Aging and plasma clearance mechanisms of morphine in humans

Abstract

There is an age-related decrease in morphine clearance (CL) with a trend toward a smaller morphine volume of distribution (Vd) with aging.1 Previous studies however have demonstrated no difference in morphine Vd, suggesting a decrease in first-pass hepatic metabolism of morphine in the elderly. Utilizing previously published data,1 morphine hydrochloride washout curves after a 10 mg intravenous bolus were digitally reconstructed. Healthy young (N=10, 26-30 yrs.) and elderly (N=10, 68-90 yrs.) subjects' washout curves were randomly identified. Each subjects' curve was analyzed individually using NIH-WinSAAM nonlinear regression modeling software.2 Assuming that morphine kinetics can be described by a linear open one-compartment model with first-order elimination, the first-order elimination rate constant (K) for morphine was higher in the elderly subjects compared to the young subjects (1.47±0.09 vs. 3.57±0.47 1/hr, Mean±SD, p < 0.001), but Vd was lower in the elderly subjects compared to the young subjects (75±3 vs. 97±8 L, Mean±SD, p < 0.001). Therefore, morphine CL was reduced in the elderly subjects compared to the young subjects (53±4 vs. 83±3 L/hr, Mean±SD, p < 0.001). Morphine's K does not represent a single physiologic process. Instead, it is a composite measure, reflecting both morphine CL and Vd since K=CL/Vd. Our results suggest that reduced morphine CL in the elderly is due, in part, to an age-related reduction in morphine's Vd in the elderly. Our findings are clinically relevant for individualizing morphine dosage regimens in acute and chronic pain management in the elderly. Our results do not support a morphine fixed-dose regimen for a given elderly patient, emphasizing instead the need for individual clinical pharmacokinetics-based morphine dosage regimens. (1. Baillie SP, Bateman DN, Coates PE, et. al., Age and Ageing, 1989; 2. Greif P, Wastney M, Linares O, et. al., Adv Exp Med Biol. 1998).