Morphine metabolism in cancer patients on increasing oral doses--no evidence for autoinduction or dose-dependence.

Four cancer patients with severe chronic pain were treated with oral morphine with increasing doses during 5-8 months. During this period the oral dose was increased 16-23-fold in each of the patients. Morphine, morphine-3- and morphine-6-glucuronide were determined with high performance liquid chromatography in plasma and urine during steady-state, at five or more occasions on different daily doses of morphine. The trough concentrations of morphine and its metabolites were linearly related to the given dose. The relation between the levels of morphine and the two glucuronides was constant in the individual patient and independent of dose and duration of treatment. The average molar ratio between the areas under the plasma concentration-time curves (AUC) for morphine-3-glucuronide and morphine was 34.0 (range 23.0-46.9). The corresponding value for the ratio between morphine-6-glucuronide and morphine was 3.9 (range 2.7-5.6). Our results show that the conjugation of morphine with glucuronic acid is proportional to the dose during long-term treatment with increasing doses, thus this metabolic pathway is not subject to auto-induction, even after very long periods of continuous treatment with high doses.