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，并代表着紧急的公共卫生 危机。近年来，50岁以上的成年人患上了阿片使用障碍(OUD)，这是一种 正在增加的重大和令人震惊的趋势。中年和老年人的OUD增加部分是 由于老年人口中疼痛、手术和身体疾病的高比率，需要阿片类药物处方 药物，包括羟考酮。羟考酮(在帕可西特™和奥施康定™中)一直是 最广泛用于止痛的药物，但也是被滥用最广泛的药物，并涉及过量死亡。 尽管羟考酮有可能被滥用，但它在减轻急性疼痛方面可以非常有效。有一件急事 需要采取干预措施，保留羟考酮的止痛特性，同时减少其滥用潜力。一个 前景看好的疼痛管理辅助治疗选项，可以同时减少虐待 潜在的阿片类药物是鼻腔内给药的神经肽催产素。催产素没有 公认的成瘾潜力，同时具有止痛特性。临床前证据 提示催产素与阿片类药物联合应用可能会减少阿片类药物的强化作用。催产素也 减少人类和动物模型中的实验性疼痛。此外，在动物和人类身上的证据支持 共同的大脑结构和功能变化与成瘾和慢性疼痛有关，这可能是 受催产素的影响。服用催产素的患者对催产素的剂量也有良好的耐受性 OUD的药物(如美沙酮)。基于这一证据，我们认为催产素将显著 减少阿片类药物滥用责任，减轻实验痛苦。30名55-75岁的健康志愿者， 一些阿片类经验将在口服羟考酮后不久自我给予48国际单位的鼻腔内催产素(或安慰剂) (0，2.5，5.0毫克)在双盲、随机、安慰剂对照的受试者内实验室研究中。主题- 将在5年内重复评估额定滥用责任以及心血管和呼吸系统反应 在给药后几个小时。还将收集疼痛测量数据，包括标准化实验 疼痛电池(即带有热和机械测试的定量感觉测试)。这项研究具有巨大的 鼻腔内催产素作为阿片类药物减量的潜在公共健康影响 上瘾的潜力和产生阿片类药物的节制作用，同时有效地减轻疼痛，这可以大大 推进药物治疗领域，开辟新的治疗方案，特别是中老年患者 可能有更高疼痛风险的成年人。该项目的结果还将促进对 潜在的虐待和疼痛之间的联系背后的行为机制。我们的多学科团队是 具有(I)鼻腔内给药催产素(Ii)人 滥用药物的给药和滥用责任测试(三)阿片类药物给药和实验疼痛 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.