Neonatal Abstinence Syndrome: Which Medication Is Best?

As many as 20 cases per 1000 live births are affected by neonatal abstinence syndrome (NAS) in the US, according to the US Pediatric Health Information System. Of those NAS infants, 50% to 80% are treated pharmacologically. However, a wide variation in care practices exists among, causing an irregularity in treatment approaches and an undeclared standard of care.

To further investigate which pharmacological treatments and approaches best treat NAS, a group of investigators conducted a systematic review and network meta-analysis on current pharmaceutical approaches for NAS. Among their findings, the team found suggestions that buprenorphine may be the optimal pharmaceutical treatment.

However, in an editorial commentary on the study, Elisha M. Wachman, MD, added further insight on the pharmacological overview, offering the notion that nonpharmacological approaches should be used and sometimes before pharmacological ones.

When asked to clarify the best approaches in their order of treatment, Wachman relayed to MD Magazine® the challenges of treating the NAS population. “One of the biggest challenges in the field right now is that there’s not an agreed upon standard of care,” she said. “That spans from how we assess the babies, the appropriate care setting for where we should be taking care of these patients, which medication to use, and how to titrate and wean it. There’s not agreement on any of the above topics.”

In the systematic review and network meta-analysis of pharmacological treatment approaches for babies with NAS, the team of investigators used data from Medline (1946-June 2018), Embase (1974-June 2018), Cochrane CENTRAL (1966-June 2018), Web of Science (1900-June 2018), and ClinicalTrials.gov (June 2018).

Among the randomized clinical trials of pharmacological treatments for NAS alone or in combination with adjuvant treatments, 2 reviewers also independently conducted abstracts, titles, full-text screenings, and data extractions in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)—Network Meta-Analyses guidelines. The Cochrane Risk of Bias tool was used to asses quality, and fixed-effect models were used to pool data due to the low number of trials that were included in the analysis.

The length of treatment served as the primary outcome while the length of stay, need for adjuvant therapy, and adverse events served as secondary outcomes. Buprenorphine, clonidine, diluted tincture of opium and clonidine, diluted tincture of opium, morphine, methadone, and phenobarbital were the medications analyzed during the length of treatment in the analysis that enrolled 18 eligible trials (N = 1072).

Among their results, the team found sublingual buprenorphine to be the optimal treatment for a reduction in the length of treatment (days: mean difference vs morphine, −12.75 [95% CI, −17.97 to −7.58]; median rank, 1 [3-1]) and length of stay (days: mean difference vs morphine, −11.43 [95% CI, −16.95 to −5.82]; median rank, 1 [3-1]) but not the need for adjuvant treatment (odds ratio vs morphine, 1.23 [95% CI, 0.46-3.44]; median rank, 3 [5-1]).

“Based on the current direct and indirect evidence from randomized clinical trials, our findings would suggest that sublingual buprenorphine is likely the most favorable pharmacological treatment for this population with respect to the overall treatment exposure and length of hospital stay without evidence for immediate harm,” Campbell-Yeo told MD Mag®.

She added that there were considerable limitations in the study, which were primarily related to the number, size, and quality of the studies that were included in the meta-analysis. Given these limitations, she would caution an immediate large-scale change in the practice of pharmacological treatment at this time.

Commenting on the systematic review and meta-analysis, Wachman explained to MD Mag® while morphine seems to be the inferior medication, it is also the most commonly used medication to treat NAS (by over half of centers). She mentioned 2 recent randomized clinical trials have shown methadone was superior to morphine, and buprenorphine was superior to morphine in terms of babies being in the hospital for less time.

“I think that has significant implications for clinical care because the most common medication is starting to be vigorously tested,” Wachman added, “and it has not been demonstrated as the superior medication in the last few studies.”

However, Wachman furthered that when physicians have to decide whether a baby needs medication and how it should be titrated, there is still no current standard. She emphasized that an abundance of variability among methods in the studies also makes it hard to draw a hard conclusion on the optimal treatment since no 1 team is conducting anything the same way.

For that reason and the fact that few studies have compared methadone and buprenorphine, Wachman stated that she doesn’t think there is a definitive conclusion as to which of the 2 is the superior treatment. She added that an increasing amount of evidence is showing morphine is unlikely to remain the preferred medication.

Returning to nonpharmacological approaches, Wachman said, “The strongest evidence supports that infants should be treated nonpharmacologicaly first. That is pretty agreed upon at this point. The evidence strongly suggests that if infants are rooming in with their mothers, if they’re breastfed, and if all of these factors are optimized, you actually need medications significantly less. That is something I think all centers should be striving to do.”

Campbell-Yeo echoed Wachman, stating, that emerging evidence is telling us that there are some primary fundamental things we can do to reduce the need for pharmacological management for NAS babies, such as keeping mothers and babies in the same room, enforcing skin-to skin contact, and promoting bonding.

Wachman added that while she does believe a percentage of babies absolutely need some degree of medication, she also believes that number is somewhere around 50% based on her own experiences and those from other centers. She thinks there is also a way to decrease the amount of medications that’s given through optimizing all these other nonpharmacological variables since babies with NAS require less medication and go home a lot sooner that route. “The focus should definitely be first on making sure that the baby is comfortable and that mom is involved.”

Looking forward, Campbell-Yeo said her team’s findings support the urgent need for a large multi -site trial examining buprenorphine in the NSA population and that healthcare providers should be questioning the current accepted practices—of using morphine or phenobarbital monotherapies, which also ranked poorly in the meta-analysis.

“Well conducted trials are urgently needed to further examine the potential promise of buprenorphine,” she said. “In the interim, another way to help determine best practice would be through the use of large-scale neonatal networks so other clinicians have access to a network of colleagues that has experience with drugs other than morphine.”

The study, titled, “Pharmacological Treatments for Neonatal Abstinence Syndrome A Systematic Review and Network Meta-analysis,” was published online in Journal of the American Medical Association (JAMA) Pediatrics.

The editorial opinion, titled, “Pharmacologic Treatment for Neonatal Abstinence Syndrome Which Medication Is Best?” was published online in Journal of the American Medical Association (JAMA) Pediatrics.