SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).

The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).

“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.

“Practice in neonatal abstinence syndrome is driven by institutional decisions. This study now provides high quality evidence to allow such groups to consider buprenorphine as a viable tool when a drug is needed for more severe neonatal abstinence syndrome,” added Dr. Kraft.

In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.

The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.

The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.

Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.

Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.

“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.

“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.

While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.

“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.

Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.

Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.

Buprenorphine is an alternative to morphine in treating NAS