Codeine – CYP2D6
Rationale
This drug gene interaction (DGI) pertains to the interaction between the CYP2D6 gene and codeine. Codeine is used to treat mild to moderate 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 codeine 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-dee-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 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.
CYP2D6 metabolizer status |
Prevalence of metabolizer status (% of patients) |
Variants (genotype) |
Implication for codeine |
|---|---|---|---|
| Poor metabolizer | ~5-10% | An individual carrying ONLY no-function alleles | Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief. |
| Intermediate metabolizer | ~2-11% | An individual carrying ONE reduced function allele and ONE no-function allele | Reduced morphine formation. |
| Normal metabolizer | ~77-92% | An individual carrying TWO normal function alleles OR TWO decreased function alleles OR ONE normal function with ONE no-function OR ONE normal function with ONE decreased function allele. | Normal morphine formation. |
| Ultrarapid metabolizer | ~1-2% | An individual carrying more than two copies of functional alleles | Increased formation of morphine following codeine administration, leading to higher risk of toxicity |
Patient’s genetic information is reported as a diplotype and this corresponds to a phenotype (i.e. metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “CYP2D6 diplotype-phenotype table”.
Results Interpretation
Codeine 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 and has published its current recommendations here.
Alternatives that are not affected by this CYP2D6 phenotype include morphine and non-opioid analgesics.
Tramadol and, to a lesser extent, hydrocodone and oxycodone are not good alternatives because their metabolism is affected by CYP2D6 activity; these agents should be avoided. 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; click here for more information on tramadol.
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
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. 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).
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.