Glutamatergic Modulation to Facilitate Naltrexone Initiation: A Randomized, Controlled Trial

项目摘要 阿片类药物使用障碍（OUD）的发病率已接近流行病的比例。 临床研究人员有明确的责任改善长期治疗的可及性， 以避免复吸、反复戒毒或吸毒过量的模式， 目前的治疗努力。当用美沙酮或丁丙诺啡维持激动剂时 是一种有效的长期治疗策略，但可能对许多人来说是不可接受的; 这可能危及寻求治疗或阻止维持治疗的开始 解毒后。长效注射用纳洛酮（XR-NTX）可强效阻断 阿片类药物治疗至少4周，现在用于戒毒后预防复吸。 因此，XR-NTX代表了激动剂治疗的有效替代方案，但其显著地降低了药物的耐受性。 由于与快速和可容忍地转换活跃用户相关联的障碍， 事实上，大约一半的人未能在现有的纳洛酮滴定方案中启动XR-NTX。 我们的数据表明，N-甲基-D-天冬氨酸受体拮抗剂氯胺酮可能是可行的， 整合到3天快速非阿片类药物为基础的纳洛酮滴定，亚麻醉剂输注 对自发和突然的戒断以及对保持产生明显的影响。在 在拟议的调查中，我们的目的是评估两个90分钟的亚麻醉氯胺酮 输注（1.41 mg/kg）与2次输注对照咪达唑仑（0.04 mg/kg）相比， 阿片类药物依赖者接受快速非阿片类药物口服纳洛酮治疗的结果 滴定，然后进行XR-NTX维持。主要结果将是 参与者启动XR-NTX。次要结果包括戒烟率，3个月的保留率， 和戒断严重性。研究人员对亚麻醉剂氯胺酮的丰富经验 输注和以拮抗剂为基础的阿片类药物依赖治疗支持这一可行性， 新颖的方案。如果成功，这项试验将代表着在识别新的 用于OUD管理的药物治疗，以及用于解决XR-NTX中的关键障碍 利用率因此，它可能为类似化合物的研究铺平道路，如氯胺酮- 就像目前正在研发的抗抑郁药一样。这可能最终有助于扩大获得 为活跃吸毒者提供有效的维持治疗选择，并将戒毒重新定位为 长期治疗的垫脚石。因此，这些数据可能会推动治疗工作， OUD，并增加获得更多一线治疗的机会。

Project Summary The incidence of opioid use disorders (OUDs) has increased to near-epidemic proportions. Clinical researchers have a clear responsibility to improve access to long-term treatment in order to avoid the pattern of relapse, recurrent detoxification admissions, or overdose characteristic of present treatment efforts. While agonist maintenance with methadone or buprenorphine represents an effective long-term treatment strategy, it may be unacceptable to many individuals; this may compromise treatment seeking or prevent the initiation of maintenance treatment following detoxification. Long-acting injectable naltrexone (XR-NTX) robustly blocks the effects of opioids for at least 4 weeks and is now indicated for relapse prevention following detoxification. XR-NTX therefore represents an effective alternative to agonist treatment, but it is significantly underutilized due to hurdles associated with rapidly and tolerably transitioning active users. Indeed, about half of individuals fail to initiate XR-NTX in existing naltrexone titration protocols. Our data suggest that the N-methyl-D-aspartate receptor antagonist ketamine may be feasibly integrated into a 3-day rapid non-opioid based naltrexone titration, with sub-anesthetic infusions exerting apparent effects on spontaneous and precipitated withdrawal as well as on retention. In the proposed investigation, we aim to evaluate whether two 90-minute sub-anesthetic ketamine infusions (1.41 mg/kg), compared to 2 infusions of the control midazolam (0.04 mg/kg), improve outcomes in opioid dependent individuals engaged in a rapid non-opioid based oral naltrexone titration, followed by XR-NTX maintenance. The primary outcome will be the proportion of participants to initiate XR-NTX. Secondary outcomes include abstinence rates, 3-month retention, and withdrawal severity. The investigators' extensive experience with sub-anesthetic ketamine infusions and with antagonist-based treatment of opioid dependence supports the feasibility of this novel protocol. If successful, this trial would represent a major advance in efforts to identify novel pharmacotherapies for OUD management, and for addressing a critical hurdle in XR-NTX utilization. Thus it may pave the way for research into analogous compounds, such as ketamine- like antidepressants currently in development. This may ultimately serve to broaden access to effective maintenance treatment options for active users, and to reposition detoxification as a stepping-stone to long-term treatment. These data may therefore advance treatment efforts for OUDs and increase access to a larger repertoire of first-line treatments.