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Buprenorphine for NAS shows promise in reducing length of stay

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Is NAS risk of readmission worth pushing for shorter treatment and stay?

Most of the 50%-80% of newborns treated for NAS are treated pharmacologically in newborn ICUs at significant cost ($93,400 for mean stay of 23 days). To date, the wide variations in care, including pharmacologic options for treating NAS, leave clinicians with no consensus regarding which medication is best. The further absence of high-quality studies that depict effective management strategies for NAS offers “little guidance to inform best practice recommendations,” Elisha M. Wachman, MD, and Martha M. Werler, DSc, wrote in an editorial published with the study.

The network analysis approach followed by Disher et al. requires some assumptions, namely “minimal bias and homogeneity of methods,” the authors observed. Yet, some of the randomized, clinical trials included in their evaluation were “not blinded and thus carry high risk of bias.” In addition, given the varied methods employed across the studies cited, “the primary findings of this meta-analysis warrant further discussion.”

Disher et al. concede that the benefits afforded with buprenorphine treatment could be more pronounced because of the dosing and weaning methods rather than from the effect of the medicine alone. Given that some studies cited did experience a shorter absolute median length of treatment with morphine, it is possible that the shortened lengths of treatment and stay concerning buprenorphine treatment “may be overestimates,” suggested Dr. Wachman and Dr. Werler.

Because of the extent of variability across studies cited, “results of the network meta-analysis by Disher et al. should be interpreted with caution.” It is worth noting that most of the studies evaluated did not “examine long-term outcomes beyond the initial birth hospitalization.” The question is: Does shorter length of treatment lead to improved long-term outcomes, or “does it put the infant at risk for readmission and altered neurobehavior and development?”

Although the researchers provide evidence of buprenorphine’s effectiveness in significantly shortening length of treatment, compared with morphine, “results should be interpreted with caution given the small number of RCTs, small sample sizes, heterogeneous methods and study populations, and lack of long-term outcome data.”

Dr. Wachman is affiliated with the department of pediatrics, Boston Medical Center. Dr. Werler is chair of the department of epidemiology, Boston University School of Public Health. The authors were supported by a grant from the National Institute of Child Health and Human Development. Dr. Werler also is supported by a grant from the Centers for Disease Control and Prevention/Massachusetts Department of Public Health. This editorial accompanied the article by Disher et al. (JAMA Pediatrics. 2019. doi: 10. 1001/jamapediatric.2018.5029).



In what is believed to be the first study of its kind to compare all available pharmacologic treatment options for relief of symptoms associated with neonatal abstinence syndrome (NAS), buprenorphine has the greatest probability of reducing duration of treatment and length of stay among newborns, reported Timothy Disher, PhD, of Dalhousie University School of Nursing, Halifax, N.S., and his associates.

A mom holding her baby with neonatal abstinence syndrome skin-to-skin Courtesy UNC Children's Hospital

It was noteworthy that the study also found morphine and phenobarbital monotherapies to be worst in overall effectiveness and ranking because these pharmacotherapies are the most frequently used treatments in the United States, according to the authors. Dr. Disher and his associates underscored the need for concern over the common rationale of treatment centers, especially in using phenobarbital, since the American Academy of Pediatrics “highlights that phenobarbital is most commonly used only as adjuvant therapy” and was not intended as a first-line treatment.

In their efforts to identify treatments that are most effective at easing the symptoms of NAS, Dr. Disher and his colleagues conducted a systematic review and network meta-analysis in June 2018, which included a search of the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Embase, and the Web of Science Core Collection. In addition, they referenced to identify relevant ongoing trials. Studies ultimately included in the review were randomized clinical trials comparing at least two pharmacotherapies prescribed for NAS that had been published in peer-reviewed journals.

Eighteen studies examining treatment for NAS among 1,072 newborns, including 10 studies published since 2000, were identified; the remaining studies were published between 1977 and 1986. Altogether, eight treatment interventions were examined across 10 studies

Dr. Disher and his associates reported that, during 2004-2014, there was a fivefold increase in the number of babies presenting with NAS, from 1.5/1,000 live births to 8.0/1,000, which represented a sevenfold increase in treatment cost in the Medicaid population during the same period, from $65.4 million to $462 million.

Although Dr. Disher and his colleagues acknowledged that buprenorphine was identified as best treatment by median ranks, “the ranks for most treatments are imprecise,” they said. According to results of their analysis, buprenorphine was associated with a reduction in 2.19 days of treatment, compared with clonidine, and 12.75 days, compared with morphine. In terms of secondary outcomes, buprenorphine was associated with a reduction in length of stay of 5.35 days, compared with clonidine, and 11.43 days, compared with morphine.

Seven of the studies evaluated (n = 394) included infants requiring adjuvant treatment. Agthe et al. reported that no infants in the concomitant diluted tincture of opium (DTO) and clonidine arm needed adjuvant treatment compared with five infants in the DTO-only arm who did. Surran et al. reported 2 of 32 infants who failed attempts to wean in the concomitant morphine and clonidine group compared with none of the 34 who were in the morphine and phenobarbital group.

In terms of adverse events, one study reported a seizure that was unrelated to treatment (Kraft et al). Agthe et al. reported three infants experiencing seizure in the DTO-only group compared with no infants who received concomitant clonidine. In Surran et al., three infants receiving concomitant phenobarbital and morphine were reported to be oversedated.

In general, the rationale explaining differences in why pharmacologic therapies affect treatment length is underdeveloped, the authors said. Buprenorphine, in particular, is favored because of its ease of dosing schedule and the possible improved safety profile given its longer half-life and greater micro-opioid receptor activity. It has been further suggested that the prolonged half-life of buprenorphine may be responsible for preventing sudden withdrawal symptoms. The researchers found no significant adverse events associated with buprenorphine treatment.

Although there were differences across buprenorphine treatment protocols, Dr. Disher and his colleagues noted that they were “broadly similar.” The authors conceded, however, that there is reason to question “how much of the observed improvement in buprenorphine may be attributable to the differences in optimization of the treatment and weaning protocols.”

Based on findings in this review, the authors caution that it is unlikely “that the current evidence base is sufficient to recommend specific large-scale changes in treatment away from the current standard of care.”

Despite recent research, which proposes trying nonpharmacologic treatments first and incorporating shared rooms for families and infants to reduce length of stay when treatment is required, up to 70% of infants ultimately require pharmacologic treatment. When drug therapy is needed, the average length of stay and overall treatment costs double, 10.9 vs. 22 days and $20,708 vs. $44,720, respectively.

Since results of the analysis show benefit, however variable, in reducing the length of treatment, “continued efforts to identify the optimal pharmacological agents are justified,” urged Dr. Disher and his associates.

Ultimately, before buprenorphine can be considered as a universally accepted standard of care in the treatment of NAS, “a large multisite pragmatic trial that compares buprenorphine with other treatments” will be needed.

One of the researchers – Chris Cameron, PhD – is an employee and holds shares of the Cornerstone Research Group, which provides consultant services to various pharmaceutical and device companies. Dr. Disher is a subcontractor for the Cornerstone Research Group. There were no other disclosures to report.

SOURCE: Disher T et al. JAMA Pediatr. 2019. doi: 10.1001/jamapediatrics.2018.5044.

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