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

Syntocinon 的阿片类药物节省和减轻疼痛特性：剂量效应测定

基本信息

批准号：
10543556
负责人：
Meredith Berry
金额：
$ 17.69万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543556
关键词：
Absence of pain sensation Acute Pain Address Affect Analgesics Animal Model Animals Area Biochemistry Brain Brain region Buprenorphine Cardiovascular system Corpus striatum structure Dose Double-Blind Method Drug Prescriptions Formulation Goals Grant Health Heroin Hour Human Impairment Individual Inflammation Intervention Intravenous Laboratory Study Link Literature Manuscripts Measures Mechanics Mediator Mentors Methadone Morbidity - disease rate Morphine Motivation Mus Neurobiology Neurons Neuropeptides Opiate Addiction Opioid Opioid replacement therapy Oral Oxycodone Oxytocin Pain Pain Disorder Pain Measurement Pain management Pathway interactions Percocet Pharmaceutical Preparations Pharmacotherapy Placebo Control Placebo Effect Placebos Prefrontal Cortex Property Public Health Randomized Rattus Recreation Reducing Agents Regulation Research Rest Rewards Scientific Advances and Accomplishments Self Administration Sensory Source Standardization Stimulus Stress Structure Supervision System Techniques Testing Translations Writing abuse liability addiction analog antinociception behavioral economics behavioral pharmacology brain pathway brain volume career chronic pain conditioned place preference hedonic inter-individual variation mortality multidisciplinary multimodal neuroimaging multimodality neurobiological mechanism neuroimaging novel novel therapeutics opioid abuse opioid epidemic opioid injection opioid misuse opioid mortality opioid overdose opioid sparing opioid use disorder opioid user overdose death pain chronification pain model pain reduction pain sensitivity pre-clinical preservation prevent respiratory response skills substance use treatment

项目摘要

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.

抽象的阿片类药物滥用是美国发病率和死亡率的一个主要来源，也是公众迫切需要解决的问题健康危机。自 2002 年以来，与阿片类药物相关的过量死亡人数增加了四倍多。羟考酮（在 Percocet™ 和 Oxycontin™）是可靠的常用止痛药物之一，但也被广泛使用被滥用并涉及过量死亡。尽管有滥用的可能性，羟考酮仍能有效减少急性发作疼痛。迫切需要采取干预措施来保留羟考酮的镇痛特性，同时减少其滥用潜力。一种有前景的疼痛管理辅助治疗选择，可以同时减少阿片类药物的滥用倾向的是 Syntocinon（鼻内制剂）神经肽催产素）。 Syntocinon 可能会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，催产素可降低阿片类药物静脉注射的自我依赖性。给药并逆转羟考酮条件性位置偏好。大鼠疼痛模型显示催产素增强抗伤害感受（阻断疼痛刺激），在人类中，使用合产素可减轻疼痛实验灵敏度。此外，动物和人类的证据支持共享的大脑结构和与成瘾和慢性疼痛相关的功能变化，可能受到催产素的调节行政。根据现有文献，我们建议缩宫素将显着减少滥用阿片类药物的责任并通过其对大脑结构、功能和功能的影响来减轻实验疼痛生物化学。 30 名健康的娱乐性阿片类药物使用者将自行施用 48 个国际单位的鼻内缩宫素（或在一项双盲、随机、安慰剂对照、内部试验中，口服羟考酮（0、2.5、5.0 mg）后不久服用安慰剂）科目实验室研究。受试者评定的滥用倾向以及心血管和呼吸系统反应将给药前和给药后 5 小时内重复评估。疼痛和神经生物学测量还将收集，包括标准化实验疼痛电池（即定量感官测试）和多模式神经成像电池（即大脑结构、功能和生物化学）。这项研究有检查鼻内催产素作为一种有前途的药物对公共卫生影响的巨大潜力减少阿片类药物成瘾的可能性，同时有效减轻疼痛，这可以大大推进这一领域药物疗法并开辟出一种新的治疗选择。这项研究还将促进科学理解滥用潜力与疼痛之间联系的神经生物学机制。这项研究还将通过发展 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疼痛； 2）与成瘾和疼痛相关的神经影像技术； 3）深化目前成瘾方面的专业知识以及阿片类药物给药和翻译背景下的人类行为药理学； 4）授予和稿件写作技巧； 5）提高管理和监督能力。这个多学科团队是非常适合在这些领域指导 PI 并实现拟议的目标。