title: Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients.
abstract: Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis.
  
  
  
  Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis.
  
  
  
  The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates.
  
  
  
  Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients.
authors.affiliation: Department of Hospital Pharmacy, Erasmus Medical Centre, wytemaweg 80-na 219, 3015, Rotterdam, The Netherlands. l.franken@erasmusmc.nl.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Franken
authors.affiliation: Palliative Care Centre, Laurens Cadenza, Rotterdam, The Netherlands.|Intensive Care, Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Anniek D
authors.initials: AD
authors.lastname: Masman
authors.affiliation: Department of Hospital Pharmacy, Erasmus Medical Centre, wytemaweg 80-na 219, 3015, Rotterdam, The Netherlands.
authors.forename: Brenda C M
authors.initials: BC
authors.lastname: de Winter
authors.affiliation: Department of Hospital Pharmacy, Erasmus Medical Centre, wytemaweg 80-na 219, 3015, Rotterdam, The Netherlands.
authors.forename: Birgit C P
authors.initials: BC
authors.lastname: Koch
authors.affiliation: Palliative Care Centre, Laurens Cadenza, Rotterdam, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Baar
authors.affiliation: Intensive Care, Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.|Pain Expertise Centre, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Department of Hospital Pharmacy, Erasmus Medical Centre, wytemaweg 80-na 219, 3015, Rotterdam, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.affiliation: Hospital Pharmacy-Clinical Pharmacology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D003198:Computer Simulation; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009020:Morphine / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000493:pharmacokinetics; D011446:Prospective Studies; D012709:Serum Albumin; D019452:Terminally Ill
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D012709:Serum Albumin; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide