Deterrents for prescription opioid abuse

 描述（由申请人提供）：处方阿片类药物的滥用正在上升，与滥用有关的死亡人数也在上升。这些趋势突出表明，需要改进战略，减少对儿童的滥用。减少处方阿片类药物滥用的一种方法是通过添加药物来改变药物的配方，如果药物摄入量超过处方剂量，则会引起不良反应。我们实验室最近的工作集中在研究药物对猴子的惩罚作用。我们已经发现，当kappa阿片激动剂salvinorin A与瑞芬太尼（一种类似于吗啡的μ阿片类药物）或可卡因一起自我给药时，会降低这些药物的选择频率。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，可以增强处方阿片类药物作为组合药物的临床有效性。然而，κ激动剂引起显著的厌恶效应（例如，烦躁不安、拟精神病、镇静），这限制了它们的临床可行性。纳呋萘芬是一种非典型κ受体激动剂，不会产生与其他κ受体激动剂相关的烦躁和拟精神病作用。它最近在日本被批准用于治疗尿道炎，这证明了它作为治疗药物的可行性。 人类我们的初步数据表明，当以与惩罚机制一致的方式将两者作为混合物自我给药时，纳呋拉芬可以降低羟考酮的强化作用。当前提案的研究计划是在猴中比较纳呋拉芬作为羟考酮自我给药的惩罚者与其他已建立的药物惩罚者的有效性。我们还将确定纳呋拉芬和其他药物惩罚剂是否调节羟考酮的抗伤害性作用。最后，我们将使用定量观察程序来比较羟考酮-纳呋拉芬混合物的副作用特征与羟考酮与已知产生显著厌恶作用的其他药物惩罚剂混合的效果。我们的中心假设是，羟考酮和所有药物惩罚者的组合将导致自我给药模式，表明滥用倾向降低，但羟考酮的抗伤害性作用将被纳呋萘芬增强，而与与其他药物惩罚者组合产生的作用相比，羟考酮-纳呋萘芬组合产生的副作用将是中度的。总之，这些研究将解决开发处方阿片类药物的滥用威慑制剂（ADF）的临床重要问题，这些制剂可有效减少滥用，而不会影响治疗效果或引起足以阻止适当临床使用的不良反应。我们提出的研究的成功完成将对减少处方阿片类药物滥用的努力产生重大影响，通过建立开发ADF的基础科学模型，并通过测试一种有前途的化合物，为减少处方阿片类药物滥用的新威慑铺平道路。

 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 produce 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.