Pharmacokinetic–Pharmacodynamic Modeling of Opioids Jörn Lötsch, MD, PhD  Journal of Pain and Symptom Management  Volume 29, Issue 5, Pages 90-103 (May 2005) DOI: 10.1016/j.jpainsymman.2005.01.012 Copyright © 2005 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 1 For bilateral nephrectomy, a total amount of 110 mg of intravenous morphine had been given to a young man with chronic severe renal failure. Unconsciousness started at a time when morphine was no longer detectable in plasma, and M6G concentrations had been high for more than a day. Hemodialysis starting 45 h after surgery almost completely cleared M6G from plasma. However, the patient remained unconscious for another 34 h. The slow equilibration of M6G between plasma and the brain seems to explain the long delay between reaching high plasma concentrations of M6G and the onset of unconsciousness, as well as the slow recovery from unconsciousness after clearing most M6G from plasma with hemodialysis. The time course of morphine dosage, the plasma concentrations of morphine, M6G, and M3G is displayed. From Angst et al.3 Journal of Pain and Symptom Management 2005 29, 90-103DOI: (10.1016/j.jpainsymman.2005.01.012) Copyright © 2005 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 2 Plasma and effect site concentrations after repeated intravenous bolus administration of opioids. Effects of opioids with fast transfer between plasma and effect site such as alfentanil (half-life of the transfer of 6 min) follow the plasma concentrations closely. In contrast, effects of opioids with slow transfer between plasma and effect site such as morphine (half-life of the transfer of 3 h) build up slowly, reaching a maximum only after several repeated administrations, and then persist longer than the plasma concentrations would suggest. The plasma concentrations of alfentanil and morphine have been set to be identical for demonstration purposes. Journal of Pain and Symptom Management 2005 29, 90-103DOI: (10.1016/j.jpainsymman.2005.01.012) Copyright © 2005 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 3 Plasma and effect site concentrations after a two-hour infusion. Although both alfentanil16 and remifentanil23 have a very fast equilibration between plasma and effect site and the effects therefore follow the plasma concentrations closely, the effects of remifentanil disappear faster than those of alfentanil. This owes to the very fast elimination of remifentanil from plasma by cleavage via blood-esterases (upper right, esteric group marked by a dotted frame), whereas alfentanil is eliminated by hepatic metabolism via CYP3A4. The dosing of the opioid has been arbitrarily adjusted to produce similar maximum concentrations. Journal of Pain and Symptom Management 2005 29, 90-103DOI: (10.1016/j.jpainsymman.2005.01.012) Copyright © 2005 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 4 Plasma and effect site concentrations after intravenous infusions of different durations τ. With a one-hour infusion, recovery from fentanyl and alfentanil it not very different. With longer infusions, the recovery of fentanyl becomes more and more slowly as compared to the recovery from alfentanil, as demonstrated with 6-hour infusions. Simulations were made similar as Shafer and Varvel.38 Journal of Pain and Symptom Management 2005 29, 90-103DOI: (10.1016/j.jpainsymman.2005.01.012) Copyright © 2005 U.S. Cancer Pain Relief Committee Terms and Conditions