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

项目摘要 阿片类药物使用障碍(ODS)的发病率已增加到接近流行的程度。 临床研究人员有明确的责任改善获得长期治疗的机会，以便 为了避免复发、反复戒毒入院或过量服药的特征 目前的治疗努力。使用美沙酮或丁丙诺啡维持激动剂时 代表一种有效的长期治疗策略，它可能是许多人不能接受的； 这可能会损害寻求的治疗或阻止开始维持治疗 在戒毒之后。长效注射用纳曲酮(XR-NTX)强效阻断 阿片类药物至少持续4周，现在表明可在戒毒后预防复发。 因此，XR-NTX代表了激动剂治疗的一种有效替代方案，但它显著地 由于与快速和可容忍的活跃用户过渡相关的障碍，未得到充分利用。 事实上，在现有的纳曲酮滴定方案中，约有一半的人未能启动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 整合到为期3天的快速非阿片类药物纳曲酮滴定中，并在亚麻醉状态下输注 对自发戒断、突发性戒断和记忆保持均有明显影响。在……里面 建议调查，我们的目的是评估两种90分钟的亚麻药氯胺酮 输注(1.41 mg/kg)，与对照组(0.04 mg/kg)输注2次相比，改善 快速口服非阿片类药物纳曲酮对阿片依赖者的影响 滴定，然后XR-NTX维护。主要结果将是 参与者启动XR-NTX。次要结果包括禁酒率、3个月的保留率、 和戒断严重程度。调查人员使用亚麻药氯胺酮的丰富经验 阿片类药物依赖的输注和以拮抗剂为基础的治疗支持这一可行性 新的协议。如果成功，这项试验将代表着鉴定小说的努力取得了重大进展 OUD管理的药物疗法，以及解决XR-NTX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。这最终可能有助于扩大获得 为活跃用户提供有效的维护治疗选项，并将戒毒重新定位为 长期治疗的垫脚石。因此，这些数据可能会推进治疗工作 并增加获得更多一线治疗方法的机会。

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.