VARIABILITY MORPHINE DISPOSITION DURING LONG-TERM SUBCUTANEOUS INFUSION IN TERMINALLY ILL CANCER-PATIENTS

Objective: To study the plasma concentrations of morphine and its gluc uronides to assess the intra-and interindividual variability of the di sposition of morphine administered by subcutaneous infusion in cancer patients. Methods: Blood samples were taken repeatedly in eight patien ts with severe cancer pain who were being treated with morphine (60 - 3000 mg per day) via chronic (8 - 160 days) subcutaneous infusion. Ven ous blood samples were collected at least weekly and, when possible, o n 3 consecutive days after dose adaptation or any other major change i n the patients' treatment. Concentrations of morphine and its glucuron ides in plasma were measured after solid-phase extraction using a vali dated highperformance liquid chromatography assay. The stability of th e morphine solutions was determined by repeated measurement of the con centrations of morphine and its degradation products in the solutions. Results: The morphine concentration in the infusion solutions remaine d unchanged during storage and infusion. The plasma concentrations of morphine and its glucuronides were within the ranges reported to the l iterature. There was, as expected, a large interindividual variability : from patient to patient, the mean of the normalised plasma concentra tions ranged from 0.3 ng.ml(-1).mg(-1) to 0.8 ng.ml(-1).mg(-1) for mor phine, from 1.0 ng.ml(-1).mg(-1) to 3.1 ng.ml(-1).mg(-1) for morphine- 6-glucuronide and from 6.8 ng.ml(-1).mg(-1) to 24.3 ng.ml(-1).mg(-1) f or morphine-3-glucuronide. Intraindividual variability was also import ant. The residual standard deviation of the mean normalised plasma con centrations calculated for each patient ranged from 26 % to 56 % for m orphine, from 20 % to 51 % for morphine-6-glucuronide and from 20 % to 49 % for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found. Conclusion: During subcutaneous infusion of mor phine, there is a large intra-and interindividual variability of the m orphine disposition which could be of clinical relevance.