Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100).The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%).These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine.Morphine is degraded in the liver to several metabolites of which morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) are biological active [1]. M6G is shown to contribute to the analgesia produced by morphine and may cause opioid related adverse effects such as sedation or nausea [2-5]. Due to first pass metabolism and slow accumulation of M6G in the brain the analgesic activity of M6G is most prominent during oral long-term treatment with morphine while single dose studies show less contribution from M6G to the analgesic effects from morphine [2,3,6]. M3G may in exceptional cases cause excitatory adverse effects such as delirium, m