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

阿片类药物使用障碍(OUD)在美国达到流行水平，超过250万人 受影响的与阿片类药物有关的意外过量死亡人数急剧增加。在维护时使用 丁丙诺啡是阿片类药物依赖者的主要治疗药物，一些患者无法接受， 它也不是普遍有效的，因为大约50%接受丁丙诺啡治疗的患者继续使用 非法阿片类药物和/或在治疗的前6个月戒除。Mu-阿片受体--纳曲酮 作为缓释(XR)制剂给予拮抗剂，为患有以下疾病的患者提供了一种替代方法 先前的激动剂试验失败或那些不适合或不同意激动剂维持的人。纳曲酮是 适合在没有阿片类激动剂的情况下寻求康复的个人，因为它提供了确保戒断的前景 并绕过目前在阿片类药物戒毒后观察到的高复发率。然而，在 目前，只有50%的患者在长期服用XR-纳曲酮后成功保留 时间限制了它的保护作用，并可能成为广泛传播和接受 以拮抗剂为主的治疗。在拟议的试验中，我们将测试一种新的药理作用 联合应用XR-纳曲酮提高维持率的探讨 丁丙诺啡每日给药。在患者接受XR-纳曲酮治疗后加用丁丙诺啡不会 产生u阿片类激动剂作用，但丁丙诺啡的剩余kappa拮抗剂作用可能提供 对长期戒断、渴求和持续存在的情绪障碍的额外缓解 XR-纳曲酮，并可能导致过早治疗、停止治疗和复发。 这项为期五年的研究的目标是测试加入丁丙诺啡是否会改善治疗保留率， 减少阿片类药物的渴望，并在随后的6个月治疗期间改善情绪 将接受六次XR-纳曲酮注射和预防复发治疗。我们将进行安慰剂对照， 1：1随机双盲双平行对照临床试验 丁丙诺啡4 mg/d与XR-纳曲酮同时使用。患有自闭症并寻求治疗的个人 使用纳曲酮的患者将被戒毒，在接受XR-纳曲酮治疗后，他们将被随机接受治疗 丁丙诺啡(N=60)或安慰剂(N=60)加5剂XR-纳曲酮，每4次 几周，每周一次的治疗。丁丙诺啡(4 mg/d)或安慰剂将在第一次XR-纳曲酮后开始使用 在最后一次注射XR-纳曲酮后逐渐减少。主要结果衡量标准将是 成功保留接受连续6次XR-纳曲酮注射的患者比例。严重程度 戒断症状、渴求、睡眠障碍和阿片类药物的使用也将被测量。如果被发现有效， 丁丙诺啡-XR-纳曲酮联合治疗将是OUD和UD治疗的重大进展 将有可能扩大受益于XR-纳曲酮的个人人口。

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.