New evidence about an old drug--risk with codeine after adenotonsillectomy.

D the past 10 years, efforts in pharmaco genomics have generated insights into the efficacy and safety of drugs, enhancing our understanding of the safety profile of even some of the oldest drugs, such as codeine sulfate, an opioid analgesic first approved in 1950 for relief of mild or moderate pain. Simultaneously, an increased awareness of the value of both personalized medicine and the reporting of rare adverse outcomes has resulted in the publication of information on adverse events that previously might not have been reported. These developments, in turn, led the Food and Drug Administration (FDA) to reanalyze the safety of — and ultimately restrict — codeine use in patients after adenotonsillectomy. The activity of codeine depends on its conversion to morphine by the cytochrome P-450 isoenzyme 2D6 (CYP2D6); morphine is subsequently metabolized to the active morphine-6-glucuronide by means of UDP-glucuronosyltransferase 2B7 (see diagram).1 The gene encoding CYP2D6 has many genetic variations that affect the amount of codeine that is converted to an active form and that result in the drug’s variable effect. Patients with a normal range of CYP2D6 activity represent 75 to 92% of the population and are called extensive metabolizers. At the low end of the activity spectrum are poor metabolizers (approximately 5 to 10% of the population), who have no functional alleles and therefore receive little to no morphine or analgesia from codeine. At the high end of the CYP2D6 activity spectrum, ultrarapid metabolizers have two or more functional alleles, and their bodies can convert codeine into large amounts of morphine. The prevalence of ultrarapid metabolism varies by ethnic group: it is lower than 1% among Chinese and Japanese patients but potentially higher than 15% among Middle Eastern and North African patients. Clinically significant toxic effects related to opioid excess have been reported in ultrarapid metabolizers, which suggests that the risk of toxic effects from codeine depends, in part, on genotype.1 In April 2012, a case series was published reporting two deaths and one case of respiratory depression in children 3 to 5 years of age who had received typical doses of codeine after tonsillectomy, adenoidectomy, or both performed because of obstructive sleep apnea.2 The two deaths occurred in children who had evidence of being ultrarapid metabolizers, and the postmortem morphine levels in these children were substantially highCodeine Metabolism Pathway. Data are from Crews et al.1 UGT2B7 CYP2D6