*Assistant Professor, Department of Pharmacotherapy, University of North Texas System College of Pharmacy, Fort Worth, Texas; †Clinical Operations Specialist, Department of Pharmacy, Medical Center Arlington, Arlington, Texas; ‡Clinical Pharmacy Manager, Department of Pharmacy, OU Medical Center, Oklahoma City, Oklahoma. Corresponding author: Caitlin M Gibson, PharmD, BCPS, University of North Texas System College of Pharmacy, Assistant Professor, Department of Pharmacotherapy, 3500 Camp Bowie Boulevard, RES-411D, Fort Worth, TX 76107; phone: 817-735-0475; e-mail: Caitlin.gibson@unthsc.edu To the Editor: With the recent rescheduling of hydrocodone combination products from schedule III to schedule II by the Drug Enforcement Administration, prescribers may select alternative opioids for pain relief in postpartum patients. In nursing mothers, efficacy as well as safety for both the mother and the infant must be carefully considered when selecting an analgesic. Providers frequently prescribe codeine combination products for pain control in postpartum mothers.1 However, codeine has been associated with central nervous system (CNS) depression in up to 16.7% of breastfeeding neonates with mothers receiving codeine-containing products for management of obstetric pain.2 Codeine is a prodrug and is metabolized hepatically by cytochrome P450 2D6 (CYP 2D6) into the active analgesic morphine.1,3,4 Genetic polymorphisms of CYP 2D6 are associated with varying responses to codeine, which result in the following phenotypes: poor metabolizers (5%-10%), intermediate metabolizers (2%-11%), extensive metabolizers (EMs; 77%-92%), and ultra-rapid metabolizers (UMs; 1%-2%)5 Patients of Ethiopian, Saudi Arabian, and Mediterranean descent are most likely to express the UM phenotype (29%, 21%, and 8.7%10%, respectively).4,5 However, other ethnic groups such as Caucasians, Asians, and African Americans also include UMs (1.2%-6.5%).4,5 Codeine exhibits weak analgesic effects, therefore poor metabolizers may experience ineffective analgesia while EMs and UMs are more prone to experience morphine accumulation and toxicity. Genetic testing for CYP 2D6 metabolism is available but is infrequently utilized due to cost, unavailability at many hospitals, time required to receive the results of send-out tests, and poor understanding of clinical decision-making based on CYP 2D6 phenotype.3,6 Codeine and morphine are excreted in breastmilk.7 A number of regulatory agencies, researchers, and clinicians have expressed safety concerns about the use of codeine in nursing mothers based on pharmacokinetic data and case reports of respiratory depression and morphine toxicity in neonates.1,3,4,6-14 In 2006, the death of an otherwise healthy 13-dayold infant raised concerns about the safety of codeine products for the management of postpartum pain in breastfeeding women.10,14 Postmortem testing revealed that the mother was an ultra-rapid metabolizer of codeine, and the baby had accumulated toxic levels of morphine in the blood.6,10,14 In response, the US Food and Drug Administration (FDA) issued a public health advisory warning and updated codeine labeling to warn that codeine may not be safe during breastfeeding, especially for women characterized as UMs.6,7,13 Since the 2006 case report, other cases describing toxicity in breastfed infants have been reported.13 The European Medicine Agency and the United Kingdom Medicines and Healthcare Products Regulatory Agency advised that codeine should not be used in mothers who are breastfeeding.13 Some experts believe the FDA’s warning should be extended to EMs as well. In a pharmacokinetic study, simulations demonstrated that neonates of mothers who are EMs have similar risk of opioid toxicity as neonates of mothers who are UMs. In the study, potentially toxic plasma morphine concentrations were reached as early as 4 days after initiation of codeine at doses less than or equal to 2.5 mg/ kg/day.8,12,13 A systematic review published in 2008 identified 34 additional cases of nonfatal neonatal toxicities (apnea, drowsiness, bradycardia, and