Morphine glucuronidation and elimination in intensive care patients: A comparison with healthy volunteers

OBJECTIVE: To evaluate the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers.Morphine glucuronidation and elimination in intensive care patients: a comparison with healthy volunteers.DESIGN AND METHODS: A population pharmacokinetic model with covariate analysis was developed with the non-linear mixed-effects modelling software NONMEM VI. The analysis included 3012 morphine and morphine-3-glucuronide (m3g) concentrations from 117 cardiothoracic surgery patients and 18 critically ill patients, who received continuous morphine infusions adapted to individual pain levels, as well as 622 morphine and M3G concentrations from a previous study of 20 healthy volunteers, who received an intravenous bolus of morphine followed by a 1-hour infusion.RESULTS For morphine a three-compartment model best described the data, while for M3G a one-compartment model was applicable. In intensive care patients with a normal creatinine concentration, M3G clearance was decreased by 76% compared with healthy subjects. 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. Model-based simulations show that in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations comparable to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain elevated.CONCLUSION In intensive care patients, elimination of M3G appeared significantly decreased compared to healthy volunteers, resulting in substantially elevated M3G concentrations, which are even more pronounced upon increased serum creatinine concentrations. Future investigations are needed to set target concentrations in this population, after which final dosing recommendations can be made.