Morphine and morphine metabolite concentrations in cerebrospinal fluid and plasma in cancer pain patients after slow-release oral morphine administration

Abstract

In 34 cancer patients treated with chronic slow-release oral morphine, plasma and cerebrospinal fluid (CSF) minimum steady-state concentrations of morphine (M), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were determined by high-performance liquid chromatography (HPLC). Both plasma and CSF morphine, M3G and M6G, concentrations were linearly related to dose of morphine. At steady state, the mean +/- SEM CSF/plasma morphine concentration ratio was 0.8 +/- 0.1. In plasma and CSF, the mean steady-state concentrations of M3G and M6G substantially exceeded those of morphine where the mean CSF M/M3G/M6G ratio was 1:47:5 (weight basis), 1:34:4 (molar basis) and the mean plasma ratio was M/M3G/M6G 1:150:23 (weight basis), 1:109:17 (molar basis). The mean M3G and M6G concentrations in CSF at steady state were 15-18% of those found in plasma. Pain relief, evaluated by a visual analogue scale (VAS), did not correlate with the CSF M3G concentrations or with the M3G/M ratio. Since CSF M6G concentrations were high, M6G could, however, contribute to pain relief. We conclude that after oral administration of slow-release morphine, there is a significant passage of the morphine glucuronide metabolites to the CSF and that the M3G and M6G metabolites in CSF are in the concentration range where they may have an influence on analgesia.