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

AATOD 2004

Presentation GoalsPresentation Goals

Use of medication to treat opioid dependence during pregnancy

Review of published prenatal buprenorphine exposure data

Randomized double-blind study

AATOD 2004

Studies of Medication During PregnancyStudies of Medication During Pregnancy

Controversial

Some say unethical

Stigma associated with medication treatment for pregnant women is severe

AATOD 2004

Goals of Opioid Agonist Treatment Goals of Opioid Agonist Treatment

Cessation of opioid use

Stabilize intrauterine environment

Increased prenatal care compliance

Enhanced pregnancy outcomes

AATOD 2004

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

AATOD 2004

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)

AATOD 2004

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

AATOD 2004

BuprenorphineBuprenorphine

Subutex or Suboxone

Buprenorphine reported to produce less physical dependence in adults

FullAgonist

FullAntagonist

Heroin

MethadoneMorphine

NaltrexoneNaloxone

Buprenorphine Nalmefene

AATOD 2004

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

AATOD 2004

PurposePurpose

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

AATOD 2004

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

AATOD 2004

Setting: Center for Addiction & PregnancySetting: Center for Addiction & Pregnancy

Interdisciplinary Approach – Psychiatry– Obstetrics– Pediatrics – Nursing

AATOD 2004

CriteriaCriteria

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

AATOD 2004

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)

AATOD 2004

Primary Outcome Measures InfantPrimary Outcome Measures Infant

Neonatal Abstinence Syndrome (NAS)

Length of Hospital Stay (LOS)

AATOD 2004

Selected Secondary Outcome MeasuresSelected Secondary Outcome Measures

Maternal

– Days of treatment

– Prenatal care visits

– Illicit drug use

Infant

– Physical birth parameters

AATOD 2004

Patient FlowPatient FlowNumber screened

1490

Not Qualify Initially1433

Qualify and sign consent57

Randomized 30

Buprenorphine15

Methadone15

Buprenorphine9

Methadone11

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

% 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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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

AATOD 2004

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