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.

项目概要尽管已经向那些有目睹阿片类药物风险的人分发了数千剂纳洛酮（NLX），我们的研究发现，与药物过量相关的死亡人数仍然很高。戒断常常使个人犹豫是否要服用 NLX，即使是在生死攸关的情况下。一旦苏醒，不良的戒断症状可能会导致服药过量的受害者寻求阿片类药物来缓解症状，他们再次面临服用过量的风险。拟议的 R21 应用的目标是测试新型吸入剂的能力。药物屈大麻酚（合成 THC）的配方，以减轻 NLX 诱发戒断的严重程度。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。证明 THC 可减少人类吗啡依赖性啮齿动物的阿片戒断症状，口服。屈大麻酚和吸食大麻已被证明可以减轻阿片类药物戒断期间的严重程度此外，在临床实验室中，大麻素已被证明具有解毒和稳定作用。镇痛作用可以缓解阿片类药物使用期间常见的肌肉和关节疼痛对于这项随机、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）联合使用。调查将招募患有阿片类药物使用障碍的健康参与者 (N=16) 测试将于 5-7 日后开始。口服吗啡（30 mg，QID）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两次测试之间的 48 小时内进行评估（> 5 个半衰期通过此实验室测试课程将包括修改后的纳洛酮挑战程序（Wang 测试）。我们的部门已使用阿片类药物戒断的基线评估超过 15 年。瞳孔缩小（瞳孔直径；mu-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盲法研究护士进行评估。预测试后观察到症状时添加的编码为“不存在”或“存在”的点。评估后，医生将给予研究药物组合并进行戒断评估。研究药物后每隔 10 分钟至 50 分钟计算总戒断评分。会议的主要目的还包括主观和临床阿片类药物戒断量表。该项目旨在评估屈大麻酚改变 NLX 诱发戒断严重程度的能力（取决于变量（DV）：总戒断评分）次要目标包括：吸入屈大麻酚组合的安全性。纳洛酮（DV：非戒断相关不良事件和生理参数）的影响屈大麻酚对纳洛酮对 µ-阿片受体（DV：瞳孔直径）的拮抗作用以及滥用的可能性吸入屈大麻酚（DV：主观药物喜好）这项概念验证研究可能会发现一种新颖的、更多的药物。针对阿片类药物过量的可耐受的紧急药物干预。