Nieves Velez de Mendizabal1,2, Ricardo Jimenez-Mendez3,4,5, Erin Cooke6,7, Carolyne J Montgomery6,7, Joy Dawes6,7, Michael J Rieder8, Katarina Aleksa9, Gideon Koren9, Carlos O Jacobo-Cabral10, Rodrigo Gonzalez-Ramirez10, Gilberto Castañeda-Hernandez10, Bruce C Carleton11,12,13. 1. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA. 2. Indiana Clinical and Translational Sciences Institute (CTSI), West Walnut Street, Indianapolis, IN, 46202, USA. 3. Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada. 4. Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, Canada. 5. Child & Family Research Institute, 950 West 28th Avenue, Rm. A3-207, Vancouver, BC, V5Z 4H4, Canada. 6. Pediatric Anesthesia Research Team, University of British Columbia, Vancouver, Canada. 7. Department of Pediatric Anesthesia, BC Children's Hospital, Vancouver, Canada. 8. Department of Physiology and Pharmacology, Western University, London, Canada. 9. The Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, Canada. 10. Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico, DF, Mexico. 11. Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada. bcarleton@popi.ubc.ca. 12. Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, Canada. bcarleton@popi.ubc.ca. 13. Child & Family Research Institute, 950 West 28th Avenue, Rm. A3-207, Vancouver, BC, V5Z 4H4, Canada. bcarleton@popi.ubc.ca.
Abstract
BACKGROUND AND OBJECTIVES: Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. METHODS: The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. RESULTS: A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. CONCLUSION: This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.
RCT Entities:
BACKGROUND AND OBJECTIVES: Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatientanalgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. METHODS: The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. RESULTS: A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. CONCLUSION: This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.
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