title: Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients.
abstract: BACKGROUND
  An appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose-adjusted plasma fentanyl concentrations in cancer patients.
  
  
  METHODS
  Blood was collected from 21 Japanese cancer patients treated with a 24-hour trans-dermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations.
  
  
  RESULTS
  Eight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day) were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal-Wallis test and post hoc Mann-Whitney U-test, P<0.01). The factors that were found to possibly affect the dose-adjusted concentration of fentanyl included aspartate aminotransferase, C-reactive protein, and estimated glomerular filtration rate, when analyzed as six independent variables (multiple regression analysis, P<0.05).
  
  
  CONCLUSIONS
  The dose-adjusted plasma concentrations of fentanyl increased with progression of cancer cachexia. Such an increase is associated with a multifactorial and systemic syndrome in cancer cachexia patients, including lower albumin, higher C-reactive protein, and impaired kidney function. In patients with cancer cachexia, we suggest that evaluation of cancer cachexia might help pain management when using a transdermal fentanyl patch in palliative care.
authors.affiliation: Department of Oncology Pharmaceutical Care and Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Suno
authors.affiliation: Department of Oncology Pharmaceutical Care and Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishie
authors.affiliation: Department of Pharmacy, Okayama University Hospital, Okayama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kajizono
authors.affiliation: Department of Pharmacy, Okayama University Hospital, Okayama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
authors.affiliation: Faculty of Health Sciences, Okayama University Medical School, Okayama, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
keywords: LC-MS/MS; cancer pain; transdermal patch