Pharmacodynamic Analysis of Morphine Time-to-Remedication Events in Infants and Young Children After Congenital Heart Surgery.

Objective: The aim of this study was to characterize the relationship between morphine plasma concentration and repeated time to postoperative remedication events in children undergoing cardiac surgery.

Methods: Data from our previously published study of morphine pharmacokinetics were utilized in this pharmacodynamic study. A population survival analysis based on hazard functions was undertaken in NONMEM(®).

Results: Hazard was best described by a Gompertz function changing in steps over time. Concentration and age were the only predictors of the hazard function. Concentration producing 50 % reduction in hazard was 19.6 (bootstrap 95 % confidence interval 5.90-49.5 ng/ml). The hazard ratio for a 1-year-old child to a 1-month-old child was 1.91 (1.35-2.86). Sensitivity to morphine decreased with age and leveled off after 1-year of life. Morphine sulfate doses >0.1 mg/kg did not noticeably increase tolerable pain durations.

Conclusion: Time to remedication is a clinically useful endpoint for assessing opioid-induced analgesia. Sensitivity to morphine treatment is age-dependent. Morphine sulfate doses of 0.1-0.2 mg/kg are adequate for the management of postoperative pain in children. Our findings may help avoid unnecessary large morphine doses in children.