High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment

Abstract

Several clinical studies have shown oral morphine and methadone to be effective in the treatment of intractable pain in patients with malignant disease. Recent pharmacokinetic studies have confirmed the rationale for regular administration of oral morphine and methadone but have revealed marked interindividual differences in the kinetics and metabolism which must be considered when titrating the oral dose according to the individual patient's need. Oral absorption of morphine in patients with malignant diseases is rapid, with peak plasma concentrations occurring at 20 to 90 minutes. Predose steady-state concentrations bear a constant relationship to dose, but vary considerably between individuals. The oral bioavailability is approximately 40% with marked patient-to-patient variations as a result of differences in presystemic elimination. The reported values for the volume of distribution range from 1.0 to 4.7 L/kg. Plasma protein binding is about 30%. The elimination half-life varies between 0.7 and 7.8 hours. Plasma clearance is approximately 19 ml/min/kg (5 to 34 ml/min/kg) and mostly accounted for by metabolic clearance. Studies in a few patients with malignant diseases treated regularly with daily doses of oral morphine ranging from 20 to 750mg indicate a linear relationship between the dose and trough concentration of morphine. Long term treatment with 10- to 20-fold increase of the oral dose over a period of 6 to 8 months does not seem to change the kinetics of oral morphine. The plasma concentrations of the main metabolite, morphine-3-glucuronide (M3G), exceed those of the parent drug by approximately 10-fold after intravenous administration and by 20-fold after oral administration. The relationship between the area under the plasma concentration-time curve (AUC) of morphine and the AUC of morphine-3-glucuronide remains constant during the development of tolerance upon long term treatment with increasing doses. Renal disease causes a significant increase in the mean plasma concentrations of morphine for 15 minutes after its administration, while mean values of terminal half-life and total body clearance are within the normal range. However, the glucuronidated polar metabolite morphine-3-glucuronide rises rapidly to high concentrations which persist for several days. Chronic liver disease causes an increase in the bioavailability of oral morphine but no, or only a slight reduction in the intravenous clearance. The elimination half-life and volume of distribution are within the normal range.(ABSTRACT TRUNCATED AT 400 WORDS)