Pharmacodynamic Analysis of Morphine Time-to-Remedication Events in Infants and Young Children After Congenital Heart Surgery
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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.
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®.
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.
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.
KeywordsMorphine Hazard Rate Hazard Function Baseline Hazard Morphine Treatment
David R. Drover and Gregory B. Hammer conceived and designed the clinical study; Kristi L. Glotzbach performed the clinical study and collected the data; Jeffery L. Galinkin developed and optimized the morphine assay; and Mohammed H. Elkomy conducted the data analysis and wrote the manuscript. All authors critically reviewed and approved the manuscript content.
Compliance with Ethical Standards
This study was funded through an NCCR/NICHD CTSA consortium project grant via the Stanford University Center for Clinical and Translational and Educational Research.
Conflict of interest
Mohammed H. Elkomy, David R. Drover, Jeffery L. Galinkin, Gregory B. Hammer, and Kristi L. Glotzbach have no conflicts of interest to declare.
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