CDA Essentials 2018 • Volume 5 • Issue 2

40 | 2018 | Issue 2 S upporting Y our P ractice Codeine is converted to morphine in vivo by the cytochrome P450 2D6 (CYP2D6) enzyme, which is encoded in the CYP2D6 gene. This gene is highly polymorphic and the multiple identified variants affect the rate of metabolism of drugs. 5 Ultra-rapid metabolizers convert a larger amount of ingested codeine to morphine. Children with these genetic variants are at a higher risk of developing toxicity, as they have higher concentrations of morphine compared with normal metabolizers. 7 In 2015, the United States Food and Drug Administration warned of the possible toxicity of codeine use for tonsillectomy and adenoidectomy in children. Such use is now contraindicated. 8 Our data suggest that a significant number of prescriptions for codeine were for >3 days, which may contribute to the risk of toxicity through accumulation of morphine. Given the highly variable phenotypic distribution of CYP2D6, variation in codeine’s analgesic activity is wide. The percentage of children with an extensive or ultra-rapid metabolism phenotype varies from 2% to 90% depending on ethnicity, 6 making codeine’s potential toxicity difficult to predict without genotyping. Because morphine can accumulate rapidly and result in respiratory depression, it should not be prescribed for more than 3 days. 10 Health Canada has recommended against using codeine for children under 12. 11 Children who require a longer duration of medication should be genotyped to determine their metabolizer phenotype. This is especially important for children who might be ultra-rapid metabolizers. Clinical practice guidelines for the safe and effective use of codeine based on metabolizer phenotype are available to guide clinicians. 6 Several safeguards can be implemented to mitigate over-prescribing of narcotic analgesics. Pharmacists can be more vigilant in screening codeine prescriptions for children and contact the prescriber to discuss appropriate dose and day supply of opioids or even recommend a non-opioid analgesic, such as acetaminophen or ibuprofen. Studies have shown that acetaminophen is at least as effective at inducing analgesia as codeine alone 12 and that ibuprofen-codeine combination tablets are no more efficacious than ibuprofen alone in relieving pain. 13 Other safeguards include prescription monitoring programs. A recent study in New York 17 collected data from a monitoring program for opioids prescribed by dentists three months before the program was established and during two consecutive three-month periods after implementation of the program. By the end of the study, the number of opioid prescriptions had decreased by 78%. Moreover, the number of non- opioid prescriptions, such as acetaminophen, increased during the same period ( p < 0.05). The results of our study suggest that, for 50% of children, dentists are prescribing codeine for far too long a duration to avoid potential morphine accumulation and are not following current treatment guidelines. 9 a References Complete list of references available at: jcda.ca/h5 Evidence of pharmacogenomic variation in codeine metabolism and related respiratory depression in children has led to drug label warnings about the use of codeine by children.