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

项目摘要 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）， 与过量用药有关，美国的死亡率仍然很高。我们的研究发现， 戒断通常使个体对施用NLX犹豫不决，即使在生死攸关的情况下。同时， 一旦恢复，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来缓解， 他们再次面临过量服用的风险。所提出的R21应用的目标是测试新型吸入剂 药物屈大麻酚（合成四氢大麻酚）的配方，以减少NLX沉淀戒断的严重程度。的 内源性大麻素系统是降低阿片类戒断严重程度的新靶点。临床前研究已经 表明THC减少吗啡依赖啮齿动物中阿片类戒断的迹象。在人类中，口服 屈大麻酚和烟熏大麻已被证明可以降低阿片类药物戒断期间阿片类药物戒断的严重程度。 解毒和稳定。此外，在临床实验室中，大麻素已被证明具有 镇痛剂的作用，可能会提供缓解肌肉和关节疼痛常见的阿片类药物 戒断对于这项随机、双盲、安慰剂对照、住院、临床实验室研究，吸入 屈大麻酚（0.00、0.35、0.70 mg）将与鼻内（IN）NLX（0.0、0.2和0.4 mg）联合给药。这 研究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（30 mg，QID）的稳定天数。在每次测试期间，单次屈大麻酚+ 纳洛酮剂量组合将在测试阶段之间的48小时内进行评估（通过该评估， 路线）。实验室测试阶段将包括改良的纳洛酮激发程序（Wang测试）， 已经用了15年了挑战始于阿片类药物戒断的基线评估， 瞳孔缩小（瞳孔直径; μ-阿片受体激活的指标）和生命体征的测量。 阿片类药物戒断的常见症状将由设盲的研究护士进行评估。每一个症状都是 当观察到症状时，添加编码为“不存在”或“存在”的点。预测试后 在评估之后，医生将给予研究药物组合。对撤出作出评估 每隔10分钟给药一次，直至研究药物给药后50分钟。总退出分数在结束时计算 会议。也可以使用主观和临床阿片类戒断量表。其主要目的是 一个项目是评估屈大麻酚改变NLX诱发戒断严重程度的能力（依赖于 变量（DV）：总戒断评分）。次要目的包括：吸入屈大麻酚联合 与纳洛酮（DV：非戒断相关不良事件和生理参数）， 屈大麻酚对纳洛酮对μ-阿片受体的拮抗作用（DV：瞳孔直径），以及 吸入屈大麻酚（DV：主观药物喜好）。这项概念验证研究可能会发现一种新的， 阿片类药物过量的可耐受的紧急药理学干预。

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.