Licit and Illicit Opioids: Comparative Studies in Humans

摘要 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相关。目前的全国毒品使用和健康调查估计， 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）。 与阿片类药物有关的过量死亡继续攀升，2014年报告了近30，000例死亡。毒理学 尸检研究的证据表明，多药治疗是阿片类药物相关的一个非常常见的发现， 死亡，特别是常见的是找到共同出现的物质与镇静性能。尽管 广泛承认非阿片类镇静剂可能会增加阿片类药物的死亡风险 过量，很少有关于阿片类药物与这些药物联合使用的药效学作用的对照数据 代理人和他们的共同处方的供应商是常见的。这些研究旨在填补这一关键的知识空白 通过评估通常与阿片类药物一起开出的具有镇静性质的药剂（即， 苯二氮卓类药物、加巴喷丁），2）与阿片类药物合用，3）尸检时发现合用 （苯二氮卓类、酒精和加巴喷丁）。将进行三项住院患者人体实验室研究， 采用严格的对照实验程序来表征 羟考酮与阿普唑仑（实验1）、酒精（实验2）或 加巴喷丁（实验3）。有适当的娱乐性药物使用史的个人，否则 健康，将被录取。在每项研究之前将有一个初始剂量探索阶段，以确保受试者的安全性， 在进行稳健的随机对照设计之前，这三项研究将采用 随机化、安慰剂对照、受试者内、双盲交叉设计，将在 控制的医院环境，适当的医疗监督可用。关键安全性结局，包括 呼出的CO2和其他呼吸功能指标，与滥用可能性相关的药效学指标， 和认知/精神表现将在所有药物单独的剂量范围内进行彻底检查。 药代动力学数据（失效日期）1)还将收集用于评估潜在的药代动力学相互作用， 潜在的作用机制和实验镇痛/痛觉数据将在实验中收集。3作为 加巴喷丁通常与阿片类药物共同用于疼痛缓解。分析方法将包括传统的 统计学和改良的等效线分析，以进一步阐明药效学的性质 交互.这些研究的结果可以直接为处方实践提供信息，并为临床提供信息。 医生和其他提供者的指南，监管决策，并可能提供新的信息 有针对性的干预措施，以减少多物质处方和滥用的危害。

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.