The potential of oxytocin to reduce opioid abuse liability and pain among older adults

摘要 阿片类药物的使用是美国发病率和死亡率的主要来源，并代表了一个紧迫的公共卫生问题。 危机近年来，50岁以上的成年人出现阿片类药物使用障碍（OUD）， 这是一个令人担忧的重大趋势，而且正在加剧。中年和老年人的OUD增加部分是由于 由于老年人群中疼痛、手术和身体疾病的发生率很高，需要阿片类药物处方 药物，包括羟考酮。羟考酮（在Percocet™和Oxycontin™中）始终是 最广泛用于止痛的药物，但也是最广泛滥用和过量死亡的药物。 尽管有滥用的可能，羟考酮可以非常有效地减少急性疼痛。目前迫切 需要采取干预措施，保持羟考酮的镇痛特性，同时减少其滥用的可能性。一 有前途的辅助治疗选择疼痛管理，这可以同时减少滥用 阿片类药物的潜力，是鼻内施用神经肽催产素。催产素没有 公认的成瘾潜力，同时具有镇痛特性。临床前证据 表明催产素与阿片类药物共同给药可能会降低阿片类药物的强化作用。催产素也 减少人类和动物模型的实验疼痛。此外，动物和人类的证据支持 与成瘾和慢性疼痛相关的共同大脑结构和功能变化， 由催产素调节。催产素的剂量也很好地耐受个人接受 用于OUD的药物（例如，美沙酮）。基于这一证据，我们认为催产素会显著地 减少阿片类药物的滥用倾向并减少实验性疼痛。30名健康的55-75岁志愿者， 一些阿片样物质使用者在口服羟考酮后不久将自我给予48 IU鼻内催产素（或安慰剂 （0、2.5、5.0 mg），在一项双盲、随机化、安慰剂对照、受试者内实验室研究中。主题- 将在5年前和5年内反复评估评定的滥用倾向以及心血管和呼吸反应 给药后2小时。还将收集疼痛测量结果，包括标准化实验性 疼痛电池（即，定量感官测试以及热和机械测试）。这项研究具有巨大的 在检查鼻内催产素作为减少阿片类药物的有前途的药物时对公共卫生影响的可能性 成瘾潜力和产生阿片类药物节省的影响，同时有效地减少疼痛，这可能大大 推进药物治疗领域，开辟新的治疗选择，特别是在中年和老年人中 成年人可能有更高的疼痛风险。该项目的结果也将促进对 潜在的虐待和疼痛之间的联系的行为机制。我们的多学科团队是 非常适合于解决所提出的目标，具有（i）鼻内催产素给药（ii）人 药物给药和滥用药物的滥用倾向测试（iii）阿片样物质给药和实验性疼痛 测试（iv）多模式疼痛评估和（v）老化。

ABSTRACT Opioid use is a major source of morbidity and mortality in the U.S. and represents an urgent public health crisis. In recent years, a surge of adults over the age of 50 have developed opioid use disorder (OUD), a significant and alarming trend that is increasing. Increases in OUD in mid-life and older adults is partially due to high rates of pain, surgery, and physical ailments in aging populations that necessitate opioid prescription medications, including oxycodone. Oxycodone (in Percocet™ and Oxycontin™) is consistently among the medications most widely prescribed for pain, but is also most widely abused and involved in overdose deaths. Despite its potential for abuse, oxycodone can be highly 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 adjunct treatment option for pain management, that could simultaneously reduce the abuse potential of opioids, is intranasal administration of the neuropeptide oxytocin. Oxytocin has no recognized addiction potential, and simultaneously has analgesic properties. Preclinical evidence suggests that oxytocin co-administered with opioids may reduce opioid reinforcing effects. Oxytocin also decreases experimental pain in human and animal models. 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. Doses of oxytocin are also well-tolerated by individuals receiving medications for OUD (e.g., methadone). Based on this evidence, we propose that oxytocin will significantly reduce abuse liability of opioids and reduce experimental pain. Thirty healthy 55-75 year old volunteers with some opioid experience will self-administer 48 IUs of intranasal oxytocin (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 measures will also be collected, including a standardized experimental pain battery (i.e., quantitative sensory testing with thermal and mechanical testing). This study has tremendous potential for public health impact in examining intranasal oxytocin as a promising agent for reducing opioid addictive potential and producing opioid-sparing effects, while effectively reducing pain, which could substantially advance the field of pharmacotherapy and carve out a novel treatment option, specifically in mid-life and older adults who may be at higher risk for pain. Results from this project will also advance scientific understanding of behavioral mechanisms underlying the link between abuse potential and pain. Our multidisciplinary team is well-suited to address the proposed aims with expertise in (i) intranasal oxytocin administration (ii) human drug administration and abuse liability testing of drugs of abuse (iii) opioid administration and experimental pain testing (iv) multi-modal pain assessments and (v) aging.