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Variability of transdermal fentanyl metabolism and excretion in pain patients

Joanna M. Cole, BA, Brookie M. Best, PharmD, MAS, Amadeo J. Pesce, PhD, DABCC


Background: The rising popularity of the fentanyl transdermal patch and the striking number of deaths attributed to its prescribed use have brought attention to the large variability of fentanyl metabolism and the need for predictive models to prevent toxicity.
Objective: The purpose of this study was to determine the amount of both intrasubject and intersubject variability in fentanyl metabolism and excretion, using urinary excretion data from patients with chronic pain prescribed the fentanyl transdermal patch.
Methods: Liquid chromatography tandem mass spectrometry analytical technique was used to quantitate fentanyl and norfentanyl concentrations in spot urine specimens, after incubation with glucuronidase. Descriptive statistics and graphical analysis were conducted using Microsoft Excel 2007. Analysis was conducted on 206 subjects with ≥2 visits listing transdermal fentanyl as current medication. Outliers and subjects with no detectable levels of drug were excluded, resulting in subject populations of 200 (all subjects analyzed) and 166 (subjects with drug concentrations above the instrument detection limit for all visits).
Results: The geometric mean metabolic ratio (MR) of norfentanyl to fentanyl was 6.2×÷ 2.4. A wide distribution was observed in total fentanyl load (1,000-fold) and MR (200-fold). The intersubject geometric standard deviation in MR was 2.4 (95% confidence interval [CI] for MR: 1-37) and the intrasubject geometric standard deviation was 1.8 (95% CI for MR: 2-20).
Conclusion: The level of intrasubject variability over time in the pharmacokinetics of the fentanyl patch is much greater than previously observed and may be due to variability in absorption, interference of metabolism by concomitant medications, and variable metabolism due to genetic polymorphisms. The variation in the MR between subjects and within subjects may explain the unpredictable adverse effects observed with use of transdermal fentanyl.


fentanyl patch, metabolism, excretion

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Muijsers RBR, Wagstaff AJ: Transdermal fentanyl: An updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs. 2001; 61: 2289-2307.

Duragesic: Fentanyl transdermal system [full prescribing information]. Raritan, NJ: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc, July 2009. Available at Accessed August 20, 2009.

Alonso-Zaldivar R: FDA renews warning for powerful painkiller patch—The agency says the drug has been misused and wrongly prescribed. Los Angeles Times. December 22, 2007. Available at Accessed August 4, 2009.

Lamb E: Top 200 drugs of 2008. Pharmacy Times. May 15, 2009. Available at Accessed August 5, 2009.

Moore TJ, Cohen MR, Furberg CD: Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med. 2007; 167: 1752-1759.

Schneider E, Brune K: Opioid activity and distribution of fentanyl metabolites. Naunyn Schmiedebergs Arch Pharmacol. 1986; 334: 267-274.

Poklis A, Backer R: Urine concentrations of fentanyl and norfentanyl during application of duragesic transdermal patches. J Anal Toxicol. 2004; 28: 422-425.

Labroo RB, Paine MF, Thummel KE, et al.: Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: Implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997; 25: 1072-1080.

Goromaru T, Matsuura H, Yoshimura N, et al.: Identification and quantitative determination of fentanyl metabolites in patients by gas chromatography-mass spectrometry. Anesthesiology. 1984; 61: 73-77.

Tateishi T, Krivoruk Y, Ueng Y-F, et al: Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg. 1996; 82: 167-172.

Feierman DE, Lasker JM: Metabolism of fentanyl, a synthetic opioid analgesic by human liver microsomes: Role of CYP3A4. Drug Metab Dispos. 1996; 24: 932-939.

Guitton J, Buronfosse T, Désage M, et al.: Possible involvement of multiple cytochrome P450s in fentanyl and sufentanil metabolism as opposed to alfentanil. Biochem Pharmacol. 1997; 53: 1613-1619.

Jin M, Gock SB, Jannetto PJ, et al.: Pharmacogenomics as molecular autopsy for forensic toxicology: Genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. J Anal Toxicol. 2005; 29: 590-598.

Mikel C, Almazan P, West R, et al.: LC-MS/MS extends the range of drug analysis in pain patients. Ther Drug Monit. 2009; 31: 746-748.

Solassol I, Bressolle F, Caumette L, et al.: Inter- and intraindividual variabilities in pharmacokinetics of fentanyl after repeated 72-hr transdermal applications in cancer pain patients. Ther Drug Monit. 2005; 27: 491-498.

Portenoy RK, Southam MA, Gupta SK, et al.: Transdermal fentanyl for cancer pain: Repeated dose pharmacokinetics. Anesthesiology. 1993; 78: 36-43.

Durcan TG, Sockalingham I, Hanna MH, et al.: Pharmacokinetic study of repeated 72 hour applications of TTS-fentanyl. Br J Anaesth. 1995; 74(Suppl 1): 139.

Larsen RH, Nielsen F, Sørensen JA, et al.: Dermal penetration of fentanyl: Inter- and intraindividual variations. Pharmacol Toxicol. 2003; 93: 244-248.

Sera S, Goromaru T, Sameshima T, et al.: Individual variations in the elimination process of fentanyl in patients. Xenobiol Metabol Dispos. 2000; 15: 495-503.

Varvel JR, Shafer SL, Hwang SS, et al.: Absorption characteristics of transdermally administered fentanyl. Anesthesiology. 1989; 70: 928-934.

Gourlay GK, Kowalski SR, Plummer JL, et al.: The transdermal administration of fentanyl in the treatment of postoperative pain: Pharmacokinetics and pharmacodynamic effects. Pain. 1989; 37: 193-202.

Van Bastelaere M, Rolly G, Van Peer A: Pharmacokinetic behaviour of transdermal fentanyl. Br J Anaesth. 1993; 70(Suppl 1): 75.

Reilly CS, Wood AJJ, Wood M: Variability of fentanyl pharmacokinetics in man: Computer predicted plasma concentrations for three intravenous dosage regimens. Anaesthesia. 1984; 40: 837-843.

Kokubun H, Matoba M, Hoka S, et al.: Relationship between serum fentanyl concentration and transdermal fentanyl dosage, and intra-individual variability in fentanyl concentration after application of fentanyl patches in patients with cancer pain. Jpn J Pharm Health Care Sci. 2007; 33: 200-205.

Anderson DT, Muto JJ: Duragesic transdermal patch: Postmortem tissue distribution of fentanyl in 25 cases. J Anal Toxicol. 2000; 24: 627-634.

Murphy MR, Hug CC Jr, McClain DA: Dose-independent pharmacokinetics of fentanyl. Anesthesiology. 1983; 59: 537-540.

Ashburn MA, Ogden LL, Zhang J, et al.: Pharmacokinetics of transdermal fentanyl delivered with and without controlled heat. J Pain. 2003; 4: 291-297.

Norfentanyl: SciFinder [database online]. Washington, DC: The American Chemical Society, 2009. Available at Accessed August 19, 2009.

Cicero TJ, Inciardi JA, Surratt H: Trends in the use and abuse of branded and generic extended release oxycodone and fentanyl products in the United States. Drug Alcohol Depend. 2007; 91(2-3): 115-120.

Fodale V, Mafrica F, Santamaria LB, et al.: Killer fentanyl: Is the fear justified [editorial]? Expert Opin Drug Saf. 2008; 7: 213-217.



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