Stress and Opioid Misuse Risk: The Role of Endogenous Opioid and Endocannabinoid Mechanisms

压力和阿片类药物滥用风险：内源性阿片类药物和内源性大麻素机制的作用

基本信息

批准号：
10399520
负责人：
Stephen Bruehl
金额：
$ 55.48万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10399520
关键词：
2-arachidonylglycerol Absence of pain sensation Acute Pain Address Algorithms Analgesics Anxiety Back Pain Benefits and Risks Cardiovascular system Chronic low back pain Clinical Crossover Design Data Development Dose Double-Blind Method Drug Exposure Elements Endocannabinoids Equilibrium Exposure to Funding Goals Iatrogenesis Impairment Individual Knowledge Laboratories Link Literature Low Back Pain Measures Mediating Medicine Mental Depression Modeling Morphine Naloxone Operative Surgical Procedures Opioid Opioid Analgesics Opioid Antagonist Opioid agonist Oral Outcome Study Oxycodone Pain Pain Measurement Pain intensity Pain management Pathway interactions Patients Pattern Pharmaceutical Preparations Physiological Placebo Control Placebos Plasma Play Postoperative Pain Property Psychological reinforcement Psychosocial Stress Randomized Rest Risk Risk Marker Role Standardization Stimulus Stress System Testing Time Weight Work base biological adaptation to stress chronic pain management chronic pain patient clinically relevant design diaries disorder risk endogenous cannabinoid system endogenous opioids experience heart rate variability indexing individual patient innovation negative affect non-drug novel opioid epidemic opioid misuse opioid therapy opioid use opioid use disorder pain patient pain relief perceived stress precision medicine prescription opioid psychosocial response response biomarker sex stressor

项目摘要

Abstract Indiscriminate prescribing of opioids for chronic pain management has contributed to the current opioid crisis. While opioids work well at stable doses for some patients, others experience poor pain relief with significant risks of developing iatrogenic opioid use disorder (OUD). Similar risks may occur in the context of extended postoperative pain management using opioids following major surgery. Ability to predict this risk/benefit balance for individual patients is limited by inadequate understanding of mechanisms influencing opioid responses and risks. To address this gap, our prior funded work has systematically evaluated mechanisms contributing to differential opioid responses. We have shown that: 1) chronic pain patients at increased risk of opioid misuse experience greater analgesia and subjective reinforcing effects of opioid analgesics (e.g., drug liking, desire to take the drug again), 2) low endogenous opioid (EO) function predicts greater analgesic responses to opioid analgesics (replicated across two studies), and 3) that low EO function and endocannabinoid (EC) levels together predict greater subjective opioid reinforcing effects. Our data are consistent with a reinforcement model in which differential opioid responding related to low EO and EC function may enhance risk of OUD. Stress is a known predictor of risk for OUD, but mechanisms are not well understood. EO and EC activity are however both known to inhibit stress responses. This project integrates diverse literatures and will test in 120 chronic low back pain patients a novel mechanistic model in which elevated stress, via links to low EO and EC activity, contributes to patterns of differential opioid responding that will enhance OUD risk via elevated opioid reinforcing properties. Primary aims are: 1) to determine whether stress-related measures are associated with analgesic and misuse-relevant subjective responses to placebo- controlled oxycodone administration, and 2) evaluate associations between stress-related measures and both EO function and EC levels, and test whether EO and EC mechanisms mediate associations between stress- related measures and oxycodone responses. This project will assess stress at multiple levels (subjective, cardiovascular reactivity to two controlled stressors, and pain-relevant heart rate variability [HRV] stress markers) with quantitative assessment of EC levels, and assessment of EO function and opioid agonist subjective and analgesic responses based on randomized, placebo-controlled crossover administration of naloxone (for EO) and oxycodone (opioid responses). Laboratory stress measures will be validated using EMA electronic diary assessment of stress. Results will provide unique mechanistic knowledge of mechanisms contributing to known associations between stress and OUD risk, in line with the goals of PAS- 18-624, and highlight a novel and clinically-pragmatic HRV measure that might predict risk-enhancing differential opioid responses before initiating opioid therapy.

抽象的不加区别地开阿片类药物治疗慢性疼痛导致了目前阿片类药物的滥用危机。虽然阿片类药物在稳定剂量下对某些患者效果良好，但其他患者的疼痛缓解效果不佳发生医源性阿片类药物使用障碍 (OUD) 的重大风险。类似的风险可能会发生在大手术后使用阿片类药物延长术后疼痛管理。有能力预测这一点由于对影响机制了解不足，个体患者的风险/收益平衡受到限制。阿片类药物的反应和风险。为了解决这一差距，我们之前资助的工作进行了系统评估导致不同阿片类药物反应的机制。我们已经证明：1）慢性疼痛患者阿片类药物滥用的风险增加阿片类药物的镇痛效果和主观强化效果更强镇痛药（例如，药物喜好、再次服用药物的愿望），2）低内源性阿片类药物（EO）功能预测对阿片类镇痛药的镇痛反应更大（在两项研究中重复），以及 3) 低 EO 功能和内源性大麻素 (EC) 水平共同预测更大的主观阿片类药物强化作用。我们的数据是与强化模型一致，其中差异阿片类药物反应与低 EO 和 EC 功能相关可能会增加 OUD 的风险。压力是 OUD 风险的已知预测因素，但机制尚不完善明白了。然而，已知 EO 和 EC 活性都可以抑制应激反应。该项目集成了不同的文献，并将在 120 名慢性腰痛患者中测试一种新的机制模型，其中压力升高与低 EO 和 EC 活性相关，导致不同的阿片类药物反应模式将通过提高阿片类药物的增强特性来增加 OUD 风险。主要目的是：1）确定是否与压力相关的措施与镇痛和滥用安慰剂相关的主观反应有关控制羟考酮给药，2) 评估压力相关措施与两者之间的关联 EO 功能和 EC 水平，并测试 EO 和 EC 机制是否介导压力- 相关措施和羟考酮反应。该项目将评估多个层面的压力（主观、心血管对两种受控压力源的反应，以及与疼痛相关的心率变异性 [HRV] 压力标记），定量评估 EC 水平，并评估 EO 功能和阿片类激动剂基于随机、安慰剂对照交叉给药的主观和镇痛反应纳洛酮（EO）和羟考酮（阿片类药物反应）。实验室压力测量将使用以下方法进行验证 EMA 电子日记压力评估。结果将提供独特的机械知识有助于压力和 OUD 风险之间已知关联的机制，符合 PAS- 的目标 18-624，并强调了一种新颖且临床实用的 HRV 测量方法，可以预测风险增加开始阿片类药物治疗前区分阿片类药物反应。