Methadone or Morphine for Neonatal Abstinence Syndrome: First Head-to-Head Comparison

William T. Basco, Jr., MD, MS


September 25, 2018

The Treatment of Neonatal Abstinence Syndrome

Although opioids have been used to treat neonatal abstinence syndrome (NAS), the safest and most effective pharmacologic treatment has not been established. A recent trial[1] sought to answer this question with a design that addressed several methodologic gaps. First, unlike some previous studies that compared morphine with other drugs for the treatment of NAS, it was both multisite and randomized. Second, it was a head-to-head, double-blind comparison of the two drugs most commonly used to treat NAS—methadone and morphine—looking at both safety and efficacy.

Term infants (n = 117) who had been exposed to opioids in utero were randomly assigned to receive either methadone (n = 59) or morphine (n = 58). Their mothers had been treated with either methadone or buprenorphine for opioid use disorder or had taken an opioid for chronic pain during pregnancy. The infants had no other acute or chronic medical conditions. The Finnegan Neonatal Abstinence Scoring System was used to assess the infants every 4 hours. When the infants reached a score above predetermined levels, medication therapy was initiated.

Because of the different dosing intervals of the two drugs, infants in the methadone group received methadone alternating with a placebo every 4 hours. Infants in the morphine group received a dose of morphine every 4 hours. All doses (active drug and placebo) looked identical to ensure blinding. Phenobarbital was used as a backup medication in case an infant did not respond to one of the active treatments.

The primary outcome of interest was the length of hospital stay, along with secondary endpoints such as the need for phenobarbital or dose escalation.

The mean gestational age of the infants was 39 weeks, and the mean birthweight was > 3 kg. Approximately 75% of the newborns had a positive urine toxicology test.

Adjusted analyses (accounting for the maternal opioid used) showed advantages for methadone on the primary and secondary outcomes. For example, the length of stay that was attributable to NAS treatment was shorter by 2.7 days in the methadone group compared with the morphine group, and the total hospital days were an average of 2.9 days shorter. Length of treatment was also shorter by 2.3 days in the methadone group. The need for phenobarbital did not differ between groups.

The researchers concluded that methadone performed better for the short-term NAS outcomes evaluated in this study compared with morphine. Even small reductions in length of stay are of benefit, given the number of infants treated annually for NAS in the nation's hospitals.


A consequence of the current epidemic of NAS is a widespread urgency to identify effective treatments that minimize toxicity and shorten hospital stays, the primary driver of the cost of NAS treatment. The methadone preparations currently available are formulated for adults and may contain preservatives or alcohol. Furthermore, the hospital-to-hospital variation in treatment approaches makes a comparison of published observational trials difficult. Nonetheless, this study represents a significant step forward and will hopefully be followed by additional randomized, head-to-head trials.


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