Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
PainLess Foundation, Leiden, The Netherlands.
Clin Pharmacol Ther. 2023 May;113(5):1080-1088. doi: 10.1002/cpt.2863. Epub 2023 Feb 22.
The widely prescribed opioid oxycodone may cause lethal respiratory depression. We compared the effects of oxycodone on breathing and antinociception in healthy young volunteers. After pharmacokinetic/pharmacodynamic (PK/PD) modeling, we constructed utility functions to combine the wanted and unwanted end points into a single function. We hypothesized that the function would be predominantly negative over the tested oxycodone concentration range. Twenty-four male and female volunteers received 20 (n = 12) or 40 (n = 12) mg oral oxycodone immediate-release tablets. Hypercapnic ventilatory responses (visit 1) or responses to 3 nociceptive assays (pain pressure, electrical, and thermal tests; visit 2) were measured at regular intervals for 7 hours. the PK/PD analyses, that included carbon dioxide kinetics, stood at the basis of the utility function: probability of antinociception minus probability of respiratory depression. Oxycodone had rapid onset/offset times (30-40 minutes) with potency values (effect-site concentration causing 50% of effect) ranging from 0.05 to 0.13 ng/mL for respiratory variables obtained at hypercapnia and antinociceptive responses. Ventilation at an extrapolated end-tidal carbon dioxide partial pressure of 55 mmHg, was used for creation of 3 utility functions, one for each of the nociceptive tests. Contrary to expectation, the utility functions were close to zero or positive over the clinical oxycodone concentration range. The similar or better likelihood for antinociception relative to respiratory depression may be related to oxycodone's receptor activation profile or to is high likeability that possibly alters the modulation of nociceptive input. Oxycodone differs from other μ-opioids, such as fentanyl, that have a consistent negative utility.
广泛应用于临床的阿片类药物羟考酮可能导致致命性呼吸抑制。本研究旨在比较羟考酮对健康年轻志愿者呼吸和镇痛的影响。通过药代动力学/药效学（PK/PD）模型，构建效用函数，将期望和不期望的终点结合为单一函数。假设该函数在测试的羟考酮浓度范围内主要为负。24 名男性和女性志愿者分别接受 20（n=12）或 40（n=12）mg 口服羟考酮速释片。在 7 小时内，定期测量志愿者的高碳酸血症通气反应（第 1 次就诊）或 3 种痛觉测试（疼痛压力、电和热测试；第 2 次就诊）的反应。基于包括二氧化碳动力学在内的 PK/PD 分析，构建了效用函数：镇痛作用的概率减去呼吸抑制的概率。羟考酮起效/失效时间较快（30-40 分钟），在高碳酸血症时呼吸变量的效能值（引起 50%效应的效应部位浓度）和镇痛反应的效能值在 0.05-0.13ng/mL 之间。使用 extrapolated 呼气末二氧化碳分压为 55mmHg 时的通气量，为 3 种痛觉测试中的每一种创建 3 个效用函数。与预期相反，在临床羟考酮浓度范围内，效用函数接近零或为正。与呼吸抑制相比，镇痛的可能性相似或更大，这可能与羟考酮的受体激活特征有关，也可能与羟考酮的高可接受性有关，后者可能改变痛觉传入的调制。羟考酮与其他 μ 阿片类药物（如芬太尼）不同，后者具有一致的负效用。
