Deterrents for prescription opioid abuse

处方阿片类药物滥用的威慑因素

• 批准号: 9139882
• 负责人: Kevin B. Freeman
• 金额: $ 40.73万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139882
• 关键词: Absence of pain sensation; Address; Adverse effects; Agonist; Analgesics; Basic Science; Behavior; Bioavailable; Clinical; Clinical effectiveness; Cocaine; Data; Dependence; Development; Dose; Drug Combinations; Effectiveness; Exhibits; Formulation; Frequencies; Goals; Hallucinations; Health; Histamine; Human; Incidence; Intake; Japan; Laboratories; Macaca mulatta; Measures; Modeling; Monkeys; Morphine; Motor; Nociception; Opioid; Outcome; Oxycodone; Pain Measurement; Pain management; Pattern; Pharmaceutical Preparations; Procedures; Pruritus; Public Health; Punishment; Reinforcement Schedule; Reporting; Research; Role; Sedation procedure; Self Administration; Self-Administered; Series; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Time; United States; Work; base; clinically significant; combinatorial; compare effectiveness; cost effective; drug development; dysphoria; improved; interest; mortality; mu opioid receptors; novel; prescription opioid; prescription opioid abuse; public health priorities; reinforcer; remifentanil; response; salvinorin A; trend

 DESCRIPTION (provided by applicant): Abuse of prescription opioids is on the rise, as are fatalities related to their abuse. These trends highlight the need for improved strategies for decreasing their abuse. One approach to reducing prescription opioid abuse is to alter the formulation of the medication by adding agents that cause untoward effects if drug intake exceeds the prescribed dose. Recent work in our laboratory has focused on the study of drugs as punishers in monkeys. We have found that the kappa opioid agonist, salvinorin A, when self-administered contingently with remifentanil (a mu opioid analogous to morphine) or cocaine, reduces the frequency of choice for these reinforcers. The prospect that kappa agonists can function as punishers is significant because they also produce analgesic effects that could enhance the clinical effectiveness of prescription opioids as combinatorial agents. However, kappa agonists cause significant aversive effects (e.g., dysphoria, psychotomimesis, sedation) that limit their clinical feasibility. Nalfurafine is an atypical kappa agonist that does not produe the dysphoric and psychotomimetic effects associated with other kappa agonists. It was recently approved for treatment of pruritis in Japan, which demonstrates its feasibility as a therapeutic in humans. Our preliminary data suggest that nalfurafine can reduce the reinforcing effects of oxycodone when the two are self- administered as mixtures in a manner that is consistent with a punishment mechanism. The research plan for the current proposal is to compare the effectiveness of nalfurafine as a punisher of oxycodone self- administration to other established drug punishers in monkeys. We will also determine if nalfurafine and other drug punishers modulate the anti-nociceptive effects of oxycodone. Lastly, we will use quantitative observational procedures to compare the side effect profiles of oxycodone-nalfurafine mixtures to the effects of oxycodone mixed with other drug punishers known to produce significant aversive effects. Our central hypothesis is that combinations of oxycodone and all drug punishers will result in self-administration patterns indicative of reduced abuse liability, but tht the anti-nociceptive effects of oxycodone will be augmented by nalfurafine while the side effects produced by the oxycodone-nalfurafine combinations will be moderate compared to the effects produced by combinations with other drug punishers. Together, these studies will address the clinically-significant problem of developing abuse-deterrent formulations (ADF) for prescription opioids that are effective at reducing abuse without compromising therapeutic effects or causing untoward effects sufficient to discourage appropriate clinical use. Successful completion of our proposed studies will make a significant impact on efforts to decrease prescription opioid abuse by establishing a basic science model for developing ADFs and by testing a promising compound that could pave the way for a new class of deterrents for reducing the abuse liability of prescription opioids.

 描述（由应用程序提供）：处方阿片类药物的滥用以及与滥用有关的死亡人数也在增加。这些趋势凸显了需要改善策略减少滥用的策略的必要性。减少处方阿片类药物滥用的一种方法是通过添加药物摄入量超过规定剂量的剂量来改变药物的公式。我们实验室的最新工作集中在将药物作为猴子的惩罚者的研究。我们发现，当与雷利芬太尼（一种类似于吗啡类似的MU阿片类药物）自我管理时，kappa阿片类动物萨尔维诺蛋白A或可卡因会降低这些加固力的选择频率。 Kappa激动剂可以充当惩罚者的前景很重要，因为它们还产生镇痛作用，可以增强处方阿片类药物作为组合剂的临床有效性。然而，卡帕激动剂会引起限制其临床可行性的显着厌恶作用（例如吞咽困难，精神症，镇静）。 Nalfurafine是一种非典型的Kappa激动剂，不会引起与其他Kappa激动剂相关的烦躁不安和心理效果。它最近被批准用于日本的瘙痒症治疗，这表明其可行性是一种治疗性 人类。我们的初步数据表明，当两者以与惩罚机制一致的方式自我管理为混合时，纳尔富丁可以减少氧气的增强作用。当前提案的研究计划是比较纳尔列芬作为氧气CODONE自我管理的惩罚者对猴子中其他既定的药物惩罚者的有效性。我们还将确定Nalfurafine和其他药物惩罚者是否调节氧气的抗吸引力作用。最后，我们将使用定量观察程序比较氧气氧型 - 纳尔福丁混合物的副作用曲线与氧气蛋白与其他已知产生明显厌恶作用的药物惩罚剂混合的效果。我们的核心假设是，氧气和所有药物惩罚者的组合将导致自我给药模式，表明滥用责任降低，但是氧气CODONE的抗吸引点效应将被纳拉列芬增强，而副作用会与纳拉富集的副作用相比，将副作用与其他效果相比。这些研究将共同​​解决针对处方阿片类药物开发滥用滥用公式（ADF）的临床意义问题，这些问题可有效减少滥用，而不会损害治疗作用或引起足以抑制适当临床使用的无效效应。通过建立开发ADF的基本科学模型并测试有希望的化合物，可以为减少新的确定降低处方OIDS的滥用责任铺平道路，从而成功完成我们提出的研究，将对减少处方OID滥用的努力产生重大影响。