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Low-dose versus high-dose methadone for the management of neonatal abstinence syndrome

Jamie L. Miller, PharmD, BCPS, BCPPS, FPPAG, Kimberly Ernst, MD, MSMI, FAAP, Stephen B. Neely, MPH, Katy Stephens, BS, Philip Barker, Grant H. Skrepnek, PhD, RPh, Peter N. Johnson, PharmD, BCPS, BCPPS, FPPAG, FCCM


Objectives: The primary objective was to compare median time to symptom relief (time from methadone initiation until two consecutive modified Finnegan [neonatal abstinence syndrome, NAS] scores < 8) between neonates receiving low-dose (0.275 mg/kg/day) versus high-dose (>0.275 mg/kg/day) methadone. Secondary objectives included assessment of factors associated with symptom relief.

Design: Retrospective cross-sectional study.

Setting: Ninety-nine bed neonatal intensive care unit within a tertiary-care academic hospital.

Participants: Seventy-two neonates who received methadone for NAS over a 7.5-year period.

Main outcome measures(s): Kaplan-Meier curves with a log-rank test and a stepwise Cox proportional-hazard model were used to analyze outcomes.

Results: The median dose for the low-dose (n = 40) and high-dose (n = 32) groups were 0.19 mg/kg/day (interquartile range [IQR], 0.12-0.24) divided every 6-12 hours and 0.4 mg/kg/day (0.3-0.44) divided every 6-8 hours, respectively. The median time to symptom relief was higher in the low-dose versus high-dose groups, 9.3 (5.8-24.6) versus 6.0 (5.4-12.5) hours, respectively (p = 0.014). Low-dose males had a longer time to symptom resolution than other groups (p = 0.008). Female premature neonates (<37 weeks gestation) had a shorter time to symptom relief than term neonates [adjusted hazard ratio = 2.96 (1.02-8.62)]. The median total duration of methadone was shorter but not statistically significant between high- versus low-dose groups, 17.5 (IQR: 11.0-25.0) versus 21.0 days (IQR: 10.0-28.0), respectively (p = 0.483).

Conclusions: Neonates receiving high-dose methadone had a significantly shorter time to symptom relief. Differences in sex were noted in response to therapy with low-dose males having a longer time to symptom relief and premature neonates a shorter time to symptom relief.


methadone, neonatal abstinence syndrome, withdrawal, pediatrics

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