Tramadol (Ultram) – CYP2D6
Rationale
This drug gene interaction (DGI) pertains to the interaction between the CYP2D6 gene and tramadol. Tramadol (brand name Ultram®) is used to treat moderate to severe pain. It belongs to a class of drugs known as opioids. Opioids bind to opioid receptors on nerve cells in order to block pain messages sent from the body through the spinal cord to the brain, resulting in pain relief. Extensive literature indicates that patients with specific genetic differences in the CYP2D6 gene may require dose adjustments of tramadol or alternative medications in order to achieve therapeutic benefits.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The CYP2D6 (sounds like “sip-2-D-6”) gene encodes an enzyme that is involved in the metabolism of codeine. There are different CYP2D6 gene versions, or variants, and each has a different effect on how well codeine works in the body. There are different CYP2D6 gene versions, or variants, and each has a different effect on how well codeine is metabolized in the body. Some variants result in a non-functioning or low-functioning CYP2D6 enzyme while other variants result in a normal-functioning CYP2D6 enzyme. A duplication of variants can lead to a hyper-active CYP2D6 enzyme. Different ‘metabolizer statuses’ are assigned to patients depending on their genetic information. See chart below for a description of each metabolizer status and any implications for treatment.
CYP2D6 metabolizer status |
Variants (genotype) |
Implication for tramadol |
|---|---|---|
| Poor metabolizer | ONLY no-function alleles | Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief. |
| Intermediate metabolizer | ONE decreased function allele AND ONE no-function allele
OR TWO decreased function alleles OR ONE normal function AND ONE no-function allele |
Reduced morphine formation. |
| Normal metabolizer | TWO normal function alleles
OR ONE normal function AND ONE decreased function allele |
Normal morphine formation. |
| Ultrarapid metabolizer | MORE THAN TWO copies of functional alleles | Increased formation of morphine following codeine administration, leading to higher risk of toxicity. |
Results Interpretation
Tramadol is a medicine used to manage several different conditions and your genes can affect how well the drug works. CPIC updates guidelines on how to best use these genetic results to support patient care. To view dosing recommendations for opioids based on CYP2D6 phenotypes, click on the most recent guideline publication on CPIC’s website and scroll down to Table 3.
Please review the FDA packet insert for additional clinical considerations such as contradictions as well as dose adjustments based on age, organ function, and drug-drug interactions.
Quality of Results
Genotyping for CYP2D6 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.
Supporting Evidence
Supporting Evidence
The Pharmacogenetics of Tramadol
Lassen D, Damkier P, Brosen K, Clin Pharmacokinet. 2015 Aug, 54 (8): 825-36
OBJECTIVE: Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the various transporters [adenosine triphosphate-binding cassette B1/multidrug resistance 1/P-glycoprotein, organic cation transporter 1, serotonin transporter (SERT), norepinephrine transporter (NET)] and receptor genes (opioid receptor μ 1 gene) give possible genetic differences that might affect the pharmacokinetics and/or pharmacodynamics of tramadol. Therefore, the aim of this review is to present a systematic walkthrough of all possible genetic factors involved in the pharmacology of tramadol.
METHODS: A systematic literature search was conducted in PubMed and EMBASE involving all metabolic enzymes, drug transporters and receptors, as well as SERT and NET that are involved in the pharmacokinetics and pharmacodynamics of tramadol. An additional search on population pharmacokinetics with genetic factors as covariates was performed separately.
RESULTS: A total of 56 studies (45 cohort and case-control studies, three case reports, six in vitro studies, and two animal studies) were included.
CONCLUSIONS: In this systematic review, the current knowledge on all possible genetic factors that might influence the metabolism or clinical efficacy of tramadol has been collected and summarized. Only the effect of CYP2D6 polymorphisms on the metabolism of tramadol and the consequent effect on pain relief has been thoroughly studied and sufficiently established as clinically relevant.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Codeine and CYP2D6
This link will take you to the main page on the CPIC website relating to CYP2D6 and codeine that also includes information on tramadol. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status). Additionally, examples of point of care clinical decision support can be found at the bottom of the page.
Please note that additional drugs may have CYP2D6 interactions. For more information on drug-gene interactions, please use the search feature on the CPIC website.