Abstract
In methadone-exposed preterm neonates, early identification of those at risk of severe neonatal abstinence syndrome (NAS) and use of a methadone dosing regimen that can provide effective and safe drug exposure are two important aspects of optimal care. To this end, we reviewed 17 methadone dosing recommendations in the international guidelines and literature and explored their variability in key dosing strategies. We selected three of the reviewed dosing regimens for their pharmacokinetics (PK) characteristics and their exposure–response relationship in three gestational age groups of preterm neonates (28, 32 and 36 gestational age weeks) at risk for development of severe NAS (defined as an umbilical cord methadone concentration of ≤60 ng/mL, following fetal exposure). We applied early (12 h after birth) vs. typical (36 h after birth) initiation of treatment. We observed that use of universally recommended dosing regimens in preterm neonates can result in under- or over-exposure. Use of a PK-guided dosing regimen resulted in effective target exposures within 24 h after birth with early initiation of treatment (12 h after birth). Future prospective studies should explore the incorporation of umbilical cord methadone concentrations for early identification of preterm neonates at risk of developing severe NAS and investigate the use of a PK-guided methadone dosing regimen, so that treatment failure, prolonged length of stay and opioid over-exposure can be avoided.
Highlights
In utero exposure to methadone is associated with an increased risk of preterm birth and can result in neonatal abstinence syndrome (NAS), with up to 40% of methadone-exposed preterm neonates developing NAS [6,7]
Only the dosing regimens from Neofax did not use stratification based on the NAS scoring system
For dosing recommendations which were based on the NAS scoring, we were unable to investigate the exact degree of exposure in preterm neonates
Summary
The increasing incidence of opioid use disorder (OUD), reaching epidemic proportions in the United States, has been associated with a substantial increase in the national prevalence of opioid misuse among women of reproductive age [1,2]. In utero exposure to methadone is associated with an increased risk of preterm birth and can result in neonatal abstinence syndrome (NAS), with up to 40% of methadone-exposed preterm neonates developing NAS [6,7]. The increasing number of these most vulnerable victims of NAS, along with the incremental health care burden with protracted length of stay and mounting health care costs, has resulted in large efforts in order to optimize the care model of this highly challenging disease [8]
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