Morphine versus Methadone in the Treatment of Neonatal Abstinence Syndrome

June 11, 2019


Davis JM, Shenberger J, Terrin N, Breeze JL, Hudak M, Wachman EM, Marro P, Oliveira EL, Harvey-Wilkes K, Czynski A, Engelhardt B, D’Apolito K, Bogen D, Lester B.  Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome. JAMA Pediatrics 2018; 172(8):741-748. PMID: 29913015.


Dr Hannah Cooney, MB BS (Hons), B.Med.Sci
Paediatric Resident Medical Officer
The Royal Women’s Hospital, Melbourne, Australia

Dr Kate Hodgson, MB BS (Hons), B.Med.Sci, FRACP
Neonatal Clinical/Research Fellow
The Royal Women’s Hospital, Melbourne, Australia
PIPER Neonatal Consultant
The Royal Children’s Hospital, Melbourne, Australia

Prof Peter Davis, MB BS, MD, FRACP
Director of Newborn Research
The Royal Women’s Hospital, Melbourne, Australia




In term infants at risk of neonatal abstinence syndrome (P), is treatment with morphine (I) more effective than treatment with methadone (C) at reducing length of hospital stay (O)?


  • Design: A multi-centre, randomized, double-blind, intention-to-treat trial.
  • Allocation: Allocation concealed.
  • Blinding: The study was blinded to participant families, investigators, staff and statisticians. Pharmacists were not blinded to assignments. Methadone, placebo and morphine solutions were visually indistinguishable.
  • Follow-up period: Infants were observed for 48 hours following cessation of study drug prior to discharge from hospital with plan for further follow up at 18 – 24 months of age.
  • Setting: Eight inpatient units in the United States from February 2014 to March 2017.
  • Patients:
    • Inclusion criteria:
      • Mothers treated with methadone or buprenorphine for an opioid use disorder or an opioid for treatment of chronic pain
      • AND receiving adequate antenatal care (at least 1 – 2 obstetric appointments in the third trimester).
    • Exclusion criteria:
      • Mothers who consumed more than 3 oz of alcohol per week during pregnancy.
      • Infants born before 37 weeks (based on solid obstetric dating criteria or early ultrasonography).
      • Infants with evidence of sepsis, major congenital abnormalities or genetic disorders.
    • Observational arm
      • Parents who declined randomization could consent to standardised institutional weight-based morphine treatment and data collection.
      • Inclusion and exclusion criteria were the same as those used in the trial.
  • Intervention: Treatment of Neonatal Abstinence Syndrome (NAS) with buprenorphine or methadone.
  • Outcomes:
    • Primary outcome: Hospital length of stay
    • Secondary outcomes:
      • Length of stay related to treatment for NAS (birth to last day of study drug treatment plus 2 days observation after treatment cessation)
      • Length of treatment with the study drug
      • Need for supplemental phenobarbital
      • Weight gain during hospitalisation
      • Need for dose escalation of the study drug
  • Analysis and Sample Size:
    • A total sample size of 184 infants requiring treatment of NAS was calculated to attain 80% power to detect a difference in mean LOS of 2.3 days
    • 183 parents consented to enrolling their infants for randomization
    • 117 of randomized infants required treatment for NAS
    • 170 infants were analysed in the observational arm of the study
    • The registered trial protocol specified a priori adjusted analyses for site and maternal opioid type.


  • Unadjusted analyses found no significant difference in primary or secondary endpoints.
  • However, after adjusting for treatment site and maternal opioid type, methadone was associated with the following statistically significant differences, compared with morphine:
    • 14% reduction in mean relative LOS corresponding to a difference of 2.9 days
    • 14% reduction in LOS attributable to NAS corresponding to a difference of 2.7 days
    • 16% reduction in length of treatment corresponding to a difference of 2.3 days.
  • Phenobarbital use was less common in methadone arm however this was not statistically significant.
Outcome Methadone (n=58) Morphine (n=58)
LOS, mean (SD) 21.8 (15.0) 23.2 (8.8)
LOS attributable to NAS, mean (SD) 18.9 (7.9) 21.1 (6.9)
LOT, mean (SD) 14.7 (8.0) 16.6 (6.9)
Adjusted methadone-morphine comparison
  Statistic P Value
LOS, mean (SD) 0.86 (0.74 – 1.00) 0.046
LOS attributable to NAS, mean (SD) 0.86 (0.77 – 0.97) 0.01
LOT, mean (SD) 0.84 (0.73 – 0.97) 0.02

Table 1: Primary and secondary outcomes.

Abbreviations: LOS, length of stay; SD, standard deviation; NAS, neonatal abstinence syndrome; LOT, length of drug treatment

  • Comparing the combined randomized cohort with the observational cohort:
    • Randomized infants had statistically significant shorter adjusted total LOS, LOS attributable to NAS, and length of drug treatment (LOT). Randomized infants also received phenobarbital less frequently than nonrandomized infants.
    • No statistically significant differences were found in any outcomes in infants randomized to receive morphine compared with the observational cohort, demonstrating that any beneficial effects were primarily attributable to methadone.


There was a modest benefit demonstrated in short term outcomes for infants receiving methadone, compared with morphine, for treatment of NAS, when adjusted for treatment site and maternal opioid type.


Misuse of opioids during pregnancy affects more than 5% of pregnancies in the United States (1). Infants exposed to alcohol or drugs in utero are at risk of developing neonatal abstinence syndrome (NAS). Several different approaches are used to treat NAS, and no universal standard exists. Morphine and methadone are commonly used pharmacological treatments (2).

This randomized, double-blind, intention-to-treat trial compared the short-term safety and efficacy of treatment with morphine versus methadone in infants with NAS.

Although 183 patients were consented, recruitment did not meet the sample size target as 66 infants did not require pharmacotherapy.  Therefore, only 117 patients were randomized to treatment groups. Analysis was performed according to the intention-to-treat principle, projected to detect a difference in primary outcome of hospital length of stay (LOS) of 2.3 days. Secondary outcomes were considered exploratory given they were not accounted for in initial power calculations.

No significant difference was found in the primary outcome of hospital LOS with unadjusted analysis. Adjusted analysis showed a reduction in mean LOS of approximately 2.9 days with the use of methadone, compared with morphine. Recruitment did not meet the sample size target; therefore, power to detect the pre-specified difference in LOS was diminished.

However, when compared to the observational arm, the randomized group had shorter LOS, LOS due to NAS, and treatment length suggesting that protocolization of care practices itself may lead to improved outcomes.

The study was delayed initially given a lack of commercially available preservative free formulation of methadone suitable for infants. Recruitment was challenging with significant numbers of parents declining randomization citing reasons including fear of social or legal ramifications. Increasing focus on non-pharmacological management of NAS, such as the Eat, Sleep, Console assessment approach (3), was apparent over the course of the study with an overall decline in pharmacotherapy requirement. Recruitment ceased before the planned sample size was attained for reasons not explicitly stated.

Previous studies have similarly suggested shorter median treatment times using methadone for NAS, compared with morphine. A retrospective study by Patrick et al. involving 1424 infants from 14 centres showed methadone to be associated with reduced LOS, compared with morphine (4). Brown et al., in a single-centre study of 31 infants demonstrated a shorter duration of pharmacotherapy with the use of methadone, compared with morphine (5). Contrary to these studies, a small retrospective study of 26 neonates by Young et al. found that methadone was associated with longer LOS, compared with morphine (6). A recent systemic review of 18 trials comparing a number of pharmacotherapies used in treatment of NAS suggested that buprenorphine is the optimal treatment with morphine the lowest ranked pharmacotherapy in terms of LOS and treatment time (7).

This study suggested treatment of NAS with methadone was somewhat better than morphine in terms of short-term outcomes and LOS. The long-term neurodevelopmental outcomes associated with methadone use are unclear and require further investigation. Standardization of pharmacotherapy approaches to NAS would require further appropriately powered trials and evidence of long-term outcomes. Indeed, with increasing success with non-pharmacological management of NAS, the pharmacological options may become less relevant.


  1. 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: 2320-2331.
  2. Hudak ML, Tan RC; Committee on Drugs; Committee on Fetus and Newborn; American Academy of Pediatrics. Neonatal drug withdrawal. Pediatrics 2012; 129: e540-e560.
  3. Grossman MR, Lipshaw MJ, Osborn RR, Berkwitt AK. A Novel Approach to Assessing Infants With Neonatal Abstinence Syndrome. Hospital Pediatrics 2018; 8: 1-6
  4. 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: 867-872.
  5. Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol 2015; 35: 278-283.
  6. Young ME, Hager SJ, Spurlock DJr. Retrospective chart review comparing morphine and methadone in neonates treated for neonatal abstinence syndrome. Am J Health Syst Pharm 2015;7 2(suppl 3):S162-S167.
  7. Disher T, Gullickson C, Singh B. Pharmacological Treatments for Neonatal Abstinence Syndrome. JAMA Pediatr 2019; 173:234-243