Tamara van Donge

Simplification of methadone dosing in preterm neonates 77 5 What is already known about this subject • The disposition of methadone is influenced by its chirality. • Polymorphisms of the CYP2B6 enzyme alters the disposition of methadone and influences plasma concentrations. • Current dosing recommendations for methadone are often complex and require a taper or weaning period. What this study adds • The clearance of methadone increases with advancing gestational age. • Pharmacokinetic differences between the two methadone enantiomers were observed (higher clearance and volume of distribution for (R)-methadone). • Complex dosing schemes can be replaced by a simplified and shortened dosing strategy. Introduction In the current prescription opioid epidemic, a dramatic increase in pregnant women who use these opioids (e.g. hydrocodone) is observed, resulting in drug dependence and addiction in their fetuses. 1-3 Methadone is frequently used to treat the withdrawal symptoms of these infants, who are often preterm, after birth that are caused by the abrupt discontinuation of prolonged in utero drug exposure. 4 Use of narcotics by pregnant women remains a serious public health concern, primarily due to the increased risk of birth defects, but also because of socioeconomic burdens caused by the increasing need for medical and social support. 4,5 According to a recent study, maternal opioid use increased from 1.2 mothers to 5.6 mothers per 1000 live births in a period between 2000 and 2009. During this period, neonates diagnosed with neonatal abstinence syndrome (NAS) increased correspondingly from 1.2 to 3.4 per 1000 live births in the United States. 6 NAS is characterized by a wide range of clinical symptoms including tremors, respiratory distress, hypertonia and excessive crying, and is mostly treated to prevent seizures. 7 Despite the development of various standardized scoring scales (e.g. Finnegan Neonatal Abstinence Severity Score or Neonatal Narcotic Withdrawal Index) and the careful training of staff utilizing these scoring tools, the observation of response to treatment of neonates with NAS remains to a large extent