CONCENTRATIONS OF MORPHINE, MORPHINE-6-GLUCURONIDE AND MORPHINE-3-GLUCURONIDE IN SERUM AND CEREBROSPINAL-FLUID FOLLOWING MORPHINE ADMINISTRATION TO PATIENTS WITH MORPHINE-RESISTANT PAIN

Recent studies have suggested that morphine-3-glucuronide (M3G) may an tagonize the analgesic effects of morphine and morphine-6-glucuronide (M6G). To investigate this hypothesis, steady-state concentrations of morphine, M6G and M3G in serum and cerebrospinal fluid (CSF) were meas ured in 11 patients receiving chronic morphine therapy (9 orally and 2 subcutaneously) for treatment of cancer-related pain. All patients ap peared to have morphine-resistant pain and had elected to proceed to i ntrathecal bupivacaine or percutaneous cordotomy. Morphine, M6G and M3 G concentrations were measured by high-performance liquid chromatograp hy. The concentrations (median and range) for morphine, M6G and M3G in serum were 193 (14-1086) nmol/l, 847 (210-4113) nmol/l and 4553 (1324 -24035) nmol/l, respectively, while in CSF concentrations of morphine, M6G and M3G were 200 (21-1461) nmol/l, 115 (30-427) nmol/l and 719 (2 49-3252) nmol/l, respectively. Median molar ratios of M6G/morphine and M3G/morphine in serum were 3.79 and 22.1, respectively, while in CSF the same ratios were 0.42 and 2.39, respectively. Median molar ratios of M3G/M6G in serum and CSF were 5.84 and 6.61, respectively. The medi an molar ratios for CSF/serum distribution of morphine, M6G and M3G we re 1.23, 0.12 and 0.14, respectively. Thus, despite their relatively p oor ability to penetrate into the CSF, the high serum concentrations o f M6G and M3G resulted in substantial concentrations of these metaboli tes in the CSF. Nevertheless, M3G/M6G ratios in our morphine-resistant patients were similar to published values in patients with well-contr olled pain, suggesting that the hypothesis that M3G plays a major role in morphine-resistance is not correct.