CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators.

The usefulness of codeine as an analgesic for children has long been debated []. Codeine itself is a weak analgesic. Analgesic effect is gained from codeine's metabolite, morphine. There are concerns that codeine might be either an ineffective analgesic or too effective and contribute to respiratory depression in those with CYP2D6 polymorphisms for the formation clearance of its metabolite, morphine []. Codeine is no longer recommended for pain management in infants and children because of deaths when it was prescribed to children with CYP2D6 ultra‐rapid (UR) polymorphism. Most children's hospitals removed this drug from their formulary because of safety concerns [, , , , ]. Codeine was always considered a reasonable analgesic for postpartum women. Morphine concentrations in the breastfed neonate had been reported to range from < 0.5 to 2.2 μg/L after mothers were given 240 mg/day in divided doses before the turn of the century (1997) []. However, disquiet around the use of codeine in postpartum women who were breastfeeding increased following a report in 2006 of a neonate who died, assumably due to breastmilk ingestion that contained high concentrations of morphine []. Although numerous investigators queried the feasibility of the neonatal morphine plasma concentration of 70 μg/L after maternal codeine ingestion [, , ] and even the veracity of the report [], breastfeeding women continue to be denied codeine for analgesia []. The senior author of reports concerning neonatal opioid toxicity after breastfeeding [, , , ] has since been exposed as fraudulent []. This has created some puzzlement in the pediatric anesthesia community about the pharmacology related to drugs contained in breastmilk and neonatal impact, particularly for codeine. Although short‐term maternal use of prescription opioids (other than codeine) is considered safe and may infrequently present a hazard to the newborn, opioids should still be used with caution, especially after multiple maternal doses with breastfed neonates younger than 46 weeks postmenstrual age. Those neonates should be observed for drowsiness and respiratory depression []. Some clarity to the importance of CYP2D6 polymorphisms can be gleaned through simulation using pharmacokinetic compartment modeling []. The compartment model needed to address five issues of imprtance [].