Letters to the Editor: Genetic Testing
Regarding the May 2016 issue, I wanted to address a few errors in the article by Dr. Singa about genetic testing.1 It is important to discuss these corrections as they reflect the most common errors and misconceptions in pain management pharmacogenetics. Dr. Singa did a very nice job in succinctly describing the reasons for the recent increase in the use of these methodologies, as well as their primary advantages for clinical decision making. I am extremely happy to see that other residents are being clinically exposed to the advances in pharmacogenomics. In our practice, we have been using these tests for several years to the great advantage of both clinicians and patients.
The primary and most common errors regarding cytochrome (CYP)-mediated opiate metabolism are with hydrocodone and methadone. The primary—and almost exclusively clinically relevant CYP metabolic pathway—is via 3A4 from hydrocodone to norhydrocodone. A much smaller amount is converted by 2D6 to hydromorphone. Studies have confirmed that the pain relief from hydrocodone is related to blood levels of norhydrocodone, not the hydromorphone.
Recently, the Food and Drug Administration (FDA) approved extended-release hydrocodone products, and corresponding studies confirmed the CYP-3A4-dependent status of all hydrocodone products. Prior to 2002 and the completion of the human genome project, the FDA did not require all relevant metabolic enzymes for a given drug to appear in the package insert.
Secondly, methadone metabolism is commonly misquoted. It is the only opioid that utilizes all 5 CYP enzymes responsible for 90% of opiate metabolism. Considering that none of the CYP enzymes has greater than 60% normal activity (extensive metabolizer) population distribution, or less than 15% normal activity population distribution, which can vary with age, it can be understood why methadone can have a half-life anywhere between 5 and 150 hours. Methadone products are 50% S and R enantiomers with S being CYP-2B6 metabolized and responsible for the rare incidence of torsades de pointes (polymorphic ventricular tachycardia), such that those at risk can be further identified.
Especially given the rapidly growing clinical use and utility of pharmacogenomic metabolic testing, it is essential that all sources quote the currently considered, correct information.
Andrew A. Konen, MD
Medical Director, Baylor Center for Pain Management
Clinical Professor of Pain Management
Texas A&M HSC-COM