Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants

Abstract

Background. To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of morphine and its metabolites. Methods. In a double-blind study, neonates and infants stratified for age [group I 0-4 weeks (neonates), group II ≥4-26 weeks, group III ≥26-52 weeks, group IV ≥1-3 yr] admitted to the paediatric intensive care unit after abdominal or thoracic surgery received morphine 100 μg kg-1 after surgery, and were randomly assigned to either continuous morphine 10 μg kg-1 h-1 or intermittent morphine boluses 30 μg kg-1 every 3 h. Pain was measured using the COMFORT behavioural scale and a visual analogue scale. Additional morphine was administered on guidance of the pain scores. Morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) plasma concentrations were measured before, directly after, and at 6, 12 and 24 h after surgery. Results. Multiple regression analysis of different variables revealed that age was the most important factor affecting morphine requirements and plasma morphine concentrations. Significantly fewer neonates required additional morphine doses compared with all other age groups (P<0.001). Method of morphine administration (intermittent vs continuous) had no significant influence on morphine requirements. Neonates had significantly higher plasma concentrations of morphine, M3G and M6G (all P<0.001), and significantly lower M6G/morphine ratio (P<0.03) than the older children. The M6G/M3G ratio was similar in all age groups. Conclusions. Neonates have a narrower therapeutic window for postoperative morphine analgesia than older age groups, with no difference in the safety or effectiveness of intermittent doses compared with continuous infusions in any of these age groups. In infants >1 month of age, analgesia is achieved after morphine infusions ranging from 10.9 to 12.3 μg kg-1 h-1 at plasma concentrations of <15 ng ml-1.