Licit and Illicit Opioids: Comparative Studies in Humans

合法和非法阿片类药物：人类比较研究

• 批准号: 10224876
• 负责人: Sharon L. Walsh
• 金额: $ 58.66万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224876
• 关键词: Absence of pain sensation; Alcohols; Alprazolam; Autopsy; Benzodiazepines; Carbon Dioxide; Cessation of life; Characteristics; Clinical; Cognitive; Comparative Study; Crossover Design; Data; Decision Making; Dose; Double-Blind Method; Drug Controls; Drug Interactions; Drug Kinetics; Drug usage; Enrollment; Ensure; Epidemic; Fentanyl; Guidelines; Health; Heroin; Hospitals; Human; Individual; Inpatients; Intervention; Knowledge; Laboratories; Laboratory Study; Measures; Medical; Metabolic Pathway; Morbidity - disease rate; Nature; Opioid; Opioid agonist; Outcome; Overdose; Oxycodone; Pain Disorder; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Physicians; Physiological; Placebos; Polypharmacy; Procedures; Property; Provider; Psychomotor Performance; Randomized; Recording of previous events; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Safety; Sedation procedure; Supervision; Surgeon; Surveys; Testing; Time; Toxicology; United States; Work; benzodiazepine abuse; cognitive performance; experience; experimental study; gabapentin; illicit drug use; illicit opioid; indexing; mortality; mortality risk; non-opioid analgesic; off-label use; opioid abuse; opioid misuse; opioid mortality; opioid overdose; opioid use disorder; overdose death; pain model; pain relief; participant safety; prescription opioid; randomized controlled design; recreational drug use; safety outcomes; sedative; statistics; targeted agent; volunteer

ABSTRACT Opioid misuse, including prescription opioids, heroin and fentanyl, is epidemic in the United States and is associated with high morbidity and mortality. The current National Survey on Drug Use and Health estimates that at least 2.6 million people met criteria for an opioid use disorder (including prescription opioids and heroin). Opioid-related overdose deaths continue to climb with nearly 30,000 deaths reported in 2014. Toxicological evidence from post-mortem studies reveals that polypharmacy is a very common finding in opioid-related deaths, and it is especially common to find co-occurring substances with sedative properties. Despite the widespread acknowledgment that non-opioid sedatives may enhance the risk of death from an opioid overdose, few controlled data exist on the pharmacodynamic effects of opioids in combination with these agents and their co-prescription by providers is common. These studies aim to fill this critical knowledge gap by assessing agents with sedative properties that commonly are 1) prescribed with opioids (i.e., benzodiazepines, gabapentin), 2) abused in combination with opioids, and 3) found in combination at autopsy (benzodiazepines, alcohol and gabapentin). Three inpatient human laboratory studies will be conducted that employ rigorous controlled experimental procedures to characterize the pharmacological interaction between oxycodone when taken in combination with either alprazolam (Experiment 1), alcohol (Experiment 2) or gabapentin (Experiment 3). Individuals with appropriate recreational drug use histories, who are otherwise healthy, will be enrolled. An initial dose finding phase will precede each study to ensure subject safety and scientific rigor before proceeding to a robust randomized controlled design. The three studies will employ randomized, placebo-controlled, within-subject, double-blind crossover designs and will be conducted in a controlled hospital setting where appropriate medical supervision is available. Key safety outcomes, including expired CO2 and other respiratory function indices, pharmacodynamic measures related to abuse potential, and cognitive/psychomotor performance will be thoroughly examined over a range of doses for all drugs alone. Pharmacokinetic data (Exp. 1) will also be collected to assess the potential pharmacokinetic interaction as an underlying mechanism of action, and experimental analgesia/algesia data will be collected in Exp. 3 as gabapentin is commonly co-prescribed for pain relief with opioids. The analytic approach will include traditional statistics and modified isobolographic analyses to further elucidate the nature of the pharmacodynamic interactions. The findings from these studies may directly inform prescribing practices and inform clinical guidelines for physicians and other providers, regulatory decision-making, and may provide new information for targeted interventions to reduce the harms of polysubstance prescribing and misuse.

抽象的 阿片类药物滥用，包括处方阿片类药物，海洛因和芬太尼，在美国流行， 与高发病率和死亡率有关。当前关于药物使用和健康估计的全国调查 至少有260万人符合阿片类药物使用障碍的标准（包括处方阿片类药物和海洛因）。 与阿片类药物相关的过量死亡继续攀升，2014年报告了近30,000例死亡。毒理学 验尸研究的证据表明，多药是阿片类药物相关的一个非常普遍的发现 死亡，尤其是找到具有镇静特性的同时发生物质。尽管有 广泛的认可，非阿片类镇静剂可能会增加阿片类药物死亡的风险 用药过量，几乎没有受控数据与阿片类药物的药效动力学作用结合在一起 代理商及其由提供商的共同处方很常见。这些研究旨在填补这个关键的知识差距 通过评估通常为1）阿片类药物处方的镇静特性的药物（即 苯二氮卓类药物，gabapentin），2）与阿片类药物结合使用，以及3）在尸检时结合使用 （苯二氮卓，酒精和加巴喷丁）。将进行三项住院的人类实验室研究 采用严格的受控实验程序来表征 羟考酮与阿普唑仑（实验1），酒精（实验2）或 加巴喷丁（实验3）。具有适当休闲毒品使用历史的个人，否则 健康，将入学。初始剂量查找阶段将在每个研究之前，以确保主题安全和 在进行强大的随机控制设计之前，科学严谨。这三项研究将采用 随机，安慰剂对照，受试者内，双盲跨界设计，将在A中进行 可以在适当的医疗监督的地方进行控制的医院设置。关键安全结果，包括 过期的二氧化碳和其他呼吸功能指数，与滥用潜力有关的药效学指标， 仅所有药物的一系列剂量，都将对认知/心理运动的表现进行彻底检查。 还将收集药代动力学数据（实验1），以评估潜在的药代动力学相互作用 将在EXP中收集基本的作用机理和实验镇痛/质量数据。 3 as 加巴喷丁通常是通过阿片类药物缓解疼痛的共同处方。分析方法将包括传统 统计和修改的同胞分析，以进一步阐明药效学的性质 互动。这些研究的发现可能直接为处方实践提供信息，并为临床提供信息 医师和其他提供者指南，监管决策，并可能为 有针对性的干预措施，以减少多义和滥用的危害。