CHRONOPHARMACOKINETIC VARIABILITY IN PLASMA MORPHINE CONCENTRATIONS FOLLOWING ORAL DOSES OF MORPHINE SOLUTION

Twenty-six patients with severe pain associated with cancer were enter ed into a study where they were required to take morphine mixture for 7 days. Prior to this, their morphine dose had been optimised to provi de the most favourable balance between pain relief and side effects. A fter 6 days of taking their optimised morphine dose at 4-hourly interv als, the patients were admitted to the Pain Management Unit such that the doses from 18:00 h on day 6 were taken under direct nursing superv ision. Frequent blood samples were collected after the 10:00 h (dose 1 ), 14:00 h (dose 2) and 18:00 h (dose 3) on day 7. There was a signifi cant difference between the 3 doses with respect to C-max values for m orphine with dose 3 > dose 1 > dose 2. Further, there was considerable variability in the percentage change of either dose 1 or dose 3 C-max values relative to dose 2. The C-max values of the active metabolite morphine-6-glucuronide (M6G), measured in 6 of the patients, for the 3 dosing intervals followed a similar trend to the parent drug; but onl y doses 1 and 2 differed significantly. Similar but less pronounced ch anges were observed in the area-under-curve parameter calculated for b oth morphine and M6G during the 3 dosing intervals. There were no sign ificant differences in the C-min or T-max parameters for either morphi ne or M6G between the 3 dosing intervals. These results suggest intra- individual variation in the absorption of morphine or changes in the v olume of distribution during the day. The clinical significance of the se data concerns the possible mismatch between the chronopharmacokinet ic variability in plasma morphine concentrations demonstrated in this communication and literature reports of circadian variability in patie nts' reports of pain.