Deterrents for prescription opioid abuse

 描述(申请人提供)：处方类阿片类药物的滥用呈上升趋势，与其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，以减少对儿童的滥用。减少处方阿片类药物滥用的一种方法是通过添加如果药物摄入量超过规定剂量而导致不良反应的药物来改变药物的配方。我们实验室最近的工作重点是研究药物对猴子的惩罚作用。我们发现，kappa阿片激动剂salvinorin A，当自己与瑞芬太尼(一种类似于吗啡的u阿片类药物)或可卡因紧急给药时，减少了这些增强剂的选择频率。Kappa激动剂可以作为惩罚者的前景是重要的，因为它们也产生止痛作用，可以提高处方阿片类药物作为组合药物的临床效果。然而，kappa激动剂会引起显著的不良反应(如烦躁不安、精神分裂、镇静)，从而限制了其临床可行性。纳呋芬是一种非典型的kappa激动剂，不会产生与其他kappa激动剂相关的烦躁不安和拟精神分裂的效果。它最近在日本被批准用于治疗瘙痒，这证明了它作为一种治疗 人类。我们的初步数据表明，当两者以符合惩罚机制的方式自我给药时，呋喃西芬可以减少羟考酮的增强作用。目前这项提案的研究计划是将纳呋芬作为羟考酮自我给药惩罚剂的有效性与其他已有的猴子药物惩罚剂进行比较。我们还将确定萘呋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-呋喃呋喃合剂的副作用与羟考酮与其他已知会产生显著不良反应的药物惩罚剂的效果。我们的中心假设是，羟考酮和所有药物惩罚剂的组合将导致自我给药模式，表明滥用责任减少，但羟考酮的抗伤害效应将被呋喃芬增强，而与与其他药物惩罚者组合产生的副作用相比，羟考酮-呋喃呋喃芬组合产生的副作用将是温和的。这些研究将共同解决临床上的重大问题，即开发处方阿片类药物的滥用威慑配方(ADF)，这些配方有效地减少滥用，而不影响治疗效果或引起足以阻止适当临床使用的不良反应。我们拟议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，方法是建立开发ADF的基础科学模型，并测试一种有前景的化合物，该化合物可能为减少处方阿片类药物滥用责任的新型威慑物质铺平道路。

 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.