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Comparative Study
. 2019 Mar 1;173(3):234-243.
doi: 10.1001/jamapediatrics.2018.5044.

Pharmacological Treatments for Neonatal Abstinence Syndrome: A Systematic Review and Network Meta-analysis

Timothy Disher  1 , Courtney Gullickson  2 , Balpreet Singh  3   4 , Chris Cameron  5   6 , Leah Boulos  7 , Louis Beaubien  8 , Marsha Campbell-Yeo  1   3   4   9
Affiliations
Comparative Study

Pharmacological Treatments for Neonatal Abstinence Syndrome: A Systematic Review and Network Meta-analysis

Timothy Disher et al. JAMA Pediatr. .

Abstract

Importance: Incidence of neonatal abstinence syndrome is rising rapidly, and optimal pharmacotherapy may meaningfully reduce length of treatment.

Objective: To compare pharmacological therapies for neonatal abstinence syndrome.

Data sources: Systematic review and network meta-analysis of Medline (1946-June 2018), Embase (1974-June 2018), Cochrane CENTRAL (1966-June 2018), Web of Science (1900-June 2018), and ClinicalTrials.gov (June 2018).

Study selection: Randomized clinical trials of pharmacological treatments for neonatal abstinence syndrome alone or in combination with adjuvant treatments. Abstract, title, and full-text screening were conducted independently by 2 reviewers (T.D. and C.G.).

Data extraction and synthesis: Data extraction was conducted independently by 2 reviewers (T.D. and C.G.) according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-Network Meta-Analyses guidelines. Quality was assessed with the Cochrane Risk of Bias tool and data were pooled with fixed-effect models as a result of the low number of trials that were included in the analysis.

Main outcomes and measures: The primary outcome was the length of treatment. The length of stay, need for adjuvant therapy, and adverse events were considered as secondary outcomes.

Results: Eighteen trials (N = 1072) were eligible for inclusion. The treatments that were included in the length of treatment analysis were buprenorphine, clonidine, diluted tincture of opium and clonidine, diluted tincture of opium, morphine, methadone, and phenobarbital. Sublingual buprenorphine was considered 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]). The results were robust to bias but sensitive to imprecision.

Conclusions and relevance: The current evidence suggests that buprenorphine is the optimal treatment for neonatal abstinence treatment, but limitations are considerable and wide-scale adoption requires a large multisite trial. Morphine, which is considered standard of care in most hospitals, was the lowest-ranked opioid for length of treatment and length of stay.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cameron is an employee and holds shares of the Cornerstone Research Group, which provides consultant services to various pharmaceutical and device companies. Mr Disher is a subcontractor for the Cornerstone Research Group. No other disclosures are reported.

Figures

Figure 1.
Figure 1.. Network Graphs
Nodes indicate treatments and edges indicate comparisons from a single study for length of treatment (A), length of stay (B), the need for adjuvant (C), and disconnected treatment for adverse events (D). The size of the nodes indicates the relative sample size in a comparison, and the width of the edges represents the number of studies. DTO indicates diluted tincture of opium.
Figure 2.
Figure 2.. Heat Plot for All Outcomes Based on Median Rank
Median rank with 95% credible interval for each treatment and outcome combination with data. Lower ranks indicate that treatments are better. The tile color indicates where treatments are placed from worst (red) to best (green) within an outcome. NA indicates no information for a treatment; DTO, diluted tincture of opium.
Figure 3.
Figure 3.. Forest Plot of Network Meta-analysis Estimates vs Placebo
Treatments effects are reported based on a fixed-effects model in comparison with morphine monotherapy for length of treatment (A), length of stay (B), and treatment failure (C). Smaller values favor the treatment being compared with morphine. DTO indicates diluted tincture of opium.
See this image and copyright information in PMC

Comment in

References

    1. Hudak ML, Tan RC; Committee on Drugs; Committee on Fetus and Newborn; American Academy of Pediatrics . Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-e560. doi:10.1542/peds.2011-3212 - DOI - PubMed
    1. Winkelman TNA, Villapiano N, Kozhimannil KB, Davis MM, Patrick SW. Incidence and costs of neonatal abstinence syndrome among infants with Medicaid: 2004-2014. Pediatrics. 2018;141(4):e20173520. doi:10.1542/peds.2017-3520 - DOI - PMC - PubMed
    1. Filteau J, Coo H, Dow K. Trends in incidence of neonatal abstinence syndrome in Canada and associated healthcare resource utilization. Drug Alcohol Depend. 2018;185(185):313-321. doi:10.1016/j.drugalcdep.2017.12.019 - DOI - PubMed
    1. Patrick SW, Kaplan HC, Passarella M, Davis MM, Lorch SA. Variation in treatment of neonatal abstinence syndrome in US children’s hospitals, 2004-2011. J Perinatol. 2014;34(11):867-872. doi:10.1038/jp.2014.114 - DOI - PubMed
    1. Veritas Health Innovation Covidence systematic review software. http://www.covidence.org. Accessed September 20, 2018.