CONCENTRATIONS OF MORPHINE AND MORPHINE METABOLITES IN CSF AND PLASMADURING CONTINUOUS SUBCUTANEOUS MORPHINE ADMINISTRATION IN CANCER PAINPATIENTS

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chron ic subcutaneous morphine infusion. There was a moderate, but statistic ally significant correlation between the daily dose of morphine and th e concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma mo rphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the m ean steady state concentration of M3G but not M6G substantially exceed ed that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (m olar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar bas is). The mean M3G and M6G concentrations in CSF were approximately 8 a nd 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were po sitively correlated to serum creatinine. Neither pain intensity, evalu ated by visual analogue scale (VAS), nor side effects showed any relat ionship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morp hine, there is a large interindividual variation in plasma morphine wi th poor relationship to the daily administered dose. In CSF this corre lation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. Ther e was an accumulation of both morphine glucuronides in patients with e levated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.