Population pharmacokinetic modelling of subcutaneous morphine in the elderly

Abstract

Summary Background The sources of variability in the blood concentrations of morphine after subcutaneous administration are unclear. Methods A population pharmacokinetic model (using NONMEM) was used to examine data on morphine disposition following its administration (5 mg) via an indwelling s.c. cannula to elderly post-operative patients. Results A two-compartment model with first order absorption was preferred. The between subject variability (BSV) was between 45 and 95% for the systemic parameters, and 71% for the absorption rate constant. The rate of subcutaneous absorption of morphine was not inherently more variable than other factors affecting morphine disposition. A sensitivity analysis supported these findings. In eight patients who received a second dose of morphine approximately 300 min after the first dose, the between occasion variability (BOV) of the parameters was up to 81% of the total variability. Conclusions A significant component of the variability in morphine disposition was due to factors that could alter within a patient between doses. Taken together, this reinforces the need to titrate the dose of morphine to clinical endpoints, and questions the concept of a fixed dose for a given patient over time, especially if given at fixed dose intervals (i.e. on a time-contingent basis).