Variability of transdermal fentanyl metabolism and excretion in pain patients

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.

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.

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 > or = 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).

The geometric mean metabolic ratio (MR) of norfentanyl to fentanyl was 6.2 x division by 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).

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.