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

吸入屈大麻酚减轻纳洛酮突然戒断严重程度的能力

基本信息

批准号：
10267744
负责人：
JERMAINE D JONES
金额：
$ 19.89万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10267744
关键词：
Accident and Emergency department Address Administrator Adverse effects Adverse event Aerosols Aggressive behavior Agonist Analgesics Anger Arthralgia Attenuated Awareness Blinded Blood Pressure Caliber Cannabinoids Cannabis Cessation of life Clinical Code Data Devices Dose Double-Blind Method Dronabinol Drug Combinations Drug Formulations Drug user Educational Curriculum Effectiveness Emergency Situation Epidemic Event Family member Fright Goals Harm Reduction Heart Rate Hour Human Individual Inhalation Inpatients Intervention Investigation Laboratories Laboratory Study Lead Life Manufacturer Name Marijuana Marinol Measurement Measures Medical Monitor Morphine Myalgia Naloxone Nausea Nursing Research Opioid Opioid Antagonist Oral Oral Administration Outcome Measure Overdose Overdose reversal Participant Patient Self-Report Patients Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physicians Physiological Placebo Control Placebos Procedures Proxy Pulse Oximetry Pupil Randomized Reaction Receptor Activation Research Research Personnel Risk Rodent Route Safety Severities Smoke Statutes and Laws Symptoms Testing Tetrahydrocannabinol Therapeutic Treatment Efficacy Ventilatory Depression Visual Withdrawal Withdrawal Symptom abuse liability analog antagonist cannabinoid receptor combat common symptom endogenous cannabinoid system human subject improved mu opioid receptors novel opioid abuse opioid overdose opioid use disorder opioid user opioid withdrawal overdose death overdose education overdose risk preclinical study prevent programs recruit response risk minimization tool

项目摘要

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.

项目摘要尽管已经向有阿片类药物的风险分配了数千剂纳洛酮（NLX）相关服用过量，美国的死亡仍然很高。我们的研究发现，害怕促成戒断通常会使个人犹豫不决，即使在生命或死亡情况下也是如此。同时，一旦复活，不良戒断症状可能会导致过量受害者寻求阿片类药物以救济他们再次有服用过量的风险。提议的R21应用的目的是测试新颖的继承能力 Dronabinol（合成THC）的形成，以减少NLX预测的戒断的严重程度。这内源性大麻素系统是降低阿片类药物戒断严重程度的新目标。临床前研究已有证明THC会降低吗啡依赖性啮齿动物中阿片类药物戒断的迹象。在人类中已证明德罗纳比醇和熏制大麻可以减少蛋白药物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药的影响可能会缓解阿片类药物期间常见的肌肉和关节疼痛提取。对于这种随机，双盲，安慰剂对照，住院，临床实验室研究，遗传 Dronabinol（.00，.35，.70 mg）将与鼻内（IN）NLX（0.0、0.2和0.4 mg）结合使用。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）。测试将开始遵循5-7 口服吗啡（30 mg，Qid）的稳定天数。在每个测试中，一个Dronabinol + 纳洛酮剂量组合将在测试之间进行48小时的评估（> 5个半衰期通过此路线）。实验室测试课程将包括修改的纳洛酮挑战程序（WANG测试），该程序将我们的部门已经使用了15年以上。挑战始于对阿片类药物提取的基线评估， MIOSIS的测量值（瞳孔直径； Mu-Apioid受体激活的指标）和生命体征。阿片类药物戒断的常见象征将由盲目的研究护士评估。每个符号是观察到症状时，编码为“不存在”或“现在”点。遵循预测试评估，实物将管理研究药物组合。进行戒断的评估学习药物后最多50分钟，以10分钟的间隔。总撤回分数是在结束时计算的会话。也使用主观和临床阿片类药物戒断量表。主要目的项目是为了评估Dronabinol改变NLX预测戒断的严重程度（依赖）的能力变量（DV）：总撤回分数）。次要目的包括：联合遗传的dronabinol的安全性与纳洛酮（DV：非差异相关的不良事件和物理参数），效果纳洛酮在µ-阿片受体（DV：学生直径）的拮抗作用上的dronabinol，以及滥用潜力吸入的Dronabinol（DV：主观药物喜欢）。这项概念证明的研究可能会确定一部小说，更多阿片类药物过量的可耐受性，紧急药物干预。