Cerebrospinal fluid and plasma pharmacokinetics of morphine infusions in pediatric cancer patients and rhesus monkeys.

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of morphine administered as a continuous infusion were studied in pediatric cancer patients and in monkeys with implanted Ommaya reservoirs. In monkeys administered a constant infusion of 0.15 mg morphine sulfate/kg/h, morphine steady-state plasma and CSF concentrations were 84.4 +/- 20.0 ng/ml and 25.3 +/- 4.9 ng/ml, respectively, for a CSF:plasma ratio of 0.30 +/- 0.05. For comparison, the monkeys also received morphine as an intravenous bolus at a dose of 0.45 mg morphine sulfate/kg. The CSF:plasma area under the concentration-time curve (AUC) ratio was 0.40 +/- 0.07, similar to that seen with continuous infusion. Morphine pharmacokinetics were also studied in cancer patients administered long-term infusions of morphine sulfate over a wide dosage range (0.04-31 mg/kg/h). The steady-state plasma concentration of morphine was linearly related to the infusion rate although variability was noted. The average clearance value was 23 ml/min/kg which is at the upper end of the estimates reported for morphine clearance using bolus administration. No evidence for morphine accumulation using long-term administration was observed. A limited number of CSF samples obtained by lumbar puncture showed comparable CSF and plasma concentrations of unbound morphine assuming morphine is approximately 30% bound in human plasma.