Clinical Pharmacokinetics

, Volume 53, Issue 6, pp 553–563 | Cite as

Evidence-Based Morphine Dosing for Postoperative Neonates and Infants

  • Elke H. J. Krekels
  • Dick Tibboel
  • Saskia N. de Wildt
  • Ilse Ceelie
  • Albert Dahan
  • Monique van Dijk
  • Meindert Danhof
  • Catherijne A. J. Knibbe
Original Research Article


Background and Objectives

From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 μg/kg1.5/h, with a 50 % dose reduction in neonates with a postnatal age (PNA) <10 days, yield similar morphine and metabolite concentrations across patients younger than 3 years. Compared with traditional dosing, this model-derived dosing regimen yields significantly reduced doses in neonates aged <10 days.


Concentration predictions of the population model were prospectively evaluated in postoperative term neonates and infants up to the age of 1 year who received morphine doses according to the model-derived algorithm. The efficacy of this dosing algorithm was evaluated using morphine rescue medication and actual average infusion rates.


Morphine and metabolite concentrations were accurately predicted by the paediatric pharmacokinetic morphine model. With regard to efficacy, 5 out of 18 neonates (27.8 %) with a PNA of <10 days needed rescue medication versus 18 of the 20 older patients (90 %) (p = 0.06). The median (interquartile range [IQR]) total morphine rescue dose was 0 (0–20) μg/kg in younger patients versus 193 (19–362) μg/kg in older patients (p = 0.003). The median (IQR) actual average morphine infusion rate was 4.4 (4.0–4.8) μg/kg/h in younger patients versus 14.4 (11.3–23.4) μg/kg/h in older patients (p < 0.001).


Morphine paediatric dosing algorithms corrected for pharmacokinetic differences alone yield effective doses that prevent over-dosing for neonates with a PNA <10 days. The fact that many neonates and infants with a PNA ≥10 days still required rescue medication warrants pharmacodynamic studies to further optimize the dosing algorithm for these patients.


Morphine Infusion Rate Rescue Medication Analgesic Efficacy Morphine Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank René Mooren for analysing the plasma samples for morphine, M3G and M6G concentrations, and Ko Hagoort for critically reading the manuscript. This study was performed within the framework of the Dutch Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organisation for Scientific Research (NWO). None of the authors has any conflicts of interest that are directly relevant to the content of this article.


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Elke H. J. Krekels
    • 1
    • 2
  • Dick Tibboel
    • 2
  • Saskia N. de Wildt
    • 2
  • Ilse Ceelie
    • 2
    • 3
  • Albert Dahan
    • 3
  • Monique van Dijk
    • 2
    • 4
  • Meindert Danhof
    • 1
  • Catherijne A. J. Knibbe
    • 1
    • 2
    • 5
  1. 1.Division of Pharmacology, Leiden Academic Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
  2. 2.Intensive Care and Department of Pediatric SurgeryErasmus MC–Sophia Children’s HospitalRotterdamThe Netherlands
  3. 3.Department of AnesthesiologyLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Department of Pediatrics, Division of NeonatologyErasmus MC–Sophia Children’s HospitalRotterdamThe Netherlands
  5. 5.Department of Clinical PharmacySt. Antonius HospitalNieuwegeinThe Netherlands

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