Pharmacodynamic Analysis of Morphine Time-to-Remedication Events in Infants and Young Children After Congenital Heart Surgery.
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.
Department of Pharmaceutics and Industrial Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Mohammed H
MH
Elkomy
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5117, USA. ddrover@stanford.edu.
David R
DR
Drover
Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
Jeffery L
JL
Galinkin
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5117, USA.|Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Gregory B
GB
Hammer
Division of Pediatric Cardiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
Kristi L
KL
Glotzbach
D000367:Age Factors; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D002675:Child, Preschool; D003198:Computer Simulation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy*; D013997:Time Factors
D000701:Analgesics, Opioid; D009020:Morphine