title: A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.|Indiana Clinical and Translational Sciences Institute (CTSI), West Walnut Street, Indianapolis, IN, 46202, USA.
authors.forename: Nieves
authors.initials: N
authors.lastname: Velez de Mendizabal
authors.affiliation: Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.|Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, Canada.|Child & Family Research Institute, 950 West 28th Avenue, Rm. A3-207, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Jimenez-Mendez
authors.affiliation: Pediatric Anesthesia Research Team, University of British Columbia, Vancouver, Canada.|Department of Pediatric Anesthesia, BC Children's Hospital, Vancouver, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Cooke
authors.affiliation: Pediatric Anesthesia Research Team, University of British Columbia, Vancouver, Canada.|Department of Pediatric Anesthesia, BC Children's Hospital, Vancouver, Canada.
authors.forename: Carolyne J
authors.initials: CJ
authors.lastname: Montgomery
authors.affiliation: Pediatric Anesthesia Research Team, University of British Columbia, Vancouver, Canada.|Department of Pediatric Anesthesia, BC Children's Hospital, Vancouver, Canada.
authors.forename: Joy
authors.initials: J
authors.lastname: Dawes
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
authors.affiliation: The Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Katarina
authors.initials: K
authors.lastname: Aleksa
authors.affiliation: The Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.affiliation: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico, DF, Mexico.
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Jacobo-Cabral
authors.affiliation: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico, DF, Mexico.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gonzalez-Ramirez
authors.affiliation: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico, DF, Mexico.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernandez
authors.affiliation: Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada. bcarleton@popi.ubc.ca.|Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, Canada. bcarleton@popi.ubc.ca.|Child & Family Research Institute, 950 West 28th Avenue, Rm. A3-207, Vancouver, BC, V5Z 4H4, Canada. bcarleton@popi.ubc.ca.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003061:Codeine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000097:blood; D010149:Postoperative Pain / Q000097:blood / Q000188:drug therapy; D011110:Polymorphism, Genetic; D062606:Tertiary Care Centers
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C061773:codeine-6-glucuronide; D019389:Cytochrome P-450 CYP2D6; C018108:morphine-3-glucuronide; D003061:Codeine