Can Type of Treatment Safely Shorten Hospital Stay in NAS?

William T. Basco, Jr., MD, MS


February 22, 2019

Neonatal Abstinence Syndrome and Length of Stay

A dramatic rise in the incidence of neonatal abstinence syndrome (NAS) is yet another unfortunate consequence of the opioid epidemic.[1] Typically, affected neonates must remain hospitalized, usually in neonatal intensive care units (NICUs), for monitoring and management of opioid withdrawal symptoms. A high proportion of newborns with NAS fail to respond to nonpharmacologic interventions alone and require a drug treatment protocol using an opioid such as morphine or methadone.[2] Hospital length of stay for these neonates averages 17-23 days.[3]

Small, prospective reports have suggested that methadone treatment of NAS, compared with morphine, can shorten length of stay. To test this approach on a larger scale, Tolia and colleagues[4] analyzed billing and other data from over 300 NICUs across 33 states and Puerto Rico. All infants were treated in 2011-2015 and had a diagnosis of NAS within the first 7 days of life. The analysis focused on infants who were at least 36 weeks gestational age and had received either morphine or methadone in the first 7 days of life. The first drug they received (morphine or methadone) was used to group infants for the comparison of outcomes.

The main outcome of interest was length of hospital stay. Secondary outcomes included the need for respiratory support, feeding problems, and discharge disposition. The analysis accounted for some maternal variables, including age, parity, race/ethnicity, whether they received prenatal care, maternal medication use, and smoking history. Limited clinical variables from each infant were also available for the analysis.

Study Findings

The analysis cohort included 7667 infants from 277 NICUs who were treated for NAS with either morphine (85%) or methadone (15%). The mothers were predominantly white (77%). Most (91%) had received prenatal care. At some point during pregnancy, 20% had used buprenorphine and 31% had used methadone. The median birth weight of the infants was 3026 g, and 17% were small for gestational age.

The median hospital length of stay was longer in the morphine-treated infants (23 days) compared with methadone-treated infants (18 days). There was no difference in disposition after discharge between the two groups. Infants in the morphine group were more likely to have received two medications for treatment of NAS (26% compared with 17% of infants treated with methadone.) The need for any respiratory support was 17% among the infants treated with morphine compared with 25% of those treated with methadone, but the need for mechanical ventilation did not differ between the two groups. There was no difference between the groups in the percentage of infants who experienced seizures. Feeding problems were more prevalent in the morphine group (20%) compared with the methadone group (15%).

Multivariable analysis, including the use of propensity scores to account for the nonrandom assignment to treatment drug, demonstrated that methadone treatment remained associated with shorter length of hospital stay. The authors concluded that treatment of NAS with methadone, in these infants, was associated with a shorter hospital length of stay even after controlling for maternal and infant factors.


A finding of interest in this study was that length of stay declined significantly with each calendar year, as did the frequency of methadone use. The authors therefore wonder whether the length of stay might have dropped even more over time had methadone use remained as prevalent in 2015 as it was in 2011.

There are many active efforts nationwide to improve upon the protocols that are used to treat infants with NAS, including trials of medications other than morphine and in settings other than the NICU. I appreciate the effort that investigators are putting into trying to better measure the distress of these infants and apply different medication and management options to improve NAS care while minimizing time in the hospital. The authors are correct to be cautious in the interpretation of these data in that this was not a randomized trial, and the variation of treatment thresholds, symptom measurement methods, and other aspects of care undoubtedly varied widely across the hospitals studied. However, this study is a good first step and makes the argument that it is worth testing these two drugs using a standardized head-to-head approach.

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