Opioid-Sparing and Pain-Reducing Properties of Syntocinon: A Dose-Effect Determination

摘要 阿片类药物滥用是美国发病率和死亡率的主要来源， 健康危机。自2002年以来，与阿片类药物过量有关的死亡人数增加了四倍多。羟考酮（在 Percocet ™和Oxycontin ™）可靠地属于通常用于疼痛的处方药，但也广泛用于治疗疼痛。 被虐待并导致过量死亡尽管有滥用的可能性，羟考酮可有效减少急性 痛苦迫切需要采取干预措施，保留羟考酮的镇痛特性， 减少其滥用潜力。这是一种有前途的疼痛管理的连续治疗选择， 同时减少阿片类药物滥用倾向的是syntocinon（ 神经肽催产素）。Syntocinon可以减少阿片类药物滥用的可能性，同时具有 镇痛特性。动物模型表明，催产素减少阿片类药物静脉注射自我- 给药并逆转羟考酮条件性位置偏爱。大鼠疼痛模型显示催产素 增强抗伤害感受（疼痛刺激的阻断），并且在人类中，辛托西农施用减少疼痛 实验灵敏度此外，动物和人类的证据支持共享的大脑结构， 与成瘾和慢性疼痛相关的功能变化，可能受催产素调节 局基于现有的文献，我们提出syntocinon将显着减少滥用 阿片类药物的易感性，并通过其对大脑结构，功能和 生物化学30名健康的娱乐性阿片类药物使用者将自我施用48 IU的鼻内合成西农（或 在一项双盲、随机化、安慰剂对照、内- 受试者实验室研究。受试者评定的滥用倾向以及心血管和呼吸反应将 在给药前和给药后5小时重复评估。疼痛和神经生物学测量 也将被收集，包括标准化的实验疼痛电池（即，定量感官测试）和 多模态神经成像电池（即，脑结构、功能和生物化学）。本研究 在检查鼻内催产素作为一种有前途的药物， 减少阿片类药物成瘾的可能性，同时有效地减少疼痛，这可以大大推进 药物治疗和开拓一种新的治疗选择。这项研究还将推进科学认识 潜在的虐待和疼痛之间的联系的神经生物学机制。这项研究也将 通过发展1）多模式评估方面的专业知识，促进PI的职业目标和独立之路 2）神经成像技术，因为它们与成瘾和疼痛有关; 3）深化成瘾的现有专业知识 和人类行为药理学在阿片类药物管理和翻译的背景下; 4）授予和 （5）提高管理和监督能力。这个多学科团队是 特别适合在这些领域指导PI并实现拟议目标。

ABSTRACT Opioid misuse is a major source of morbidity and mortality in the U.S. and represents a pressing public health crisis. Opioid-related overdose deaths have more than quadrupled since 2002. Oxycodone (in Percocet™ and Oxycontin™) is reliably among the medications commonly prescribed for pain, but is also widely abused and involved in overdose deaths. Despite its abuse potential, oxycodone is effective for reducing acute pain. There is an urgent need for interventions that preserve the analgesic properties of oxycodone while curtailing its abuse potential. A promising adjunctive treatment option for pain management, that could simultaneously reduce the abuse liability of opioids, is syntocinon (the intranasal formulation of the neuropeptide oxytocin). Syntocinon may reduce opioid abuse potential, and simultaneously has analgesic properties. Animal models have shown that oxytocin decreases opioid intravenous self- administration and reverses oxycodone conditioned place preference. Rat models of pain show that oxytocin enhances anti-nociception (blocking of painful stimuli), and in humans, syntocinon administration decreases pain sensitivity experimentally. Further, evidence in animals and humans support the shared brain structure and function changes associated with both addiction and chronic pain, which may be modulated by oxytocin administration. Based on the existing literature, we propose that syntocinon will significantly reduce abuse liability of opioids and reduce experimental pain via its effects on brain structure, function and biochemistry. Thirty healthy recreational opioid users will self-administer 48 IUs of intranasal syntocinon (or placebo) shortly after oral oxycodone (0, 2.5, 5.0 mg) in a double-blind, randomized, placebo-controlled, within- subjects laboratory study. Subject-rated abuse liability and cardiovascular and respiratory responses will be assessed before and repeatedly for 5 hours following drug administration. Pain and neurobiological measures will also be collected, including a standardized experimental pain battery (i.e., quantitative sensory testing) and a multi-modal neuroimaging battery (i.e., brain structure, function, and biochemistry). This study has tremendous potential for public health impact in examining intranasal oxytocin as a promising agent for reducing opioid addictive potential, while effectively reducing pain, which could substantially advance the field of pharmacotherapy and carve out a novel treatment option. This study will also advance scientific understanding of neurobiological mechanisms underlying the link between abuse potential and pain. This research will also facilitate the PI’s career goals and path to independence by developing expertise in 1) multi-modal assessments of pain; 2) neuroimaging techniques as they relate to addiction and pain; 3) deepen current expertise in addiction and human behavioral pharmacology in the context of opioid administration and translation; 4) grant and manuscript writing skills; and 5) enhance management and supervision skills. This multidisciplinary team is uniquely suited to mentor the PI in these areas and address the proposed aims.