Codeine and CYP2D6

Codeine is a medication with multiple uses; most commonly being used for pain and cough suppression. Codeine targets pain receptors in the brain called mu receptors. Codeine alters pain perception in the body and reduces activity in the parts of the brain involved in coughing. Codeine is used to treat the symptoms of pain and coughing, but it does not treat the underlying cause of these symptoms.

Codeine can come in several forms including tablets, capsules, and solutions. Depending on the severity of the pain, codeine can be taken every 4 to 6 hours as needed. Codeine should not be used in patients under the age of 16. The body naturally converts some codeine into morphine, so it may be addictive and habit-forming, making it especially important to follow the treatment regimen outlined by a physician.

The enzyme that can impact how well codeine works is known as “cytochrome P450 2D6” (CYP2D6; “sip two dee six”). The sequence of DNA bases that make up the gene that produces this enzyme converts varying levels of codeine to morphine, which produces the pain-relieving and cough suppressing effects. Patients can possess a variety of forms of this enzyme, each impacting how well codeine will work for them.

Depending on what variant CYP2D6 gene a person has, they can produce too much morphine from codeine, too little morphine, or the desired amount. The amount of morphine produced determines how well codeine works, along with other non-genetic factors.

Patients that make too much morphine can experience drowsiness and an increased risk for other side effects. About 5% of people have the version of the gene that results in overproduction of morphine. About 7% of patients have a version of the gene that results in underproduction of morphine. These individuals will likely not experience any benefit from codeine. Finally, most patients (88%) have normal version of CYP2D6, and will experience the intended relief from mild to moderate pain. In order to find out if codeine will work for a patient, a genetic test can be used in order to determine which version of CYP2D6 is present.

An African-American female, Jessica, starts taking codeine with acetaminophen for the first time. She is the mother of a breastfed baby, and has been prescribed codeine for pain-relief associated with the recent childbirth. She does not know anything about her CYP2D6 genotype and asked her pediatrician if it would be okay to breastfeed her baby while taking this medication. Jessica learned that only a little bit of active codeine, called morphine, enters the breast milk and will not hurt the baby. Ever since the first day she began taking codeine with acetaminophen, she felt very drowsy and nauseous. Four days later, her baby is unusually sleepy and has grayish looking skin. When the baby is taken to the pediatrician for examination, the doctor orders a blood test. The results showed a morphine level much higher than normal. Jessica consents to a genetic test and finds out she has a form of the CYP2D6 gene that makes her convert codeine to morphine much more than the average person.

Mothers to breastfeed babies should be cautious if they are prescribed codeine-containing medications. Although the majority of people have normal CYP2D6 function, some variants are overactive and make dangerous amounts of morphine from normal doses of codeine. If taking codeine-containing medications while breastfeeding, mothers should pay attention to symptoms of excess morphine, such as strong feelings of nausea and drowsiness. If this occurs, it could mean the mother has a ‘dangerous’ variant of the CYP2D6 gene and should talk to their doctor or pharmacist right away.

CYP2D6 testing does not completely rule out the risks of taking codeine, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to codeine. The links are to external websites and will be checked regularly for consistency.

• Codeine Prescribing Information
• Codeine Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Codeine

Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clinical Pharmacology and Therapeutics. 2012 Feb;91(2): 321-6.

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Codeine Sulfate; [cited 2012 Oct 23]; [about 6 screens]. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fa3ed180-298a-4f9d-9d05-15182d7218bf/.

Madadi P, Moretti M, Djokanovic N, et al. Guidelines for maternal codeine use during breastfeeding. Canadian Family Physician. 2009;55:1077–1078.

Madadi P, Ross CJ, Hayden MR, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case–control study. Clinical Pharmacology & Therapeutics. 2008;85(1):31–35.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Codeine; [cited 2012 Oct 23]; [about 2 screens]. Available from: https://www.pharmgkb.org/chemical/PA449088/.