The Ability of the Inhaled Dronabinol to Reduce the Severity of Naloxone-Precipitated Withdrawal

项目总结 尽管已经向那些有可能目睹阿片类药物的人分发了数千剂纳洛酮(NLX)- 与服药过量相关，美国的死亡率仍然很高。我们的研究发现，对沉淀的恐惧 戒断往往会让个人在使用NLX时犹豫不决，即使在生死攸关的情况下也是如此。同时， 一旦苏醒，不良的戒断症状可能会导致过量的受害者寻求阿片类药物的缓解，使 他们再次面临服药过量的风险。建议的R21应用程序的目标是测试一种新型吸入剂的能力 药物屈诺比诺(合成THC)的配方，以减轻NLX催促戒断的严重程度。这个 内源性大麻素系统是降低阿片类药物戒断严重程度的新靶点。临床前研究已经 证明了THC减少了吗啡依赖啮齿动物的阿片类药物戒断迹象。在人类身上，口服 屈诺比诺和烟熏大麻已被证明可以减轻阿片类药物期间阿片类药物戒断的严重程度 解毒稳定。此外，在临床实验室中，大麻类药物已被证明具有 止痛剂的作用，可以缓解阿片类药物中常见的肌肉和关节疼痛 戒烟。这项随机、双盲、安慰剂对照的住院临床实验室研究，吸入 屈诺比诺(0.00、0.35、0.70毫克)将与鼻腔(IN)NLX(0.0、0.2和0.4毫克)联合使用。这 调查将招募患有阿片类药物使用障碍的健康参与者(N=16)。测试将在5-7之后开始 口服吗啡稳定天数(30 mg，qid)。在每一次测试过程中，一个单独的Dronabinol 纳洛酮剂量组合将在两次测试之间的48小时内进行评估(通过此方法获得5个半衰期 路线)。实验室测试将包括修改后的纳洛酮挑战程序(Wang测试)，该程序 我们部门已经使用了15年以上。挑战始于对阿片类药物戒断的基线评估， 测量瞳孔缩小(瞳孔直径；阿片受体激活的指标)和生命体征。 阿片类药物戒断的常见症状将由盲人研究护士评估。每个症状都是 当观察到症状时，添加编码为“不在”或“存在”的点数。后续预试 评估后，医生将管理研究药物组合。对撤军进行评估 在研究药物后，间隔10分钟至50分钟。总提款分数在#年末计算 那次会议。主观和临床阿片类药物戒断量表也被使用。这样做的主要目的是 该项目是评估屈诺比诺改变NLX催促戒断(依赖)的严重程度的能力 变量(DV)：总戒断分数)。次要目标包括：吸入联合用药的安全性 使用纳洛酮(DV：非戒断相关不良事件和生理参数)时， 屈诺比诺对纳洛酮对阿片受体的拮抗作用(DV：瞳孔直径)和滥用潜能 吸入屈诺比诺(DV：主观吸食毒品)。这项概念验证研究可能会确定一部小说，更多 阿片类药物过量可耐受的紧急药物干预。

PROJECT SUMMARY Despite having distributed thousands of doses of naloxone (NLX) to those at risk of witnessing an opioid- related overdose, deaths in the U.S. remain high. Our research has found that the fear of precipitating withdrawal often makes individuals hesitant to administer NLX, even in life-or-death situations. Meanwhile, once revived, the adverse withdrawal symptoms may lead the overdose victim to seek opioids for relief, putting them again at risk of overdose. The goal of the proposed R21 application is to test the ability of a novel inhaled formulation of the drug dronabinol (synthetic THC), to reduce the severity of NLX-precipitated withdrawal. The endocannabinoid system is a novel target for reducing opioid withdrawal severity. Preclinical studies have demonstrated that THC decreases signs of opioid withdrawal in morphine-dependent rodents. In humans, oral dronabinol and smoked cannabis have been shown to reduce the severity of opioid withdrawal during opioid detoxification and stabilization. Additionally, in the clinical laboratory, cannabinoids have been shown to have analgesics effects that may provide relief from the muscle and joint pain commonly seen during opioid withdrawal. For this randomized, double-blind, placebo-controlled, inpatient, clinical laboratory study, inhaled dronabinol (.00, .35, .70 mg) will be combined with intranasal (IN) NLX (0.0, 0.2 and 0.4 mg). This investigation will recruit healthy participants with Opioid Use Disorder (N=16). Testing will begin following 5-7 days of stabilization on oral morphine (30 mg, QID). During each testing session, a single dronabinol + naloxone dose combination will be assessed with 48 hours between testing sessions (> 5 half-lives via this route). Laboratory testing sessions will consist of a modified naloxone challenge procedure (Wang Test) that our division has used for over 15 years. The challenge begins with baseline assessment of opioid withdrawal, measurements of miosis (pupil diameter; an indicator of mu-opioid receptor activation), and vital signs. Common symptoms of opioid withdrawal will be assessed by a blinded research nurse. Each symptom is coded as either “absent” or “present” points added when a symptom is observed. Following pre-test assessments, the physician will administer the study drug combination. Assessments of withdrawal are made at 10-minute intervals up to 50 minutes after study drug. The total withdrawal score is calculated at the end of the session. The Subjective and Clinical Opioid Withdrawal Scales also be utilized. The primary aim of this project is to assess the ability of dronabinol to alter the severity of NLX-precipitated withdrawal (dependent variable (DV): total withdrawal score). Secondary aims include: the safety of inhaled dronabinol in combination with naloxone (DV: non-withdrawal-related adverse events & physiological parameters), the effects of dronabinol on naloxone’s antagonism of the µ-opioid receptor (DV: pupil diameter), and the abuse potential of inhaled dronabinol (DV: subjective drug liking). This proof-of-concept study may identify a novel, more tolerable, emergency pharmacological intervention for opioid overdose.