Nancy A. Melville

December 18, 2017

SAN DIEGO, California ― For infants of mothers who were treated for opioid use disorder with buprenorphine, rates of neonatal abstinence syndrome (NAS) were found to be lower compared to infants whose mothers were treated with methadone, new research shows. In addition, use of methadone at doses higher than 50 mg was associated with a significantly higher risk for NAS.

"If the baby is exposed to more than 50 mg in the mother during the pregnancy, they are three times more likely to develop NAS, which has plenty of adverse implications for the baby and the mother," first author Raghavendra Parige, MD, of the Australian National University Medical School and ACT Health, in Canberra, told Medscape Medical News.

The findings were presented here at the American Academy of Addiction Psychiatry (AAAP) 28th Annual Meeting.

"Watershed Dose"

The observational study included 218 pregnant women treated with methadone or buprenorphine and their newborns, who were delivered at a single center between January 2001 and December 2016.

Among the mothers, 194 were treated with methadone and 24 with buprenorphine. Fewer patients were treated with buprenorphine because methadone is still widely considered the standard of care for opioid use disorder.

Overall, 54% (n = 118) of the neonates developed NAS, defined using the modified Finnegan Neonatal Abstinence Scoring System (FNASS) as a score of 8 or higher on three consecutive scores or 12 or higher on two consecutive scores.

In the methadone group, 56% (n = 109) of infants were born with NAS, compared to 37% (n = 9) in the buprenorphine group.

When the methadone group was stratified into low-dose (7.5 - 50 mg) and high-dose (51 - 170 mg) groups, the results showed a significant increase of NAS in the high-dose group (n = 89; 64%) in comparison with the low-dose group (n = 20; 36%; P = .001).

"Most previous studies have shown no correlation between the dose of methadone and incidence of NAS, so it is interesting that we found this dose-related association," said Dr Parige.

"We have come to the conclusion that the watershed dose of methadone for NAS is 50 mg."

No significant differences in NAS were seen in relation to buprenorphine dose, and there were no differences in the groups in terms of gestational age, preterm delivery, birth weight, head circumference, or maternal heroin use.

There were also no correlations in either group in terms of the severity of NAS and factors such as length of treatment with morphine, total morphine dose (in mg), length of hospital stay, and peak FNASS score.

Considering the extensive negative implications of NAS, the need to better understand measures to reduce the burden are essential, said Dr Parige.

"On average, these babies tend to spend 20 days in the neonatal intensive care unit. The rates of cesarean delivery are higher, as are fatal complications, including seizures; the baby often can't breastfeed, and of course the hospital costs are much higher."

The findings add to growing evidence that buprenorphine should be considered as a first-line treatment of opioid-dependent pregnant women, the investigators note.

"Considering that prescription opioid abuse is a major public health problem, physicians need to consider buprenorphine as a treatment option for pregnant women, as it is more accessible in outpatient and primary care setting, where they can access antenatal care as well."

The findings of reduced NAS in infants exposed to buprenorphine are consistent with previous studies, including the Maternal Opioid Treatment: Human Experimental Research (MOTHER) trial, an eight-center randomized, controlled, double-blind trial on the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine.

A review of 37 studies involving NAS published this year in Reviews on Recent Clinical Trials also showed consistent findings of reduced NAS effects with buprenorphine.

Dose-Dependent Risk Questioned

However, Matthew R. Grossman, MD, a senior author of that study, who is assistant professor of pediatrics at Yale School of Medicine, in New Haven, Connecticut, said he has not observed differences associated with the dose of methadone, as reported in the current study.

"The risk of NAS, as far as we can tell, doesn't so much have to do with the degree of the addiction but with the infant's exposure," he told Medscape Medical News.

"If [infants] are exposed to an opioid, particularly methadone, my experience with more than 500 of these infants is that they will all have withdrawal symptoms, regardless of the dose."

As previously reported by Medscape Medical News, Dr Grossman and his team have challenged the use of the FNASS. They found that management of infants using a scoring system that rates function in eating, sleeping, and consolability dramatically reduced the need for morphine treatment of infants with NAS in comparison with management using the FNASS.

The additional findings regarding buprenorphine, however, should prompt a rethinking of the treatment of some women with methadone, he said.

"We have sort of accepted that methadone is better, but I think we probably need to reconsider that to some degree. Clearly, when the mothers are on buprenorphine, the withdrawal for the infants isn't as bad," said Dr Grossman

The authors and Dr Grossman have disclosed no relevant financial relationships.

American Academy of Addiction Psychiatry (AAAP) 28th Annual Meeting. Abstract 28, presented December 10, 2017.

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