From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Anesthesiology. 2018 May;128(5):932-942. doi: 10.1097/ALN.0000000000002138.
Previous studies integrated opioid benefit and harm into one single function-the utility function-to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example.
Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic-pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression.
The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression.
The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs.
先前的研究将阿片类药物的益处和危害整合到一个单一的函数中——效用函数——根据其预期效果（镇痛）来确定药物毒性（呼吸抑制）。本研究进一步使用阿片类镇痛药阿芬太尼的呼吸和镇痛作用来细化效用函数的概念。
将来自 48 名健康志愿者的三项先前研究的数据合并，并使用群体药代动力学-药效学分析进行重新分析，以创建效用概率函数。定义了四个特定条件：无严重呼吸抑制的足够镇痛概率、有严重呼吸抑制的足够镇痛概率、无严重呼吸抑制的不足镇痛概率和有严重呼吸抑制的不足镇痛概率。
根据阿片类药物效应部位浓度的不同，成功识别了这四种情况。在阿芬太尼效应部位浓度为 68ng/ml 时，达到了无严重呼吸抑制的最佳镇痛概率，超过了最不希望的效果（即有严重呼吸抑制的不足镇痛）的概率（优势比为 4.0）。在更高的效应部位浓度下，镇痛的概率降低，并超过了严重呼吸抑制的概率。
成功地进一步开发了效用函数，允许根据预期和非预期效果评估特定条件。这种方法可用于比较药物的毒性作用与其预期作用，并可能成为评估新化合物相对于现有药物优势的有用工具。
