲酮注射和预防疗法。我们将进行安慰剂对照， 双盲，两次平行手臂临床试验，其随机分配为1：1，以评估安全性和功效 丁丙诺啡4 mg/d与XR-NELTREXONE同时施用。有Oud寻求治疗的人 纳曲酮将被解毒，在接收XR-NELTREXONE之后，它们将被随机进行治疗 与丁丙诺啡（n = 60）或安慰剂（n = 60），另外5剂XR-NELTREXONE，每4剂 几周和每周治疗。丁丙诺啡（4 mg/d）或安慰剂将在第一个XR-NELTREXONE之后开始 在最终的XR纳曲酮注射后，剂量和逐渐减小。主要结果措施将是 成功保留的患者比例连续六次接收XR纳曲酮注射。严重程度 还将测量渴望，睡眠障碍和阿片类药物使用的戒断症状。如果发现有效， 丁丙诺啡联啡酚 - 纳曲酮治疗将是OUD和 将有可能扩大从XR-NELTREXONE中受益的个体人群。