Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva, Switzerland.
Basic Clin Pharmacol Toxicol. 2012 Mar;110(3):219-26. doi: 10.1111/j.1742-7843.2011.00814.x. Epub 2011 Nov 9.
Pain is characterized by its multi-dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state-of-the-art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. For the so-called weak opioids such as codeine, experimental human studies showed that analgesia relies mainly upon biotransformation into morphine. However, the time-course of plasma concentrations of morphine did not always reflect the time-course of effects, the major site of action being the central nervous system. For tramadol, a correlation has been observed between the analgesic response and the PK of the (+)R-O-demethyl-tramadol metabolite. For 'stronger' opioids such as oxycodone, studies assessing the PK/PD of oxycodone suggested that active metabolite oxymorphone also strongly contributes to the analgesia and that analgesia may also be partially related through an action to peripherally located κ-opioid receptors. Different models have been proposed to describe the time-course of buprenorphine. An effect-compartment model was adopted to describe the PK/PD of morphine and its active metabolite, morphine-6-glucuronide (M6G). A longer blood-effect site equilibration half-life t(1/2) k(e0) was observed for M6G, suggesting a longer onset of action. The studies assessing the PK/PD of fentanyl and its derivatives showed a short t(1/2) k(e0) for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time-course of the analgesic effects can be close to the plasma concentrations (alfentanil and derivates) or observed with a prolonged delay (codeine, buprenorphine, morphine). These PK/PD data can be used to better characterize the differences between opioids, and partly explain the important observed variability among opioids in experimental conditions and should be systematically evaluated during drug development to better predict their selection in specific clinical conditions.
疼痛具有多维性质，这在一定程度上解释了为什么对于镇痛药来说，药代动力学/药效动力学（PK/PD）关系并不简单。这篇综述的第一部分概述了 PK、PD 和 PK/PD 模型，以及在镇痛研究中使用的群体方法。第二部分更新了阿片类药物 PK/PD 关系的最新进展，重点介绍了在实验性人类疼痛模型中获得的数据，这是一种用于描述镇痛药药效学的有用工具。对于像可待因这样的所谓弱阿片类药物，实验性人体研究表明，镇痛主要依赖于生物转化为吗啡。然而，血浆中吗啡浓度的时间过程并不总是反映作用的时间过程，主要作用部位是中枢神经系统。对于曲马多，已经观察到镇痛反应与（+）R-O-去甲基曲马多代谢物的 PK 之间存在相关性。对于像羟考酮这样的“更强”阿片类药物，评估羟考酮 PK/PD 的研究表明，活性代谢物羟吗啡酮也强烈有助于镇痛，并且镇痛也可能部分通过作用于外周κ-阿片受体来实现。已经提出了不同的模型来描述丁丙诺啡的时间过程。采用效应室模型来描述吗啡及其活性代谢物吗啡-6-葡萄糖醛酸苷（M6G）的 PK/PD。观察到 M6G 的血效平衡半衰期 t(1/2) k(e0)较长，提示作用开始较慢。评估芬太尼及其衍生物 PK/PD 的研究表明，镇痛的 t(1/2) k(e0)较短，为 0.2 至 9 分钟，反映出起效较快。总之，根据血浆和效应部位之间转移的速度以及活性代谢物的参与，镇痛作用的时间过程可以与血浆浓度（阿芬太尼及其衍生物）接近，也可以观察到较长的延迟（可待因、丁丙诺啡、吗啡）。这些 PK/PD 数据可用于更好地描述阿片类药物之间的差异，并在一定程度上解释在实验条件下阿片类药物之间观察到的重要可变性，并且在药物开发过程中应系统地进行评估，以更好地预测它们在特定临床情况下的选择。
