title: Oral morphine dosing predictions based on single dose in healthy children undergoing surgery.
abstract: BACKGROUND
  Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose.
  
  
  OBJECTIVE
  The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens.
  
  
  METHODS
  Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg-1, 200 mcg·kg-1, 300 mcg·kg-1). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG), and absorption half-time (TABS). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg-1) at different dosing intervals (3, 4, 5, 6, 8, 12 h).
  
  
  RESULTS
  The oral morphine formulation had F 0.298 (CV 36.5%), TLAG0.45 (CV 63.6%) h and TABS0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg-1achieved a mean CMAX10 mcg·l-1. Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l-1; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l-1at steady state.
  
  
  CONCLUSIONS
  Oral morphine 200 mcg·kg-1then 100 mcg·kg-14 h or 150 mcg·kg-16 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.
authors: Department of Anaesthesia, Great Ormond Street Hospital, London, UK.
authors: Joy M
authors: JM
authors: Dawes
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Erin M
authors: EM
authors: Cooke
authors: Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand.
authors: Jacqueline A
authors: JA
authors: Hannam
authors: Department of Anaesthesia, Evelina London Children's Hospital and St Thomas' Hospital, London, UK.
authors: Katherine A
authors: KA
authors: Brand
authors: Department of Anaesthesia, Royal Hospital for Sick Children, Edinburgh, UK.
authors: Pamela
authors: P
authors: Winton
authors: Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors: Ricardo
authors: R
authors: Jimenez-Mendez
authors: Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children, Toronto, ON, Canada.
authors: Katarina
authors: K
authors: Aleksa
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Gillian R
authors: GR
authors: Lauder
authors: Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors: Bruce C
authors: BC
authors: Carleton
authors: Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children, Toronto, ON, Canada.
authors: Gideon
authors: G
authors: Koren
authors: Departments of Paediatrics, University of Western Ontario, London, ON, Canada.
authors: Michael J
authors: MJ
authors: Rieder
authors: Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand.
authors: Brian J
authors: BJ
authors: Anderson
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Carolyne J
authors: CJ
authors: Montgomery
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013514:Surgical Procedures, Operative
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: analgesics; morphine; opioids; pediatrics; pharmacokinetics; toxicity