Population pharmacokinetic modelling of subcutaneous morphine in the elderly

SummaryBackgroundThe sources of variability in the blood concentrations of morphine after subcutaneous administration are unclear.MethodsA 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.ResultsA 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.ConclusionsA 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).