Maharaj Anil R, Montana Michael C, Hornik Christoph P, Kharasch Evan D
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
Department of Anesthesiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.
Br J Anaesth. 2025 Mar;134(3):681-692. doi: 10.1016/j.bja.2024.10.042. Epub 2025 Jan 20.
Patients with obstructive sleep apnoea (OSA) are considered more sensitive to opioids and at increased risk of opioid-induced respiratory depression. Nonetheless, whether OSA treatment (continuous positive airway pressure, CPAP; or bilevel positive airway pressure, BIPAP) modifies this risk remains unknown. Greater opioid sensitivity can arise from altered pharmacokinetics or pharmacodynamics. This preplanned analysis of a previous cohort study of remifentanil clinical effects in OSA tested the null hypothesis that the pharmacokinetics, pharmacodynamics, or both of remifentanil, a representative μ-opioid agonist, are not altered in adults with treated or untreated OSA.
A single-centre, prospective, open-label, cohort study administered a stepped-dose, target-controlled remifentanil infusion (target effect-site concentrations 0.5, 1, 2, 3, 4 ng ml) to awake adult volunteers (median age 52 yr, range 23-70) without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). Type III (in-home) polysomnography verified OSA. Remifentanil plasma concentrations, end-expired CO, thermal heat tolerance, and pupil diameter (miosis) were assessed. Population pharmacokinetic (clearance, volume of distribution) and pharmacodynamic (miosis, thermal heat tolerance, end-expired CO) models were developed.
Remifentanil clearance (median) was 147, 143, and 155 L h (P=0.472), and volume of distribution was 19.6, 15.5, and 17.7 L (P=0.473) for subjects without OSA, untreated OSA, or treated OSA, respectively. Total body weight was an influential covariate on both remifentanil clearance and central volume of distribution. There were no statistically or clinically significant differences between the three groups in miosis EC or Emax, or the slopes of thermal heat tolerance or end-expired COvs remifentanil concentration. At a plasma remifentanil concentration of 4 ng ml, in participants without OSA, with untreated OSA, or with treated OSA, respectively, model-estimated pupil area (12%, 13%, and 17% of baseline, P=0.086), thermal heat tolerance (50°C, 51°C, and 51°C, P=0.218), and end-expired CO (6.3 kPa, 6.4 kPa, and 6.7 kPa, P=0.257) were not statistically different between groups.
OSA (untreated or treated) did not influence remifentanil pharmacokinetics or pharmacodynamics (miosis, analgesia, respiratory depression). Results support the null hypothesis that neither pharmacokinetics nor pharmacodynamics of remifentanil, a representative μ-opioid, are altered in adults with treated or untreated OSA. These findings provide a mechanistic explanation for the lack of influence of OSA or OSA treatment on the clinical miotic, sedative, analgesic, or respiratory depressant response to remifentanil in awake adults. The conventional notion that OSA alters sensitivity to the effects of opioids in awake adults is not supported by our findings, such that opioid dosing might not need adjustment for pharmacokinetic or pharmacodynamic considerations.
ClinicalTrials.gov, NCT02898792, https://clinicaltrials.gov/ct2/show/NCT02898792. First Posted: September 13, 2016.
阻塞性睡眠呼吸暂停（OSA）患者被认为对阿片类药物更敏感，且发生阿片类药物引起的呼吸抑制的风险增加。然而，OSA治疗（持续气道正压通气，CPAP；或双水平气道正压通气，BIPAP）是否会改变这种风险仍不清楚。阿片类药物敏感性增加可能源于药代动力学或药效学的改变。这项对先前关于瑞芬太尼在OSA中临床效应的队列研究的预先计划分析，检验了零假设，即代表性μ阿片受体激动剂瑞芬太尼在接受或未接受治疗的成年OSA患者中的药代动力学、药效学或两者均未改变。
一项单中心、前瞻性、开放标签的队列研究，对无OSA（n = 20）、未治疗的OSA（n = 33）或已治疗的OSA（n = 21）的清醒成年志愿者（中位年龄52岁，范围23 - 70岁）进行了逐步剂量、靶控瑞芬太尼输注（靶效应室浓度0.5、1、2、3、4 ng/ml）。III型（家庭）多导睡眠图证实了OSA。评估了瑞芬太尼血浆浓度、呼出末二氧化碳、热耐受和瞳孔直径（瞳孔缩小）。建立了群体药代动力学（清除率、分布容积）和药效学（瞳孔缩小、热耐受、呼出末二氧化碳）模型。
无OSA、未治疗的OSA或已治疗的OSA受试者的瑞芬太尼清除率（中位数）分别为147、143和155 L/h（P = 0.472），分布容积分别为19.6、15.5和17.7 L（P = 0.473）。总体重是影响瑞芬太尼清除率和中央分布容积的协变量。三组在瞳孔缩小的半数有效浓度（EC）或最大效应（Emax），或热耐受或呼出末二氧化碳与瑞芬太尼浓度的斜率方面，在统计学或临床上均无显著差异。在血浆瑞芬太尼浓度为4 ng/ml时，无OSA、未治疗的OSA或已治疗的OSA参与者的模型估计瞳孔面积（分别为基线的12%、13%和17%，P = 0.086）、热耐受（50°C、51°C和51°C，P = 0.218）和呼出末二氧化碳（6.3 kPa、6.4 kPa和6.7 kPa，P = 0.257）在组间无统计学差异。
OSA（未治疗或已治疗）不影响瑞芬太尼的药代动力学或药效学（瞳孔缩小、镇痛、呼吸抑制）。结果支持零假设，即代表性μ阿片类药物瑞芬太尼在接受或未接受治疗的成年OSA患者中的药代动力学和药效学均未改变。这些发现为OSA或OSA治疗对清醒成年人中瑞芬太尼的临床缩瞳镇静、镇痛或呼吸抑制反应缺乏影响提供了机制解释。我们的研究结果不支持OSA改变清醒成年人对阿片类药物效应敏感性的传统观念，因此在药代动力学或药效学方面可能无需调整阿片类药物剂量。
ClinicalTrials.gov，NCT02898792，https://clinicaltrials.gov/ct2/show/NCT02898792。首次发布：2016年9月13日。
