Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients

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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).

Conclusion

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.

Most cited references 14

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Towards a simple objective framework for the investigation and treatment of cancer cachexia: the Glasgow Prognostic Score.

Euan Douglas, Donald C. McMillan (2014)

Progress in the treatment of progressive involuntary weight loss in patients with cancer (cancer cachexia) remains dismally slow. Cancer cachexia and its associated clinical symptoms, including weight loss, altered body composition, poor functional status, poor food intake, and poorer quality of life, have long been recognised as indicators of poorer prognosis in the patient with cancer. In order to make some progress a starting point is to have general agreement on what constitutes cancer cachexia. In recent years a plethora of different definitions and consensus statements have been proposed as a framework for investigation and treatment of this debilitating and terminal condition. However, there are significant differences in the criteria used in these and all include poorly defined or subjective criteria and their prognostic value has not been established. The aim of the present review was to examine the hypothesis that a systemic inflammatory response accounts for most of the effect of cancer cachexia and its associated clinical symptoms on poor outcome in patients with cancer. Furthermore, to put forward the case for the Glasgow Prognostic Score to act a simple objective framework for the investigation and treatment of cancer cachexia.

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Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved.

Jose Gomez, J Castell-Conesa, R Jover … (2002)

The hepatic drug-metabolizing cytochrome P-450 (CYP) enzymes are down-regulated during inflammation. In vitro studies with hepatocytes have shown that the cytokines released during inflammatory responses are largely responsible for this CYP repression. However, the signaling pathways and the cytokine-activated factors involved remain to be properly identified. Our research has focused on the negative regulation of CYP3A4 (the major drug-metabolizing human CYP) by interleukin 6 (IL-6) (the principal regulator of the hepatic acute-phase response). CYP3A4 down-regulation by IL-6 requires activation of the glycoprotein receptor gp130; however, it does not proceed through the JAK/STAT pathway, as demonstrated by the overexpression of a dominant-negative STAT3 factor by means of an adenoviral vector. The involvement of IL-6-activated kinases such as extracellular signal-regulated kinase ERK1/2 or p38 is also unlikely, as evidenced by the use of specific chemical inhibitors. It is noteworthy that IL-6 caused a moderated induction in the mRNA of the transcription factor C/EBPbeta (CCAAT-enhancer binding protein beta) and a marked increase in the translation of C/EBPbeta-LIP, a 20-kDa C/EBPbeta isoform lacking a transactivation domain. Adenovirus-mediated expression of C/EBPbeta-LIP caused a dose-dependent repression of CYP3A4 mRNA, whereas overexpression C/EBPalpha and C/EBPb-LAP (35 kDa) caused a significant induction. Our results support the idea that IL-6 down-regulates CYP3A4 through translational induction of C/EBPbeta-LIP, which competes with and antagonizes constitutive C/EBP transactivators. From a clinical point of view, these findings could be relevant in the development of therapeutic cytokines with a less repressive effect on hepatic drug-metabolizing enzymes.

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Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions.

Simon Paine, K Thummel, Evan D. Kharasch … (1997)

The synthetic opioid fentanyl undergoes extensive metabolism in humans. Systemic elimination occurs primarily by hepatic metabolism. When administered as a lozenge for oral transmucosal absorption, swallowed fentanyl is subject to first pass metabolism in the liver and possibly small intestine. Little is known, however, about the identity and formation of human fentanyl metabolites. This investigation identified routes of human liver microsomal fentanyl metabolism and their relative importance, tested the hypothesis that fentanyl is metabolized by human duodenal microsomes, and identified the predominantly responsible cytochrome P450 isoforms. A GC/MS assay using deuterated internal standards was developed for fentanyl metabolites. Piperidine N-dealkylation to norfentanyl was the predominant pathway of liver microsomal metabolism. Amide hydrolysis to despropionylfentanyl and alkyl hydroxylation to hydroxyfentanyl were comparatively minor pathways. Hydroxynorfentanyl was identified as a minor, secondary metabolite arising from N-dealkylation of hydroxyfentanyl. Liver microsomal norfentanyl formation was significantly inhibited by the mechanism-based P450 3A4 inhibitor troleandomycin and the P450 3A4 substrate and competitive inhibitor midazolam, and was significantly correlated with P450 3A4 protein content and catalytic activity. Of six expressed human P450 isoforms (P450s 1A2, 2B6, 2C9, 2D6, 2E1, and 3A4), only P450 3A4 exhibited significant fentanyl dealkylation to norfentanyl. These results indicate the predominant role of P450 3A4 in the primary route of hepatic fentanyl metabolism. Human duodenal microsomes also catalyzed fentanyl metabolism to norfentanyl; the average rate was approximately half that of hepatic metabolism. Rates of duodenal norfentanyl formation were diminished by troleandomycin and midazolam, and were significantly correlated with P450 3A4 activity, suggesting a prominent role for P450 3A4. These results demonstrate that human intestinal as well as liver microsomes catalyze fentanyl metabolism, and N-dealkylation by P450 3A4 is the predominant route in both organs. The fraction of fentanyl lozenge that is swallowed likely undergoes significant intestinal, as well as hepatic, first-pass metabolism. Intestinal and hepatic first-pass metabolism, as well as systemic metabolism, may be subject to individual variability in P450 3A4 expression and to drug interactions involving P450 3A4.

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Author and article information

Journal

Journal ID (nlm-ta): Ther Clin Risk Manag

Journal ID (iso-abbrev): Ther Clin Risk Manag

Journal ID (publisher-id): Therapeutics and Clinical Risk Management

Title: Therapeutics and Clinical Risk Management

Publisher: Dove Medical Press

ISSN (Print): 1176-6336

ISSN (Electronic): 1178-203X

Publication date Collection: 2015

Publication date (Electronic): 08 May 2015

Volume: 11

Pages: 751-757

Affiliations

[1 ]Department of Oncology Pharmaceutical Care and Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

[2 ]Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

[3 ]Department of Pharmacy, Okayama University Hospital, Okayama, Japan

[4 ]Faculty of Health Sciences, Okayama University Medical School, Okayama, Japan

Author notes

Correspondence: Manabu Suno, Department of Oncology Pharmaceutical Care and Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama 700-8558, Japan, Tel +81 86 235 6597, Fax +81 86 235 6597, Email sunoma@ 123456pharm.okayama-u.ac.jp

[*]

These authors contributed equally to this work

Article

Publisher ID: tcrm-11-751

DOI: 10.2147/TCRM.S79374

PMC ID: 4431473

PubMed ID: 26056457

SO-VID: 7a955911-7f44-4489-99e4-02a4d32a95bc

License:

The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients

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Abstract

Background

Methods

Results

Conclusion

Most cited references 14

Towards a simple objective framework for the investigation and treatment of cancer cachexia: the Glasgow Prognostic Score.

Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved.

Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions.

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