Treating Pregnant Opioid Dependent Women: Examining Buprenorphine and Methadone

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Treating Pregnant Opioid Dependent Women
Examining Buprenorphine and Methadone

• Hendrée E. Jones, Ph.D. Associate Professor
• Department of Psychiatry
• and Behavioral SciencesJohns Hopkins University
  School of Medicine
• Baltimore, Maryland

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Presentation Goals

• Use of medication to treat opioid dependence
  during pregnancy
• Review of published prenatal buprenorphine
  exposure data
• Randomized double-blind study

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Studies of Medication During Pregnancy

• Controversial
• Some say unethical
• Stigma associated with medication treatment for
  pregnant women is severe

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Goals of Opioid Agonist Treatment

• Cessation of opioid use
• Stabilize intrauterine environment
• Increased prenatal care compliance
• Enhanced pregnancy outcomes

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Methadone is effective during pregnancy

• Methadone is recommended for the treatment of
  opioid dependent pregnant women
• Over 30 years of experience and research
• Does not appear to have teratogenic potential

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Methadone is not a Magic Bullet Medication

• Neonatal Abstinence Syndrome (NAS)
• Neuralgic excitability (hyperactivity,
  irritability, sleep disturbance)
• Gastrointestinal dysfunction
• (uncoordinated sucking/swallowing,
• vomiting)
• Autonomic Signs (fever, sweating, nasal
  stuffiness)

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The NAS of Opioid Exposed Neonates

• 55-90 exhibit NAS
• Methadone dose relationship to NAS severity is
  inconsistent
• Onset within 48 to 72 hours after birth
• Subacute signs for a year

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Buprenorphine

• Subutex or Suboxone
• Buprenorphine reported to produce less physical
  dependence in adults

Full
Full
Antagonist
Agonist
Heroin
Buprenorphine
Nalmefene
Morphine
Naloxone
Naltrexone
Methadone
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Case Reports and Open-Label Studies

• Since 1995, 23 reports of prenatal exposure to
  buprenorphine
• Approximately 338 babies and number of cases
  ranged from 1 to 153 (median6)
• 61 NAS with 48 requiring treatment
• NAS appears in 12-48 hrs,
• peaks 72-96 hrs
• Duration 120-168 hrs

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Purpose

• Compare methadone and buprenorphine in pregnant
  opioid-dependent women and to provide preliminary
  safety and efficacy data for a larger
  multi-center trial

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Randomized Controlled Study

• Double-blind (staff and patient)
• Double-dummy (two medications)
• Two groups Methadone or Buprenorphine
• Flexible dosing
• Methadone 20-100 mg
• Buprenorphine 4-24 mg

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Setting Center for Addiction Pregnancy

• Interdisciplinary Approach
• Psychiatry
• Obstetrics
• Pediatrics
• Nursing

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Criteria

• Inclusion
• 18 - 40 years of age
• Gestational age 16 - 30 weeks
• Opioid dependent (DSM-IV, SCID I)
• Opioid positive urine

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Criteria

• Exclusion
• Methadone positive urine at admission
• DSM IV axis I current diagnosis other than
  psychoactive substance use
• Serious medical or psychiatric illness
• Diagnosis of preterm labor
• Congenital fetal malformation
• Current alcohol abuse/dependence
• Benzodiazepine use
• (8 or more times/month and/or 2 or more times
  /week)

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Primary Outcome Measures
Infant

• Neonatal Abstinence Syndrome (NAS)
• Length of Hospital Stay (LOS)

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Selected Secondary Outcome Measures

• Maternal
• Days of treatment
• Prenatal care visits
• Illicit drug use
• Infant
• Physical birth parameters

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Patient Flow
Number screened 1490
Not Qualify Initially 1433
Qualify and sign consent 57
Randomized 30
Buprenorphine 15
Methadone 15
Buprenorphine 9
Methadone 11
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Induction

• Patients stabilized on immediate release morphine
  (IRM) prior to randomization
• Is transition from IRM to methadone or
  buprenorphine similar?
• Withdrawal scores over first 3 days appeared mild
  for both medications

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Induction
Adapted from Jones,H.E. et al., In press. Drug
and Alcohol Dependence
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Maternal OutcomeDrug Use During Pregnancy
Methadone N11
Buprenorphine N9
Urine Samples
opioid 15.6 16.7 cocaine 11.2 15.2 ampheta
mine 0.0 0.0 barbiturates 0.0
0.0 benzodiazepine 0.4 2.5 THC 7.5
0.0
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Maternal Characteristics
Methadone N11
Buprenorphine N9
African-American 63.6 88.9 Gestation
(weeks) 23.6 22.8 Education
(yrs) 10.0 10.3 Employed 0.0 0.0 Age
(yrs) 30.3 30.0 Smoked Cigarettes 81.8 77.8
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Maternal Outcomes
Methadone N11
Buprenorphine N9
Days in Treatment 99.9 115.6 Prenatal
care visits 3.4 3.6 LOS mom 2.2
2.2 C section 9.1 11.1 Tox. delivery
(mom) 9.1 0.0 Normal presentation 100
100 Preterm birth 9.1 0.0 Gestational
age delivery 38.8 38.8 Ave. dose at delivery
(mg) 79.1 18.7
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Birth Outcomes
Methadone N11
Buprenorphine N9 deliveries (10 babies)
Treated for NAS 45.5 20.0 Morphine
Drops 93.1 23.6 Birth Weight (gm)
3001.8 3530.4 LOS baby 8.1 6.8
NICU treatment 18.0 10.0 APGAR 1 8.3
8.1 APGAR 5 8.9 8.7 Length
(cm) 49.6 52.8 Head Cir. (cm) 33.2 34.9
data safety monitoring board recommended
removing twin data from these variables
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NAS Time Course
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Limitations of Study

• Small sample size
• I/E criteria limits generalizability
• Nicotine exposure and effect on NAS needs more
  study
• Long-term outcomes beyond scope of study

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Conclusions

• Both methadone and buprenorphine provide positive
  benefits to mothers
• 100 of infants had NAS signs/symptoms
• Tendency for fewer buprenorphine-exposed babies
  to be treated for NAS
• Significantly fewer days of hospitalization with
  buprenorphine exposure

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Bottom Line

• Both medications have strong support to document
  safety and efficacy for mother and infant
• NAS is only part of the complete riskbenefit
  ratio
• A greater range of medication options will
  improve the treatment of pregnant women

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Future Directions

• Multi-center trial comparing methadone and
  buprenorphine
• 8 sites submitted applications
• May provide data needed to change FDA labeling
  for methadone and buprenorphine
• Develop infrastructure for studying other
  medications and womens health issues during
  pregnancy

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Acknowledgements

• Patients and infants
• Rolley Ed Johnson
• NIDA R01 DA12220 (P.I.Johnson/Jones)
• Co-Investigators
• Staff at Center for Addiction and Pregnancy
• Staff at BPRU