Deterrents for prescription opioid abuse

处方阿片类药物滥用的威慑因素

• 批准号: 9029806
• 负责人: Kevin B. Freeman
• 金额: $ 45.96万
• 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/9029806
• 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; Drug Formulations; Effectiveness; Exhibits; Frequencies; Goals; Hallucinations; Histamine; Human; Incidence; Intake; Japan; Laboratories; Macaca mulatta; Measures; Modeling; Monkeys; Morphine; Motor; Nociception; Opioid; Outcome; Oxycodone; Pain; Pain Measurement; Pain management; Pattern; Pharmaceutical Preparations; Procedures; Pruritus; Public Health; Punishment; Reinforcement Schedule; Relative (related person); 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; public health relevance; 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（由申请人提供）：处方阿片类药物的滥用正在增加，与其滥用相关的死亡人数也在增加。这些趋势凸显了减少处方阿片类药物滥用的改进策略的必要性。我们实验室最近的工作重点是研究在猴子身上使用卡帕阿片受体激动剂萨尔维诺林 A 的药物。自行服用瑞芬太尼（一种类似于吗啡的μ阿片类药物）或可卡因，可以减少选择这些强化剂的频率。κ激动剂可以作为惩罚剂发挥作用的前景是重要的，因为它们还产生镇痛作用，可以增强临床效果。处方阿片类药物作为组合药物。然而，κ激动剂会引起显着的厌恶作用（例如烦躁、拟精神病、镇静），从而限制了其临床可行性。纳芙拉芬是一种非典型 kappa 激动剂，不会产生与其他 kappa 激动剂相关的烦躁和拟精神病作用，最近在日本被批准用于治疗瘙痒症，这证明了其作为治疗方法的可行性。 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给药时，纳芙拉芬可以降低羟考酮的增强作用。当前提案的研究计划是比较纳芙拉芬与羟考酮的有效性。我们还将确定纳芙拉芬和其他药物惩罚剂是否调节羟考酮自我给药的抗伤害作用。最后，我们将使用定量观察程序来比较羟考酮-纳芙拉芬混合物的副作用与羟考酮与已知会产生显着厌恶作用的其他药物惩罚剂混合的效果。将导致表明滥用倾向减少的自我给药模式，但羟考酮的抗伤害作用将增强与纳芙拉芬组合产生的副作用相比与其他药物惩罚剂组合产生的副作用是温和的，这些研究将共同​​解决开发处方阿片类药物的防滥用制剂 (ADF) 的临床重大问题。有效减少滥用，同时又不影响治疗效果或造成足以阻止适当临床使用的不良影响，成功完成我们拟议的研究将通过建立基础科学对减少处方阿片类药物滥用的努力产生重大影响。开发 ADF 的模型，并测试一种有前途的化合物，该化合物可以为减少处方阿片类药物滥用倾向的新型威慑药物铺平道路。