From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (A.D., C.J.v.D., M.N., M.v.V., E.O.) Trevena Inc., Chesterbrook, Pennsylvania (M.J.F., M.A.D.).
Anesthesiology. 2020 Sep;133(3):559-568. doi: 10.1097/ALN.0000000000003441.
To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility.
Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) - P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate.
The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia.
These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range.
为了更好地了解奥列西定的呼吸行为，一种 μ 阿片受体激动剂，它选择性地参与 G 蛋白偶联信号通路，减少 β-arrestin 通路的激活，作者比较了它与吗啡的效用功能。假设在等镇痛作用下，奥列西定会比吗啡产生更少的呼吸抑制，并且这反映在优越的效用上。
对先前一项比较奥列西定和吗啡在健康男性志愿者呼吸和镇痛作用的试验（n = 30）的数据进行了重新分析。进行了群体药代动力学-药效学分析，并作为构建效用函数的基础，效用函数是镇痛概率 P（analgesia）和呼吸抑制概率 P（respiratory depression）的客观函数。效用函数=P（analgesia≥0.5）-P（respiratory depression≥0.25），其中镇痛≥0.5是指冷压测试中手撤回潜伏期至少增加 50%，呼吸抑制≥0.25是指至少降低 25%的高碳酸血症通气反应。数值为中位数±估计标准误差。
两种药物具有相似的镇痛效能值（奥列西定：27.9±4.9ng/ml；吗啡 34.3±9.7ng/ml；效能比，0.81；95%置信区间，0.39 至 1.56），吗啡降低 50%高碳酸血症通气反应的效应部位浓度为 33.7±4.8ng/ml，而奥列西定降低 25%的效应部位浓度为 27.4±3.5ng/ml（效能比，2.48；95%置信区间，1.65 至 3.72；P<0.01）。在临床相关的 0 至 35ng/ml 浓度范围内，奥列西定的效用函数为正，表明镇痛的概率超过呼吸抑制的概率。相比之下，吗啡的函数为负，表明呼吸抑制的概率大于镇痛的概率。
这些数据表明，在考虑镇痛和呼吸抑制时，奥列西定在临床浓度范围内的安全性优于吗啡。
