Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Comparative effectiveness of opioid replacement agents for neonatal opioid withdrawal syndrome: a systematic review and meta-analysis

Journal of Perinatology volume 39, pages 1535–1545 (2019)Cite this article

Subjects

Abstract

Objective(s)

To compare short-term treatment outcomes of opioid pharmacotherapy for neonatal opioid withdrawal syndrome (NOWS).

Study design

PubMed/MEDLINE, Embase, PsycINFO, and The Cochrane Library were searched from inception through September 30, 2018. Primary outcome was treatment duration (LOT). Secondary outcomes included hospitalization duration (LOS) and rate of adjunct drug needed (RAD).

Results

Of 753 publications, 11 studies met inclusion criteria. There was no difference in LOT (WMD −1.39 [−5.79 to –3.01] days, I2 82%) or LOS (WMD −1.48 [−5.75 to –2.79] days, I2 92%) between morphine and methadone. RAD with morphine was higher (RR 1.51 [1.35–1.69], I2 0%). Buprenorphine was associated with shorter LOT (WMD 7.70 [0.88–14.53] days, I2 76%) and LOS (WMD 5.61 [−0.01 to –11.24] days, I2 60%) compared with morphine, in addition to methadone according to two cohort studies.

Conclusions

Methadone had superior primary treatment success compared with morphine. Buprenorphine was associated with the shortest overall durations of treatment and hospitalization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Tolia VN, Patrick SW, Bennett MM, Murthy K, Sousa J, Smith PB, et al. Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl J Med. 2015;372:2118–26.

    Article  Google Scholar 

  2. Patrick SW, Davis MM, Lehman CU, Cooper WO. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012. J Perinatol: Off J Calif Perinat Assoc. 2015;35:667.

    Article  CAS  Google Scholar 

  3. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134:e547–61.

    Article  Google Scholar 

  4. Osborn DA, Jeffery HE. Cole MJ, Opiate treatment for opiate withdrawal in newborn infants. Cochrane Datab Syst Rev. 2010;10:Cd002059.

  5. Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn infants. Cochrane Datab Syst Rev. 2010;10:Cd002053.

  6. Hudak ML, Tan RC. Neonatal drug withdrawal. Pediatrics. 2012;129:e540–60.

    Article  Google Scholar 

  7. Bogen DL, Whalen BL, Kair LR, Vining M, King BA. Wide variation found in care of opioid-exposed newborns. Acad Pedia. 2017;17:374–80.

    Article  Google Scholar 

  8. Crocetti MT, Amin DD, Jansson LM. Variability in the evaluation and management of opiate-exposed newborns in Maryland. Clin Pediatr. 2007;46:632–5.

    Article  Google Scholar 

  9. Sarkar S, Donn SM. Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. J Perinatol: Off J Calif Perinat Assoc. 2006;26:15–7.

    Article  CAS  Google Scholar 

  10. Mehta A, Forbes KD, Kuppala VS. Neonatal abstinence syndrome management from prenatal counseling to postdischarge follow-up care: results of a national survey. Hosp Pediatr. 2013;3:317–23.

    Article  Google Scholar 

  11. Disher T, Gullickson C, Singh B, Cameron C, Boulos L, Beaubien L, et al. Pharmacological treatments for neonatal abstinence syndrome: a systematic review and network meta-analysis. JAMA Pediatr. 2019;173:234–43.

    Article  Google Scholar 

  12. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Method. 2014;14:135.

    Article  Google Scholar 

  13. Sutter MB. Morphine versus methadone for opiate exposed infants with neonatal abstinence syndrome. NLM identifier: NCT02851303 https://clinicaltrials.gov/ct2/show/NCT02851303?type=Intr&cond=Neonatal+Abstinence+Syndrome&rank=14.

  14. Martin G. Comparison of buprenorphine to morphine in treatment of neonatal abstinence Syndrome (NAS). NLM identifier: NCT01708707 https://clinicaltrials.gov/ct2/show/NCT01708707?type=Intr&cond=Neonatal+Abstinence+Syndrome&rank=11.

  15. Kushnir A. Treatment of neonatal abstinence syndrome with clonidine versus morphine as primary therapy. NLM identifier: NCT03092011 https://clinicaltrials.gov/ct2/show/NCT03092011?type=Intr&cond=Neonatal+Abstinence+Syndrome&draw=2&rank=1.

  16. Gauda E. Sublingual buprenorphine treatment for neonatal abstinence syndrome - Pilot Study. NLM identifier: NCT02249026 https://clinicaltrials.gov/ct2/show/NCT02249026?type=Intr&cond=Neonatal+Abstinence+Syndrome&rank=25.

  17. Davis JM, Lester B. Improving outcomes in neonatal abstinence syndrome. NLM identifier: NCT01958476 https://clinicaltrials.gov/ct2/show/NCT01958476type=Intr&cond=Neonatal+Abstinence+Syndrome&rank=6.

  18. Brooks S. Methadone Demonstration Project. NLM identifier: NCT03134703 https://clinicaltrials.gov/ct2/show/NCT03134703?type=Intr&cond=Neonatal+Abstinence+Syndrome&rank=20.

  19. Bada HS. Non-opiate treatment after prenatal opiate exposure to prevent postnatal injury to the young brain (No-POPPY). NLM identifier: NCT03396588 https://clinicaltrials.gov/ct2/show/NCT03396588?type=Intr&cond=Neonatal+Abstinence+Syndrome&rank=18.

  20. Hall ES, Rice WR, Folger AT, Wexelblatt SL. Comparison of neonatal abstinence syndrome treatment with sublingual buprenorphine versus conventional opioids. Am J Perinatol. 2018;35:405–12.

    Article  Google Scholar 

  21. Burke S, Beckwith AM. Morphine versus methadone treatment for neonatal withdrawal and impact on early infant development. Glob Pediatr health. 2017;4:2333794x17721128.

    PubMed  PubMed Central  Google Scholar 

  22. Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol: Off J Calif Perinat Assoc. 2015;35:278–83.

    Article  CAS  Google Scholar 

  23. Young ME, Hager SJ, Spurlock D Jr. Retrospective chart review comparing morphine and methadone in neonates treated for neonatal abstinence syndrome. Am J Health-Syst Pharm: AJHP: Off J Am Soc Health-Syst Pharm. 2015;72(23Suppl 3):S162–7.

    Article  Google Scholar 

  24. Hall ES, Wexelblatt SL, Crowley M, Grow JL, Jasin LR, Klebanoff MA, et al. A multicenter cohort study of treatments and hospital outcomes in neonatal abstinence syndrome. Pediatrics. 2014;134:e527–34.

    Article  Google Scholar 

  25. 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: Off J Calif Perinat Assoc. 2014;34:867–72.

    Article  CAS  Google Scholar 

  26. Lainwala S, Brown ER, Weinschenk NP, Blackwell MT, Hagadorn JI. A retrospective study of length of hospital stay in infants treated for neonatal abstinence syndrome with methadone versus oral morphine preparations. Adv Neonatal Care: Off J Natl Assoc Neonatal Nurses. 2005;5:265–72.

    Article  Google Scholar 

  27. Kraft WK, Adeniyi-Jones SC, Chervoneva I, Greenspan JS, Abatemarco D, Kaltenbach K, et al. Buprenorphine for the treatment of the neonatal abstinence syndrome. New Engl J Med. 2017;376:2341–8.

    Article  CAS  Google Scholar 

  28. Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction. 2011;106:574–80.

    Article  Google Scholar 

  29. Kraft WK, Gibson E, Dysart K, Damle VS, Larusso JL, Greenspan JS, et al. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics. 2008;122:e601–7.

    Article  Google Scholar 

  30. Hall ES, Isemann BT, Wexelblatt SL, Meinzen-Derr J, Wiles JR, Harvey S, et al. A cohort comparison of buprenorphine versus methadone treatment for neonatal abstinence syndrome. J Pediatr. 2016;170:39–44.e1.

    Article  CAS  Google Scholar 

  31. Bada HS, Sithisarn T, Gibson J, Garlitz K, Caldwell R, Capilouto G, et al. Morphine versus clonidine for neonatal abstinence syndrome. Pediatrics. 2015;135:e383–91.

    Article  Google Scholar 

  32. Esmaeili A, Keinhorst AK, Schuster T, Beske F, Schlosser R, Bastanier C. Treatment of neonatal abstinence syndrome with clonidine and chloral hydrate. Acta Paediatr. 2010;99:209–14.

    CAS  PubMed  Google Scholar 

  33. Devlin LA, Lau T, Radmacher PG. Decreasing total medication exposure and length of stay while completing withdrawal for neonatal abstinence syndrome during the neonatal hospital stay. Front Pedia. 2017;5:216.

    Article  Google Scholar 

  34. Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B, Singh R. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. J Perinatol: Off J Calif Perinat Assoc. 2013;33:954–9.

    Article  CAS  Google Scholar 

  35. Coyle MG, Ferguson A, Lagasse L, Liu J, Lester B. Neurobehavioral effects of treatment for opiate withdrawal. Arch Dis Child Fetal neonatal Ed. 2005;90:F73–4.

    Article  CAS  Google Scholar 

  36. Coyle MG, Ferguson A, Lagasse L, Oh W, Lester B. Diluted tincture of opium (DTO) and phenobarbital versus DTO alone for neonatal opiate withdrawal in term infants. J Pediatr. 2002;140:561–4.

    Article  CAS  Google Scholar 

  37. Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009;123:e849–56.

    Article  Google Scholar 

  38. Davis JM, Shenberger J, Terrin N, Breeze JL, Hudak M, Wachman EM, et al. Comparison of safety and efficacy of methadone vs morphine for treatment of neonatal abstinence syndrome: a randomized clinical trial. JAMA Pedia. 2018;172:741–8.

    Article  Google Scholar 

  39. Tolia VN, Murthy K, Bennett MM, Greenberg RG, Benjamin DK, Smith PB, et al. Morphine vs methadone treatment for infants with neonatal abstinence syndrome. J Pediatr. 2018;203:185–9.

    Article  CAS  Google Scholar 

  40. Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363:2320–31.

    Article  CAS  Google Scholar 

  41. Kraft WK, Stover MW, Davis JM. Neonatal abstinence syndrome: pharmacologic strategies for the mother and infant. Semin Perinatol. 2016;40:203–12.

    Article  Google Scholar 

  42. Boumeester NJ, AB, Tibboel D, et al. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants, ad young children. Br J Anaesth. 2004;92:208–17.

    Article  Google Scholar 

  43. Kraft WK. Buprenorphine in neonatal abstinence syndrome. Clin Pharmacol Ther. 2018;103:112–9.

    Article  CAS  Google Scholar 

  44. Blume HK, Garrison MM, Christakis DA. Neonatal seizures: treatment and treatment variability in 31 United States pediatric hospitals. J Child Neurol. 2009;24:148–54.

    Article  Google Scholar 

  45. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133–53.

    PubMed  Google Scholar 

  46. Corr TE, Hollenbeak CS. The economic burden of neonatal abstinence syndrome in the United States. Addiction. 2017;112:1590–9.

    Article  Google Scholar 

  47. MacMillan KDL, Rendon CP, Verma K, Riblet N, Washer DB, Volpe Holmes A. Association of rooming-in with outcomes for neonatal abstinence syndrome: a systematic review and meta-analysis. JAMA Pedia. 2018;172:345–51.

    Article  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA

    Jennifer J. Lee, Jerri Chen, Lisa Eisler, Guohua Li & Lena S. Sun

  2. Department of Epidemiology, Mailman School of Public Health, and the Center for Injury Epidemiology and Prevention, Columbia University, New York, NY, USA

    Guohua Li

  3. Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, MA, USA

    Jonathan M. Davis

  4. The Tufts Clinical and Translational Science Institute, Boston, MA, USA

    Jonathan M. Davis

  5. Department of Pediatrics, Columbia University Medical Center, New York, NY, USA

    Lena S. Sun

Authors
  1. Jennifer J. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerri Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa Eisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guohua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jonathan M. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lena S. Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lena S. Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, J.J., Chen, J., Eisler, L. et al. Comparative effectiveness of opioid replacement agents for neonatal opioid withdrawal syndrome: a systematic review and meta-analysis. J Perinatol 39, 1535–1545 (2019). https://doi.org/10.1038/s41372-019-0437-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-019-0437-3

Search

Advanced search

Quick links