Codeine Therapy and CYP2D6 Genotype

Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics. Codeine has also been prescribed to prevent coughing, though the antitussive administration is most often in liquid formulations and in conjunction with other medications. (1, 2) The hepatic CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, including codeine. The CYP2D6 enzyme converts codeine into its active metabolite, morphine, which provides its analgesic effect. Consequently, pain relief may be inadequate in individuals who have 2 inactive copies of CYP2D6 (“poor metabolizers”, PMs), because of reduced morphine levels. In contrast, individuals who have more than 2 normal-function copies of the CYP2D6 gene (“ultrarapid metabolizers”, UMs) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with therapeutic doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing, which in some instances can be fatal. Nursing mothers with ultrarapid CYP2D6 metabolism may also produce breast milk containing higher than expected levels of morphine that can lead to severe adverse events in their infants. (3) The FDA-drug label for codeine states that even at labeled dosage regimens, individuals who are UMs may have life-threatening or fatal respiratory depression or experience signs of overdose (Table 1). The label also contains a boxed warning, which states that respiratory depression and death have occurred in children who received codeine following tonsillectomy, adenoidectomy, or both, and had evidence of being CYP2D6 UMs. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, another analgesic should be used to avoid the risk of severe toxicity with a “normal” dose of codeine. CPIC also recommends avoiding codeine in individuals identified as CYP2D6 PMs due to the possibility of lack of effect (Table 2). (4) The Dutch Pharmacogenetics Working Group (DPWG) have published codeine dosing recommendations based on CYP2D6 genotype, and condition being treated (cough or pain), typical dosing, and additional risk factors, such as reduced kidney function or co-medication with CYP3A4 inhibitors. For UMs, the DPWG recommends an alternative to codeine for the treatment of pain (for example, oxycodone) (Table 3). (5)