MOTHER (2010): NAS after Methadone or Buprenorphine Exposure

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Jones HE, et al. "Neonatal abstinence syndrome after methadone or buprenorphine exposure". New England Journal of Medicine. 2010. 363(24):2320-2331.
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Clinical Question

What is the difference in treatment requirements for Neonatal Abstinence Syndrome (NAS) in neonates of mothers requiring opiate maintenance treatment in pregnancy with either methadone or buprenorphine?

Bottom Line

Neonates of mothers treated with buprenorphine in pregnancy required less morphine, had shorter hospital stays and shorter duration of treatment for NAS than neonates of mothers treated with methadone.

Major Points

Methadone has previously been regarded as the standard of care for opiate maintenance treatment in pregnant mothers with a history of opiate use disorder (DSM-IV previously dependency and abuse). This is the largest study of its kind to date and demonstrated that the use of buprenorphine is an acceptable treatment option for opiate dependent pregnancy women. risk, it also is associated with a trend towards increased mortality.



  • Multicenter, double-blind, double-dummy, randomized, controlled trial
  • N=175 pregnant women
    • Buprenorphine (N=86 assigned, N=58 completed study)
    • Methadone (N=89 assigned, N=73 completed study)
  • Setting: 8 international sites (6 in US, 1 in Austria and 1 in Canada)
  • Enrollment: May 4, 2005 to October 31 2008
  • Mean follow-up: Pregnancy duration and minimum of 10 days post-partum for NAS surveillance
  • Analysis:
  • Primary outcome: Number of neonates requiring treatment for NAS, peak NAS score, total amount of morphine needed to treat NAS, the length of stay in hospital and neonatal head circumference


Inclusion Criteria

  • Opiate-dependent (DSM-IV) women
  • Ages 18-41
  • English or German Speaking (Austrian Site)
  • Singleton pregnancy between 6 and 30 weeks gestation (based on last menstrual period)
  • Planned to deliver at one of the 8 study site hospitals
  • New opiate maintenance treatment start
  • Ongoing opiate maintenance treatment but willing to change treatment to randomized medication

Exclusion Criteria

  • Pending legal action that would impact participation
  • Concurrent alcohol dependence (DSM-IV)
  • Concurrent benzodiazepine use

Baseline Characteristics

  • Mean age: Methadone 27 years, Buprenorphine 25 years
  • Mean Gestational Age: 18.7 weeks in both
  • Percentage Previously In Opiate Maintenance Treatment in the past 30 days: Methadone 47%, Buprenorphine 41%


  • Prior to randomization all participants received rapid-release morphine
    • Significant concerns regarding withdrawal in pregnancy leading to adverse neonatal outcomes (preterm birth, stillbirth, placental abruption) and maternal (risk of relapse)
    • Risk of precipitated withdrawal in transition from methadone to buprenorphine for patients previously receiving opiate maintenance therapy and randomized to study, therefore required a "washout" period to prevent this achieved with morphine
  • Buprenorphine (subutex) without naloxone used as at the time of the study FSA had not approved naloxone for use in pregnancy (suboxone = buprenorphine/naloxone)
  • Double blind, double dummy, flexible dose study
    • dose increases 2 mg for buprerophine and 5-10 mg for methadone
    • dose range buprenorphine 2 - 32 mg in SL tablets and 20-140 mg of liquid methadone
    • daily observed dosing of medications,
    • participants took either buprenorphine or placebo SL AND either methadone or placebo (in fixed volume), placebo doses were flavor matched
  • N=86 randomized to buprenorphine
  • N=89 randomized to methadone
  • participants were given monetary vouchers for urine samples clear from illicit substances
  • NAS assessment completed for a minimum of 10 days after birth
  • neonates examined q4h, with NAS scoring twice daily
    • Finnegan scale for NAS 28 item scoring for treatment decision on morphine dose requirements
    • raters were trained by an expert rater with intraclass correlation coefficient used for degree of agreement between expert rater and site rater


Comparisons are methadone vs buprenorphine treatment

Primary Outcomes

Treated for NAS
57% vs 47% (OR 0.7; CI 0.2-1.8; P=0.26)
NAS peak score
12.8 vs 11 (P=0.04)
Total Amount of morphine for NAS (mg)
10.4 vs 1.1 (P<0.0091)
Duration of infant's hospital stay (days)
17.5 vs 10 (P<0.0091)
Infants head circumference (cm)
33 vs 33.8 (P=0.03)

Secondary Outcomes

Duration of treatment for NAS (days)
9.9 vs 4.1 (P<0.003125)
Birth weight (g)
2878.5 vs 3093.7 (P=0.03)
Positive Urine drug screen at delivery
15% vs 9% (OR 0.5, CI 0.1-2.7 P=0.27)

Adverse Events

Methadone treated mothers had a higher rate of non life threatening, nonserious maternal events (P=0.003) and nonserious materal cardiovascular events (P=0.001). There was no difference between the groups in any serious or nonserious neonatal adverse events.


There were significantly more drop outs in the buprenorphine group than the methadone group (33% vs 18% P=0.02). 20 of the buprenorphine drop outs were secondary to medication dissatisfaction. A lower attrition rate in the buprenorphine group could have accounted for the improved outcomes of this group, however this data and the benefits in reduced NAS severity with buprenorphine has been replicated in studies since publication.


Funded by the National Institute on Drug Abuse; number, NCT00271219.

Further Reading

<references/ 1. Jones H.E. et al (2010) Neonatal ABstinence Syndrome after Methadone or Buprenorphine Exposure. NEJM. 363;24 p2330-2331 >