Treating Pregnant Opioid Dependent Women:
Examining Buprenorphine and Methadone
Treating Pregnant Opioid Dependent Women:
Examining Buprenorphine and Methadone
Hendrée E. Jones, Ph.D. Associate Professor
Department of Psychiatryand Behavioral Sciences
Johns Hopkins University School of MedicineBaltimore, Maryland
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Presentation GoalsPresentation 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 PregnancyStudies 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 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 pregnancyMethadone 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” MedicationMethadone 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 NeonatesThe 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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BuprenorphineBuprenorphine
Subutex or Suboxone
Buprenorphine reported to produce less physical dependence in adults
FullAgonist
FullAntagonist
Heroin
MethadoneMorphine
NaltrexoneNaloxone
Buprenorphine Nalmefene
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Case Reports and Open-Label StudiesCase 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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PurposePurpose
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 StudyRandomized 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 & PregnancySetting: Center for Addiction & Pregnancy
Interdisciplinary Approach – Psychiatry– Obstetrics– Pediatrics – Nursing
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CriteriaCriteria
Inclusion:– 18 - 40 years of age– Gestational age 16 - 30 weeks– Opioid dependent (DSM-IV, SCID I)– Opioid positive urine
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CriteriaCriteria 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 InfantPrimary Outcome Measures Infant
Neonatal Abstinence Syndrome (NAS)
Length of Hospital Stay (LOS)
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Selected Secondary Outcome MeasuresSelected Secondary Outcome Measures
Maternal
– Days of treatment
– Prenatal care visits
– Illicit drug use
Infant
– Physical birth parameters
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Patient FlowPatient FlowNumber screened
1490
Not Qualify Initially1433
Qualify and sign consent57
Randomized 30
Buprenorphine15
Methadone15
Buprenorphine9
Methadone11
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InductionInduction
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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InductionInduction
Methadone Buprenorphine
Levene’s Test of
Equality of Error
Variance
F (df); p value
Mean (95% CL) Mean (95% CL)
IRM transition
Dose (95% CL) 268.0 (214.0-322.0) 207.5 (161.0-253.9)
Range 100-390 mg 140-300 mg
Induction Dose
(95% CL) 53.5(48.6-58.4) 10.9 (10.2-11.7)
Range 20-70 mg 8-14 mg
Induction Un-
transformed Total
Withdrawal score 3.1 (1.42-4.85) 1.5 (-0.37-3.46) 3.27 (1,16); .089
Induction Log
transformed Total
Withdrawal score .43 (.25-.62) .42 (.21-.63) 1.70 (1,16); .211
Induction Log
transformed Total
Withdrawal score
with co-variates .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 OutcomeDrug Use During PregnancyMaternal OutcomeDrug Use During Pregnancy
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
Methadone N=11
Buprenorphine N=9% + Urine Samples
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% 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
Methadone N=11
Buprenorphine N=9
Maternal CharacteristicsMaternal Characteristics
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Maternal OutcomesMaternal Outcomes
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
MethadoneN=11
BuprenorphineN=9
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Birth Outcomes Methadone N=11
BuprenorphineN=9 deliveries (10 babies)
* data safety monitoring board recommended removing twin data from these variables
% 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
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0
2
4
6
8
10
12
14
16
18
20
22
24
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Observation Day
MethadoneBuprenorphine
Ave
rag
e P
eak
NA
S S
core
(n=8)
(n=8)
(n=9)
(n=9)
½
(n=9)
(n=8)
(n=5)
(n=4)
(n=5)
(n=4) (n=4)(n=2)
(n=0)
(n=5) (n=5)
(n=1)
NAS Time Course
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Limitations of StudyLimitations 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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ConclusionsConclusions 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 LineBottom 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 DirectionsFuture 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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AcknowledgementsAcknowledgements
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