• Sabine J G M Ahlers, Pyry A J Välitalo, Mariska Y M Peeters, Laura van Gulik, Eric P A van Dongen, Albert Dahan, Dick Tibboel, and Catherijne A J Knibbe.
• From the *Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; †Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; ‡Department of Anaesthesiology, Intensive Care and Pain Management, Nieuwegein, The Netherlands; §Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; and ∥Intensive Care and Department of Pediatric Surgery, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, The Netherlands.
• Anesth. Analg. 2015 Nov 1;121(5):1261-73.

BackgroundAlthough morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations.MethodsA population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion.ResultsFor morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers.ConclusionsUnder the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made.

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