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

阿片类药物使用障碍（OUD）在美国达到流行病的比例，超过250万人 受影响的非故意阿片类药物相关过量死亡人数急剧增加。在维护时， 丁丙诺啡是阿片类药物依赖个体的主要治疗方法，但这对某些患者来说是不可接受的， 也不是普遍有效的，因为大约50%的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。纳洛酮，一种μ阿片受体 拮抗剂，作为缓释（XR）制剂，提供了一种替代方法的患者， 既往激动剂试验失败或不适合或不同意激动剂维持治疗的患者。纳曲酮是 适合那些在没有阿片类激动剂的情况下寻求康复的人，因为它提供了确保禁欲的承诺 并避免目前观察到的阿片类药物戒毒后的高复吸率。但 目前，只有50%的患者成功地保留了长时间的XR-纳洛酮治疗， 时间限制了它的保护作用，并可能成为广泛传播和接受的障碍。 拮抗剂治疗。在拟议的试验中，我们将测试一种新的药物的有效性， 一种通过将XR-纳洛酮与以下药物联合使用来增加成功保留XR-纳洛酮患者比例的方法 每天服用丁丙诺啡。在患者接受XR-纳洛酮后添加丁丙诺啡不会 产生μ阿片激动剂作用，但丁丙诺啡的剩余κ拮抗剂作用可提供 接受治疗的患者中持续存在的长期戒断、渴望和情绪障碍得到额外缓解 XR-纳洛酮，可能导致过早停药和复发。 这项为期五年的研究的目标是测试添加丁丙诺啡是否会改善治疗保留， 减少阿片类药物的渴望，并在随后的6个月治疗期间改善情绪， 将接受六次XR-纳洛酮注射和复发预防治疗。我们将进行一个安慰剂对照， 双盲、两个平行组临床试验，1：1随机化，以评价 丁丙诺啡4 mg/d与XR-纳洛酮同时给药。寻求治疗的OUD患者 在接受XR-纳洛酮后，他们将被随机分配到治疗组 与丁丙诺啡（N = 60）或安慰剂（N = 60）联合使用5次额外剂量的XR-纳洛酮，每4 周，每周治疗。丁丙诺啡（4 mg/d）或安慰剂将在首次XR-纳洛酮给药后开始给药 在最后一次注射XR-纳洛酮后逐渐减少。主要结局指标将是 成功保留接受连续6次XR-纳洛酮注射的患者比例。严重程度 还将测量戒断症状渴望、睡眠障碍和阿片类药物使用。如果发现有效， 联合丁丙诺啡-XR-纳洛酮治疗将是治疗OUD的显著进步， 将有可能扩大受益于XR-纳曲酮的人群。

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.