Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, United States.
Department of Behavioral Science, Rush University, Chicago, IL, United States.
Pain. 2019 Mar;160(3):676-687. doi: 10.1097/j.pain.0000000000001447.
We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.
我们试图复制先前的发现，即内源性阿片（EO）功能低下预示着更强的吗啡镇痛作用，并通过检查循环内源性大麻素和相关脂质是否调节 EO 相关的预测效应来扩展这些发现。46 名慢性下背痛患者提供了内源性大麻素分析的血液样本，然后在 3 种药物条件下分别进行了相同的实验室试验：生理盐水安慰剂、静脉内（i.v.）纳洛酮（阿片拮抗剂；总剂量 12mg）和 i.v. 吗啡（总剂量 0.09mg/kg）。在每个试验中，参与者在递增药物剂量后 4 次按顺序评估下背痛强度、诱发热痛强度和非疼痛主观效应。每个主要结局（下背痛强度、诱发热痛强度和非疼痛主观效应）的平均吗啡效应（吗啡-安慰剂差异）和阿片阻断效应（纳洛酮-安慰剂差异；以指数 EO 功能）是通过平均 4 个递增剂量得出的。EO 功能与吗啡引起的背痛缓解之间的关系受到内源性大麻素的显著调节[2-花生四烯酸甘油（2-AG）和 N-花生四烯酸乙醇胺（AEA）]。只有内源性大麻素水平较低的患者，EO 功能低下才预示着更强的吗啡镇痛作用。内源性大麻素还显著调节了 EO 对吗啡相关视觉模拟量表诱发疼痛强度变化的影响（2-AG）、药物喜好（AEA 和 2-AG）以及再次服用的愿望（AEA 和 2-AG）。在没有显著相互作用的情况下，较低的 EO 功能预示着更强的吗啡镇痛作用（如过去的工作）和欣快。结果表明，当内源性大麻素水平较低时，EO 对阿片类药物药物镇痛和主观反应的作用最大。这些发现可能有助于指导个性化疼痛医学算法的基于机制的预测因子的开发。
