Proceedings of the Symposium “Updates of the Clinical Pharmacology of Opioids with Special Attention to Long-Acting Drugs” Pharmacokinetic–Pharmacodynamic Modeling of Opioids

The effects of opioids usually parallel the plasma concentrations but with a temporal shift. This temporal shift differs between opioids. It is small with alfentanil or remifentanil and very long with the active metabolite of morphine, morphine-6-glucuronide (M6G). The mathematical and experimental techniques for modeling these pharmacokineticpharmacodynamic (PK/PD) relationships were developed in the late 1970s. The delay between plasma concentrations and effects is accounted for by the introduction of a hypothetic effect compartment, which is linked to the plasma compartment by a first-order transfer function with a rate constant ke0. The effects are then linked to the concentrations at effects site by standard pharmacodynamic models such as sigmoid (“Emax”) models or power models, depending on the actual effect measure. These principles were first applied to the opioids fentanyl and alfentanil in 1985. Since then, PK/PD of opioids have been repeatedly assessed, using EEG derived parameters, pupil size, and experimental and clinical pain as effect measures. The opioids of the fentanyl group, methadone, morphine, and piritramid, are today well characterized with respect to their PK/PD properties. Alfentanil and remifentanil are very fast equilibrating opioids with equilibration half-lives between plasma and effect site of about 1 minute. They are followed by fentanyl and sufentanil, each with equilibration half-lives of about 6 min. Methadone equilibrates with a half-life of about 8 min. Morphine, in contrast, equilibrates with a half-life of 2–3 h. The slowest opioid with respect to plasma-effect site transfer is M6G, with an equilibration half-life of about 7 h. PK/PD modeling has advanced the understanding of the time course of the clinical effects of opioids after various dosing regimens. It may provide a rational basis for the selection of opioids in clinical circumstances. PK/PD modeling of opioids may also be employed for the design and the interpretation of experiments addressing clinical effects of opioids. J Pain Symptom Manage 2005;29:S90–S103. 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.