• Sjoerd de Hoogd, Sebastiaan C Goulooze, Abraham J Valkenburg, KrekelsElke H JEHJDivision of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands., Monique van Dijk, Dick Tibboel, and KnibbeCatherijne A JCAJDepartment of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands. c.knibbe@antoniusziekenhuis.nl.Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden.
• Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.
• Pediatr. Res. 2021 Feb 18.

BackgroundMorphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine.MethodsData on morphine rescue requirements guided by validated pain scores in children (n = 35, 3-36 months) after cardiac surgery receiving morphine as loading dose (100 μg kg-1) with continuous infusion (40 μg kg-1 h-1) from a previous study on morphine pharmacokinetics were analysed using repeated time-to-event (RTTE) modelling.ResultsDuring the postoperative period (38 h (IQR 23-46)), 130 morphine rescue events (4 (IQR 1-5) per patient) mainly occurred in the first 24 h (107/130) at a median morphine concentration of 29.5 ng ml-1 (range 7-180 ng ml-1). In the RTTE model, the hazard of rescue morphine decreased over time (half-life 18 h; P < 0.001), while the hazard for rescue morphine (21.9% at 29.5 ng ml-1) increased at higher morphine concentrations (P < 0.001).ConclusionsIn this study on protocolized morphine analgesia in children, rescue morphine was required at a wide range of morphine concentrations and further increase of the morphine concentration did not lead to a decrease in hazard. Future studies should focus on a multimodal approach using other opioids or other analgesics to treat breakthrough pain in children.ImpactIn children receiving continuous morphine infusion, administration of rescue morphine is an indicator for insufficient effect or an event. Morphine rescue events were identified at a wide range of morphine concentrations upon a standardized pain protocol consisting of continuous morphine infusion and morphine as rescue boluses. The expected number of rescue morphine events was found to increase at higher morphine concentrations. Instead of exploring more aggressive morphine dosing, future research should focus on a multimodal approach to treat breakthrough pain in children.

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