The incidence of neonatal abstinence syndrome (NAS) has been climbing steadily, according to a 2016 Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention (CDC). The report, published August 12, indicated that the number of NAS cases rose from 1.5 per 1,000 hospital births in 1999 to 6 per 1,000 in 2013.
Yet guidelines for treating NAS have been lacking, according to a study in JAMA Pediatrics. The study, published online June 18, found that although several different approaches are being used, “no universal evidence-based pharmacological treatment strategy exists.” The article also noted that the FDA hasn’t approved any drug for treating infants who have NAS.
The authors of the JAMA Pediatrics study said that, without clear treatment guidelines, caregivers have typically chosen either methadone or morphine to treat their young NAS patients.
Which medication—methadone or morphine—is better, and how to decide on an appropriate dose? Some studies have suggested basing the dose on the infant’s weight; others, on the severity of NAS, as assessed by the Finnegan Neonatal Abstinence Scoring System.
The JAMA Pediatrics team set out to answer the medication questions. They designed a treatment plan, then carried out what they believe is the first multisite, double-blind, randomized trial comparing the safety and efficacy of methadone and morphine in NAS. They published their results online June 18.
Study sites were eight U.S. newborn units housing 116 infants. The mothers had been treated during pregnancy with buprenorphine or methadone for an opioid use disorder, or with an opioid prescribed for chronic pain.
The 58 subjects in one study group were given morphine every four hours. The 58 in the other group were dosed every four hours with either methadone (given every eight hours, because of its longer half-life) or placebo (given four hours after the methadone, so caregivers wouldn’t know which medication they were giving). The starting dose was based on the infant’s weight and the severity score; successive doses were adjusted, based on how severe the symptoms The study ran from February 9, 2014 to March 6, 2017.
aMethadone or placebo.
The authors specified that the morphine used was diluted, commercial, preservative-free, neonatal morphine.
They explained that commercial methadone contains 15% alcohol as a preservative. Because alcohol could affect outcomes, the U.S. Food and Drug Administration (FDA) required preparation of a preservative-free methadone solution for this study, using methadone powder (Mallinckrodt Inc).
Primary: Length of hospital stay
Secondary: Length of stay attributable to NAS; Length of stay attributable to treatment for NAS
- Shorter hospital stay (16 vs 20 days [for morphine patients])
- Shorter hospital stay related to NAS (16 vs 19 days)
- Shorter length of stay attributable to treatment (11.5 vs 15 days)
Study infants given methadone had better short-term outcomes than those treated with morphine. Differences were modest, but statistically significant. The authors are continuing to assess longer-term outcomes.
Implications for Treatment
Formulations. The methadone used in this study resulted from extensive prestudy work to guarantee the stability, purity, and sterility of the preparation—an expensive, time-consuming process, according to the authors. They also said that drugs used for treating newborns are usually “adult formulations that contain preservatives that have not been proven to be safe and could affect neurodevelopmental outcome”—and they noted the need for a commercially available methadone solution—”preservative free and safe for newborns.”
The authors also commented on the preservative issue in terms of buprenorphine. They pointed out that in a recent study in the New England Journal of Medicine, Kraft and colleagues showed that buprenorphine, given under the tongue, was more effective than morphine in treating NAS. But the buprenorphine formulation used in the Kraft study contained significant enough amounts of alcohol to possibly ultimately limit the widespread use of the medication, according to the JAMA Pediatrics authors.
Other Measures. The authors pointed out that shortening the length of hospital stay—even modestly—could have important economic effects, given the thousands of NAS infants treated each year. An article in Pediatrics in March estimated that, adjusting for inflation, total hospital costs for NAS births covered by Medicaid jumped from $65.4 million in 2004 to $462 million in 2014, the most recent year with available data.
The authors called for a better understanding of the factors influencing the severity of NAS, and the differences in long-term safety of the treatment options. This, they believe, will “help refine best practices and reduce the societal and financial burden of NAS, while improving short- and longer-term outcomes in this highly vulnerable population.”
Centers for Disease Control and Prevention. Incidence of neonatal abstinence syndrome — 28 states,1999–2013. MMWR 2016;65:799–802. doi: http://dx.doi.org/10.15585/mmwr.mm6531a2.
Davis JM, Shenberger J, Terrin N, et al. Comparison of safety and efficacy of methadone vs. morphine for treatment of neonatal abstinence syndrome. A randomized clinical trial. JAMA Pediatr. 2018;E1-E7. Published online June 18, 2018. doi:10.1001/jamapediatrics.2018.1307.
Kraft WK, Adeniyi-Jones SC, Chervoneva I, et al. Buprenorphine for the treatment of the neonatal abstinence syndrome. N Engl J Med. 2017;376(24):2341-2348.
Winkelman TNA, Villapiano N, Kozhimannil KB, Davis MM, Patrick SW. Incidence and costs of neonatal abstinence syndrome among infants with Medicaid: 2004-2014. Pediatrics. March 2018;141(4):e20173520. doi:10.1542/peds.2017-3520.
(Also see “When Mom Is Better Than Morphine: Shorten Stay and Decrease Costs For Babies With Methadone-Related NAS.” http://atforum.com/2018/04/when-mom-is-better-than-morphine-shorten-stay-and-decrease-costs-for-babies-with-methadone-related-nas/)