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

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Abstract

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.

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Author contributions

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.

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Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5117, USA

    David R. Drover & Gregory B. Hammer

  2. Department of Pharmaceutics and Industrial Pharmacy, Beni-Suef University, Beni-Suef, Egypt

    Mohammed H. Elkomy

  3. Division of Pediatric Cardiology, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA

    Kristi L. Glotzbach

  4. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

    Gregory B. Hammer

  5. Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    Jeffery L. Galinkin

Authors
  1. Mohammed H. Elkomy
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  2. David R. Drover
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  3. Jeffery L. Galinkin
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  4. Gregory B. Hammer
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  5. Kristi L. Glotzbach
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Corresponding author

Correspondence to David R. Drover.

Ethics declarations

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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Elkomy, M.H., Drover, D.R., Galinkin, J.L. et al. Pharmacodynamic Analysis of Morphine Time-to-Remedication Events in Infants and Young Children After Congenital Heart Surgery. Clin Pharmacokinet 55, 1217–1226 (2016). https://doi.org/10.1007/s40262-016-0398-z

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  • DOI: https://doi.org/10.1007/s40262-016-0398-z

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