Oral morphine dosing predictions based on single dose in healthy children undergoing surgery

Background: Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose.

Aims: The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens.

Methods: Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg^-1 , 200 mcg·kg^-1 , 300 mcg·kg^-1 ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (T_LAG ), and absorption half-time (T_ABS ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg^-1 ) at different dosing intervals (3, 4, 5, 6, 8, 12 h).

Results: The oral morphine formulation had F 0.298 (CV 36.5%), T_LAG 0.45 (CV 63.6%) h and T_ABS 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg^-1 achieved a mean C_MAX 10 mcg·l^-1 . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l^-1 ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l^-1 at steady state.

Conclusions: Oral morphine 200 mcg·kg^-1 then 100 mcg·kg^-1 4 h or 150 mcg·kg^-1 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.