Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain

Abstract

Objectives: (1) To determine the pharmacokinetics of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) in children with cancer receiving morphine as immediate-release morphine liquid or sustained-release tablets. (2) To determine differences with age within the group and from adults. (3) To explore relationships between plasma concentration and pain measurements.

Study design: Blood samples were collected and plasma analyzed by high-performance liquid chromatography with electrochemical and fluorescence detection. Population pharmacokinetic parameters were derived with the program P-PHARM.

Results: Forty children with a median age of 11.4 years (range 1.7 to 18.7 years) received a median dose of 1.4 mg/kg/d (range 0.4 to 24.6 mg/kg/d). A median of 4 blood samples per child was collected. Plasma clearance of morphine was 23.1 mL/min per kg body weight. The volume of distribution was 5.2 L/kg. Molar ratios of M3G/morphine, M6G/morphine, and M3G/M6G were 21.1, 4.7, and 4.2, respectively. Children <11 years had significantly higher clearance and larger volume of distribution for morphine and its glucuronides than older children and adults. Regression analysis indicated average plasma morphine concentration equal to dose (mg/kg/d) × 8.6 (95% confidence interval 7.4 to 9.9). Significant pain was present in 30% of the children. Higher pain scores were recorded in children with average morphine concentrations <12 ng/mL (P < .01 MW).

Conclusion: Age differences in morphine pharmacokinetics exist within children and compared with adults. The study supports a starting dose of 1.5 to 2.0 mg/kg/d to provide plasma morphine concentrations >12 ng/mL in children with cancer pain unrelieved by mild to moderate strength analgesia. (J Pediatr 1999;135:47-55)