Steady-state kinetics and dynamics of morphine in cancer patients: Is sedation related to the absorption rate of morphine?

Eighteen patients suffering from chronic pain due to cancer completed a bal anced, double-blind, double-dummy, two period cross-over trial comparing th e pharmacokinetics (PK) and pharmacodynamics (PD) of morphine and its metab olites, morphine-3-glucuronide and morphine-6-glucuronide, after administra tion of morphine given as controlled-release (CR) tablets (every 12 h) and immediate-release (IR) tablets (every 6 h). The same total daily dose of mo rphine was given in both study periods. Patients received both test formula tions for 4 days and on the final day of each period, peripheral venous blo od samples for analysis of morphine, morphine-3-glucuronide, and morphine-6 -glucuronide were obtained. Pain intensity sedation, and continuous reactio n time (CRT) were assessed. No significant differences could be demonstrate d in AUC/dose, C-min, C-max or fluctuation index values between the two tre atments (IR and CR tablets) for either morphine or its metabolites. T-max f or morphine and its metabolites occurred significantly later after administ ration of CR tablets than after administration of IR tablets. There were no significant differences between the IR and the CR formulation with respect to analgesia and side effects, and there was no difference in the patients ' overall impression of the two treatments. More important, there was no di fference between the T-max and the time to peak sedation after administrati on of IR tablets (P = 0.63). However, due to the relatively small number of patients and the variability in the data, the statistical power of the tes t was only 0.074. The risk of a type II error is 0.926. These data demonstr ate the PK and PD similarities and differences between CR and IR morphine. They suggest that there may be a relationship between T-max (determined by absorption rate) and sedation, but further evaluation of this potential rel ationship is needed. (C) U.S. Cancer Pain Relief Committee, 1999.