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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 Sciences
Johns Hopkins University School of Medicine
Baltimore, Maryland
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
Agonist
Heroin
Morphine
Methadone
Full
Antagonist
Buprenorphine
Nalmefene
Naloxone
Naltrexone
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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 (median=6)
 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
Buprenorphine
9
Methadone
15
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
Methadone
Mean ( 95% CL)
IRM transition
Dose (95% C L)
Range
Ind uction Dose
(95% CL)
Range
Ind uction Untransformed Total
Withd rawal sc ore
Ind uction L og
transformed Total
Withd rawal sc ore
Ind uction L og
transformed Total
Withd rawal sc ore
with co-variates
Buprenorphine
Mean ( 95% CL)
Levene’s Test of
Equality of Error
Variance
F (df); p value
268.0 (214.0-322.0) 207.5 (161.0-253.9)
100-390 mg
140-300 mg
53.5(48.6-58.4)
20-70 mg
10.9 (10.2-11.7)
8-14 mg
3.1 (1.42-4.85)
1.5 (-0.37-3.46)
3.27 (1,16); .089
.43 (.25-.62)
.42 (.21-.63)
1.70 (1,16); .211
.43 (.25-.62)
.42 (.21-.63)
.67 (1,16); . 426
Adapted from Jones,H.E. et al., In press. Drug and Alcohol Dependence
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Maternal Outcome
Drug Use During Pregnancy
Methadone
% + Urine Samples
N=11
Buprenorphine
N=9
opioid
15.6
16.7
cocaine
11.2
15.2
amphetamine
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
N=11
% African-American
Buprenorphine
N=9
63.6
88.9
Gestation (weeks)
23.6
22.8
Education (yrs)
10.0
10.3
0.0
0.0
% Employed
Age (yrs)
30.3
Smoked Cigarettes
30.0
81.8
77.8
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Maternal Outcomes
Days in Treatment
Methadone
N=11
99.9
Buprenorphine
N=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
N=11
Buprenorphine
N=9 deliveries
(10 babies)
% Treated for NAS
45.5
20.0
Morphine Drops
93.1
23.6
3001.8
3530.4
8.1
6.8
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
Birth Weight (gm)*
LOS baby
% NICU treatment
* 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
risk:benefit 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 women’s 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
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