Nicola M. Parry, DVM

May 05, 2017

Among newborns with neonatal abstinence syndrome (NAS), using sublingual buprenorphine almost halves the treatment time compared with using oral morphine, a new study shows.

Walter K. Kraft, MD, from Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, and colleagues published the results of their study online May 4 in the New England Journal of Medicine, and will present the study May 7 at the Pediatric Academic Societies (PAS) 2017 Annual Meeting in San Francisco, California.

"In the intention-to-treat analysis, the median duration of treatment was 15 days in the buprenorphine group and 28 days in the morphine group," the authors write.

"This difference translated into a similarly significant reduction in the length of hospital stay."

Approximately two thirds of infants exposed to opioids during pregnancy require pharmacologic treatment to control withdrawal symptoms of NAS, including seizures, poor feeding, and loose stool.

Although administration of an opioid is an effective treatment approach for these infants, data are lacking to guide clinicians in selecting an opioid. Morphine is most commonly used to treat these infants, and this requires lengthy hospital stays.

Sublingual buprenorphine is used to treat adults with opioid withdrawal symptoms, the authors write. Its long half-life and high therapeutic index for respiratory depression may also make it useful for treatment of NAS, and phase 1 data have suggested that buprenorphine may be more effective than morphine for this indication.

The researchers therefore conducted the Blinded Buprenorphine or Neonatal Morphine Solution (B-BORN) trial, enrolling 63 infants who had been exposed to opioids during gestation and who had signs of NAS.

The researchers randomly assigned the infants to receive either sublingual buprenorphine every 8 hours or oral morphine every 4 hours, and a matched placebo to maintain blinding. If NAS symptoms persisted at maximum doses of opioid, infants received supplemental phenobarbital. After infants had symptom stability for at least 48 hours, opioid treatment doses were decreased in 10% steps.

The primary endpoint was the length of treatment for symptoms of neonatal opioid withdrawal. Secondary endpoints were the length of hospitalization, the percentage of infants who required supplemental phenobarbital, and safety.

The researchers found that sublingual buprenorphine significantly reduced median length of treatment when compared with oral morphine (15 days vs 28 days; difference, −13 days; 95% confidence interval [CI], −21 to −7 days; P < .001), as well as length of hospitalization (21 days vs 33 days; difference, −12 days; 95% CI, −22 to −7 days; P < .001).

However, there was no significant difference (P = .36) in need for supplemental phenobarbital between infants who received buprenorphine (15%) and those who received morphine (23%).

Overall, the frequency of adverse events was also similar in both groups, with 13 arising in seven infants who received buprenorphine, and 10 arising in eight infants who received morphine (P = .79). No safety issues were identified in the trial. Safety measures, including infants' respiratory rate and liver function, were similar in both groups.

In a news release from the meeting, Dr Kraft emphasized the significant public health implications of this study, especially as the rate of NAS has increased almost fivefold during the last 15 years.

"Our findings provide evidence that buprenorphine can safely and effectively serve to reduce the significant burden of neonatal abstinence syndrome on individual infants and families, and hospitals," he concluded.

The study's findings are compelling, Stephen Patrick, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, told Medscape Medical News.

"The data are potentially very important, because we have seen a massive increase in the number of infants with symptoms of drug withdrawal from opioids over the last 2 decades," he explained. However, innovations in treatments for NAS have been lacking, he said, adding that these data could potentially be "a game changer."

Nevertheless, Dr Patrick stressed the need for additional research to further evaluate buprenorphine in NAS, including to repeat the findings in this study. As is the case with any intervention for use in infants shortly after birth, additional drug comparisons would also be beneficial, he added, suggesting that comparing the use of methadone vs buprenorphine in NAS would be useful. "Some longer-term follow-up data would be helpful, too," Dr Patrick concluded.

One coauthor reports receiving personal fees and nonfinancial support from Chiesi USA Inc, outside the submitted work. Another coauthor reports having served as an unpaid consultant to Chiesi Farmaceutici S.p.A. Two authors reports receiving nonfinancial support from Indivior PLC during the conduct of the study. Three authors report receiving grants from the National Institutes of Health/National Institute on Drug Abuse during the conduct of the study. The remaining authors and Dr Patrick have disclosed no relevant financial relationships.

New Engl J Med. Published online May 4, 2017. Full text

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