This 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®). One goal of CPIC is to provide peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing the use of pharmacogenomic tests into actionable prescribing decisions for patient care. CPIC guidelines follow standardized formats, include systematic grading of evidence and clinical recommendations, use standardized terminology, are peer-reviewed, and are published in a leading journal (in partnership with Clinical Pharmacology and Therapeutics) with simultaneous posting to cpicpgx.org, where they are regularly updated.
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 protein while other variants result in a normal-functioning CYP2D6 protein. A duplication of variants can lead to a hyper-active CYP2D6 protein. 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.
a Alternatives that are not affected by this CYP2D6 phenotype include morphine and non-opioid analgesics. Some other opioid analgesics, such as hydrocodone and oxycodone, are metabolized by CYP2D6. To avoid treatment complications, opioids that are not metabolized by CYP2D6, including morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone, along with non-opioid analgesics, may be considered alternatives for use in CYP2D6 poor and ultrarapid metabolizers.
b There is substantial evidence for decreased efficacy of tramadol in poor metabolizers and a single case report of toxicity in an ultrarapid metabolizer with renal impairment following tramadol use post-surgery. Use of other analgesics in CYP2D6 poor and ultrarapid metabolizers is preferable.
*Guidelines for treatment based on metabolizer statuses are determined by the Clinical Pharmacogenomics Implementation Consortium (CPIC®).
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%.
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.
Other drugs with CYP2D6 interactions can be found here.