Bethesda, MD
November 1, 2012
Association for Medical Education and Research in Substance Abuse
Betty Ford Award Plenary Address
Treating Opioid-dependent Women during Pregnancy:
How Research Findings Can Inform Clinical Practice
Hendrée E. Jones, PhD
Senior Research Psychologist, RTI International
Adjunct Professor, Department of Psychiatry and Behavioral Sciences and
Department of Obstetrics and Gynecology
Johns Hopkins University School of Medicine
2
Disclosures
 Discussing 2 medications, methadone and buprenorphine.
Neither medication is approved for use in pregnant women.
Both medications are currently labeled by the US Food and
Drug Administration (FDA) as Category C for use in pregnancy
for the treatment of maternal opioid dependence: “Animal
reproduction studies have shown an adverse effect on the fetus
and there are no adequate and well-controlled studies in
humans, but potential benefits may warrant use of the drug in
pregnant women despite potential risks.”
 Reckitt-Benckiser Pharmaceuticals Inc. for active and placebo
Subutex tablets and time and travel reimbursement
3
Acknowledgements
 Study patients and infants
 Staff at the Center for Addiction and Pregnancy,
Behavioral Pharmacology Research Pharmacy and
Nursing staff
 Johns Hopkins University Co-Investigators:
– Drs. Donald Jasinski, Lauren Jansson, Robert
Dudas, Lorraine Milio, Martha Velez,
Vickie Walters, Eric Strain, George Bigelow
 National Institute on Drug Abuse
– R01 DAs: 015764, 015738, 017513, 015778,
018410, 018417, 015741, 15832
 Maternal Opioid Treatment: Human Experimental
Research (MOTHER) Site PIs and investigative teams
 Reckitt-Benckiser Pharmaceuticals Inc. for active and
placebo Subutex tablets
4
Outline
• Historical
and current context of opioid
use and opioid agonist treatment during
pregnancy
• Comparison of methadone v.
buprenorphine: maternal and neonatal
outcomes
♦ Primary and secondary outcome findings
♦ Latest key secondary analysis study
results
♦ Impact of behavioral intervention for
smoking cessation
• Clinical implications and unanswered
questions
5
Historical Context
Concern over pregnant women using
substances in the United States has been
an important health issue in the United
States for more than a century:
•
•
•
In the 1800s, 66–75% of individuals with
opium use disorders were women
The most common substance source of
opium for women was medical
prescriptions to treat pain
During the late 1800s physicians
recognized the neonatal opioid withdrawal
syndrome, and the need to treat the
newborns of mothers who had taken opium
during pregnancy with morphine in order
to prevent morbidity and mortality
Kandall, Substance and shadow, 1996. Earle, Medical Standards, 1888.
6
Historical Context
♦ By the 1900s physicians becoming better educated about
the drawbacks of prescribing narcotics, and legitimate
supplies of narcotics then shrank
♦ Women unable to stop using substances were forced to
seek them from illegitimate sources
♦ Passage of the Harrison Narcotic Act of 1914 greatly
changed narcotic prescribing and dispensing practices,
requiring that addictive substances needed to be
prescribed by a licensed health professional
♦ Some enlightened physicians treated opioid addiction
with morphine
♦ In 1919, this practice was prohibited by the Supreme
Court
► Result: Segregation of the treatment of substance use
disorders from general medical practice
Kandall, Substance and shadow, 1996.
7
Historical Context: Methadone
•
•
•
•
•
Schedule II opioid
Synthetically derived
μ opioid receptor agonist
Antagonist at NMDA receptors
Half-life estimated to fall in the
range of 24-36 hours
8
Historical Context: Methadone
•
Developed and first used as an analgesic
in Germany prior to World War II
•
First utilized in the United States in the
1940s for medication-assisted withdrawal
for heroin addicted individuals, using
decreasing doses over a 7-10 day period
•
Follow-up research found relapse rates
exceeding 90%
♦ In the 1960s, Dole and Nyswander found
that heroin-dependent patients could be
safely maintained on methadone
♦ Effective dosing leads to tolerance and a
reduction or elimination of craving for
heroin
9
Historical Context
Neonatal abstinence syndrome (NAS)
Treated
baby
 Neurologic excitability
hyperactivity, irritability, sleep
disturbance
 Gastrointestinal dysfunction
uncoordinated sucking, swallowing,
vomiting
 Autonomic signs
fever, sweating, nasal
stuffiness
Finnegan and Kaltenbach. Neonatal abstinence syndrome. In: R.A. Hoekelman, S.B. Friedman, N.M. Nelson and H.M.
Seidel, Editors, Primary Pediatric Care (2nd ed.), Mosby Year Book, St. Louis, MO 1992):1367–1378.
10
Historical Context
40 years of documented benefits
of methadone during pregnancy
 Prevention of erratic maternal opioid
levels lessens fetal exposure to
repeated withdrawal episodes
 Reduces fetal exposure to illicit drugs
 Decreases risks to fetus of infection
from HIV, hepatitis and sexually
transmitted infections
 Reduces the incidence of obstetrical
and fetal complications
 Improves newborn outcomes
Review by Kaltenbach et al., Obstet Gynecol Clin North Am 1998.
11
Historical Context
 In the 1970s, a positive relationship
between maternal methadone dose and
NAS severity was reported
 Thus, early recommendations were to
maintain pregnant women on
methadone doses between 20 to 40 mg
per day
 Subsequently, 3 decades of research
have shown an inconsistent
relationship between maternal
methadone dose and NAS severity
 Only in the last 10 years have pregnant
women been appropriately medicated
using the same principles as those
used for non-pregnant patients
Review by Cleary et al., Addiction. 2010.
12
Historical Context
Methadone Dosing
during Pregnancy
 Often methadone dose needs
adjustment upwards as
gestational age increases
 Greater plasma volume
 Increased renal blood flow
 Induction of CYP3A
 Possible contribution of CYP3A7
from fetus
Pond et al., 1985; Swift et al., 1989; Jarvis et al., 1999; Wolff et al., 2004
12
13
Historical Context
Fetal Physiologic Effects of Maternal Methadone Administration
Trough
mean
Peak
mean
136.5
128.3*
 HR Variability
5.9
3.7*
 # Accelerations
3.6
0.5*
 Movement Bouts
66.8
63.6
 Movement Duration
26.9
13.7*
 Motor Activity Total 1627.8
880.1*
 Heart Rate
* p < .05
Jansson et al., 2005
13
14
Historical Context
140
Days Retained in CAP Treatment
122
120
Methadone Tapering v.
Maintenance
104
95
100
80
 Guidance regarding tapering v.
maintenance was based largely
on sound clinical judgment
60
40
20
30
14
0
% Mothers with Positive Urine Drug Screen at Delivery
100
3 meth taper (n=67)
3 meth taper+MM (n=8)
80
60
40
7 meth taper (n=28)
7 meth taper+MM (n=20)
57
53
MM (n=52)
33
MM = Methadone Maintenance
23
20
 Methadone maintenance
facilitates retention of patients
and reduces drug use
 Biggest concern with
methadone during pregnancy is
the potential for occurrence of a
neonatal abstinence syndrome
15
0
Jones et al., 2008.
14
15
Historical Context:
Summary
 For over 4 decades methadone has been the recommended
standard of care for treating opioid-dependent pregnant patients
 Methadone maintenance is superior to tapering for pregnant
patients
 Maternal methadone dosing may need to be increased as
gestational age advances
 Fetal heart rate and variability as well as fetal movements are
reduced following single daily dosing of methadone
 NAS is an expected yet treatable complication in methadoneexposed infants
15
16
Current Context
National Survey on Drug Use
and Health 2008/9
♦ The two most common drugs
used by non-pregnant women
have been alcohol and tobacco
Past Month Use
Self-Reported Use (%)
100
80
60
Any Illicit Drug
Marijuana
Cocaine
Opioids
Alcohol
Tobacco
♦ This same statement is true for
pregnant women
♦ Among pregnant women in the
United States, approximately
16.3% smoke cigarettes, 10.8%
drink alcohol, and 4.4% used illicit
drugs in the past month
40
20

0
Pregnant
Not Pregnant
SAMHSA Office of Applied Statistics, 2009-2010; Patrick et al., JAMA, 2012.
17
Current Context
Weighted National Estimates of
the Rates of Maternal Opiate Use per 1000
Hospital Births per Year
5.63
 A retrospective, serial, cross-sectional analysis
of a nationally representative sample of
newborns with NAS.
 Clinical conditions were identified using ICD-9CM diagnosis codes.
 NAS and maternal opiate use were described as
an annual frequency per 1000 hospital births.
Rate of Maternal Opiate Use
per 1000 Hospital Births
6
5
4
3
2
2.2
1.2
1.25
1
0
2000
2003
2006
2009
in the United States—one infant every hour—suffers from neonatal abstinence syndrome (NAS)
Low Birthweight, Respiratory Diagnoses, and Medicaid Coverage in 2009
Weighted National Estimates of the Rates of NAS
per 1000 Hospital Births per Year
100
78.1
60
4
45.5
30.9
40
19.1
20
7
0.7
0
Low1
Birthweight
Respiratory
2
Diagnoses
NAS neonates
non-NAS neonates
Medicaid
3
Coverage
Rate of NAS per 1000 Hospital Births
Percentage
80
3.4
3
1.8
2
1.5
1.2
1
0
2000
2003
2006
2009
18
Current Context
Policy and Opinion Setting Bodies have given attention to this issue
Neonatal Drug Withdrawal. Mark L. Hudak, Rosemarie C. Tan, THE COMMITTEE ON
DRUGS and THE COMMITTEE ON FETUS AND NEWBORN. Pediatrics; originally
published online January 30, 2012.
ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction
in pregnancy. ACOG Committee on Health Care for Underserved Women;
American Society of Addiction Medicine. Obstet Gynecol. 2012 May;119(5):1070-6.
19
Current Context
MEDIA AND POLITICAL ATTENTION
July, 2012. New York Senator Charles
Schumer called on the FDA to provide
clear labels so women and health
care professionals know the potential
dangers of the medication they are
taking. He said that SAMHSA must
educate physicians to better identify
symptoms of prescription drug
abuse, and NIH and CDC need to
conduct more research that will help
mothers avoid addiction.
20
Current Context
Why are more individuals, including
pregnant women, using opioids?
 There has been an increase in the access to
these medications
 Pain became the 5th vital sign in the early 21st
century
 Federal prosecutors allege in documents
filed in U.S. District Court that Chris and Jeff
George from Florida dramatically increased
the numbers of pain clinics in Florida and
routed opioid pain medications to Kentucky,
Ohio and South Carolina.
21
Current Context
Issues facing pregnant drug users
and their children
 Exposure to violence
and trauma
 Generational drug use
 Lack of formal
education
 Lack of job acquisition
and maintenance skills
 Gender
inequality/malefocused society
 Legal involvement
 Multiple drug exposures
 Limited parenting skills
and resources
 History of child abuse
and neglect
 Multiple psychiatric
issues
 Unstable housing
 Lack of positive and
supportive relationships
 Food insecurity and lack
of nutrition
These factors with or without drug use can
influence mother and child outcomes
22
Current Context
Factors Influencing Mother and
Child Outcomes
 Exposure to violence/trauma
 Multiple drug exposures (e.g.,
alcohol and tobacco)
 Poor maternal/child
attachment
 Child abuse
 Psychiatric status of caregiver
22
 Stable caregiver and
environment
 Nutrition
22
23
Current Context
Comprehensive Care
 Interdisciplinary approach
–
–
–
–
–
–
Psychiatry
Psychology
Obstetrics
Pediatrics
Nursing
Social Work
 Multiple modalities
– Medically-assisted withdrawal
and aftercare
– Methadone with behavioral
treatment
23
24
Summary
♦ While occurring less frequently than alcohol and tobacco use,
opioid misuse during pregnancy is nonetheless a serious and
growing public health problem
♦ This increase in use of opioids by pregnant women appears to be
fueling an increase in the incidence of neonatal opioid withdrawal
♦ Opioid use by pregnant women is often complicated by polydrug
use, and often occurs intertwined with complex personal,
interpersonal, family, social, and environmental factors that can
contribute to adverse consequences
♦ Multi-faceted interventions are needed to help prevent and treat
opioid-dependence among women during pregnancy and their
infants
24
25
Buprenorphine
 A derivative of the opioid alkaloid
thebaine
 Schedule III opioid
 μ opioid receptor partial agonist
 primarily antagonistic actions on κ
opioid and δopioid receptors
 Half-life estimated to fall in the
range of 24-60 hours
Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl.
1), 5–27.
26
Buprenorphine: Formulations
 Buprenorphine mono product (e.g.,
Subutex)
 Buprenorphine + naloxone (e.g.,
Suboxone)
- 4:1 ratio to prevent misuse by injection
 2 mg and 8 mg sublingual tablets
 2 mg/0.5 mg and 8 mg/2 mg sublingual
film strips
Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl.
1), 5–27.
27
Buprenorphine and Pregnancy
 Since 1995, over 40 published
reports of prenatal exposure to
buprenorphine maintenance
 Approximately 750 babies
prenatally exposed to
buprenorphine (number of
cases per report ranged
from 1 to 159; Median=14)
 Dose range 0.4 to 32 mg
 88% reported concomitant drug use
Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl.
1), 5–27.
28
Buprenorphine: Maternal Outcomes
• Research with buprenorphine not as
extensive as with methadone
• Well-tolerated and generally safe
• In contrast to the research with
methadone, little research has compared
buprenorphine to a non-treated control
group
• Rather, buprenorphine has been
compared in both retrospective and
prospective studies to methadone
• Majority of research would suggest that
maternal outcomes are not in any way
different than for methadone
Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl.
1), 5–27.
29
PROMISE Study
Morphine drops
% Treated for NAS
120
50
8
4000
80
30
60
3000
6
20
40
2000
4
10
20
1000
2
0
0
0
0
■ Methadone
10
8
15
6
10
■ Buprenorphine
APGAR at 1 minute
% NICU treatment
20
(n=11)
(n=10, 1 twin set)
APGAR at 5 minutes
10
* P=.021.
p = .021
10
5000
100
40
Neonatal length of stay
Birth weight (gm)
Length (cm)
Head circumference
(cm)
80
50
8
60
6
40
4
4
5
2
2
0
0
0
40
30
20
20
0
10
 PROMISE study
combined with
double-blind
RCT in Vienna
(Fischer et al., 2006)
provided preliminary
data
 The advancement of
treatment research
for opioid-dependent
pregnant women may
be best served
through a multisite
international network
able to conduct
randomized
controlled trials
0
Jones et al., Drug Alcohol Depend, 2005.29
30
Location of MOTHER Study Sites
Lead Site Johns Hopkins U PI: H Jones
Brown U PI: B Lester
Thomas Jefferson U PI: K Kaltenbach
U Vermont PI: S Heil
U Vienna PI: G Fischer
U Toronto PI: P Selby
Vanderbilt U PI: P Martin
Wayne State U PI: S Stine
Coordinating Center PI: A Arria
**
*
* **
*
*
31
MOTHER Study:
Participants
Eligibility
 18 to 40 years of age
 Gestational age 6 to 30 weeks
 Opioid-dependent (DSM-IV, SCID I)
 Opioid-positive urine
 Single-fetus pregnancy
 Plan to deliver at site hospital
 No medical or other conditions
contraindicating participation
 No pending legal action potentially
preventing participation
 Without benzodiazepine or alcohol
disorders
Jones et al., N Engl J Med, 2010.
32
MOTHER Study:
Design
MOTHER Experimental Design
Cocaine +
Cocaine -
Early EGA
Late EGA
Initial
consent
Screening
Medical
clearance
Early EGA
•
Buprenorphine
Methadone
Late EGA
Randomized clinical trial
– 8 sites
– Double-blind
– Double-dummy
– Stratified
– Parallel group
– Flexible dosing:
♦ 20 to 140 mg methadone
♦ 2 to 32 mg buprenorphine
Pre-delivery
 Induction
 Daily dosing
 Weekly assessments
28 days
Post-delivery
Jones et al., N Engl J Med, 2010.
33
MOTHER Study:
Screening
Refused
participation
(n=243)
Screened
(N=1,074)
at 8 sites
Excluded
(n=656)
Failed to meet
inclusion criteria
(n=557)
 27% outside EGA range (n=149)
 22% benzodiazepine use (n=124)
Randomized
(n=175)
at 7 sites
 19% medical reason (n=105)
 10% alcohol use (n=57)
Jones et al., N Engl J Med, 2010.
34
MOTHER Study:
Randomization
Randomized
(n=175)
at 7 sites
Buprenorphine
(n=86)
Methadone
(n=89)
Completed
(n=73)
Completed
(n=58)
Premature
discontinuance
(n=28)
20
Dissatisfied
with medication
2
Premature
discontinuance
(n=16)
Jones et al., N Engl J Med, 2010.
35
MOTHER Study:
Baseline Comparisons
MOTHER Results Baseline: Completers
Total Sample
(N=131)
Methadone
(n=73)
Buprenorphine
(n=58)
% or
Mean (SE)
26.6 (.5)
% or
Mean (SE)
27.7 (.7)
% or
Mean (SE)
25.3 (.7)
White
87.8%
84.9%
91.4%
Black
9.2%
13.7%
3.4%
Other
3.1%
1.4%
5.2%
11.3 (.2)
11.3 (.3)
11.3 (.2)
16.0%
13.7%
19.0%
83.2%
79.5%
87.9%
18.7 (.5)
18.7 (.8)
18.7 (.7)
Maternal age in years
Race
Years of education
Employed
Legal status
(uninvolved)
Estimated weeks of
gestational age at study
entry
Notes: Site was a blocking factor in all analyses;
Bonferroni’s principle was used to set family wise α = .0045.
 Randomized
participants compared
by study condition had
no statistically
significant differences
in baseline
characteristics
 Completers compared
by study condition had
similar results
Jones et al., N Engl J Med, 2010.
36
MOTHER Study:
Primary Outcomes
100
Treated for
NAS
[Yes]
25
NAS peak
score
Total amount of
morphine for
15 NAS (mg)
20
75
10
15
50
• Compared with methadoneexposed neonates,
buprenorphine-exposed
p = .00000012
neonates
10
5
25
5
0
0
0
Days of infant
hospital stay
Head
circumference
50
(cm)
20
15
40
p = .00012
30
10
5
0
■ Methadone
■ Buprenorphine
20
10
– Required 89% less
morphine to treat NAS
– Spent 43% less time in the
hospital
– Spent 58% less time in the
hospital being medicated
for NAS
• Both medications in the
context of comprehensive
care produced similar
maternal treatment and
delivery outcomes
0
Notes: Significant results are encircled. Site was a blocking factor in all analyses. The O’BrienFleming α spending function resulted in α = .0091 for the inferential tests of the Medication
Condition effect for the 5 primary outcome measures at the conclusion of the trial.
36
Jones et al., N Engl J Med. 2010.
37
MOTHER Study:
Secondary Outcomes
Medication dose at
delivery, mg
Drug screen at
delivery [Positive]
Premature
discontinuance [Yes]
50
100
25
Medical
complications at
100 delivery [Yes]
40
20
80
30
15
60
20
10
40
25
10
5
20
0
0
0
0
75
50
■ Methadone
Normal
presentation
[Yes]
100
75
Cesarean section
[Yes]
■ Buprenorphine
Maternal weight
gain, kg
Number of
prenatal
obstetrical visits
50
10
40
8
30
6
6
20
4
4
10
2
2
500
0
0
0
0
10
2000
8
1500
50
25
0
Amount of voucher
Money earned
for drug-negative tests,
US$
Note: Bonferroni’s principle was used to set familywise α =
.003125 (nominal α = .05/16) for the secondary outcome measures.
1000
 Clinically
meaningful
attrition rate in
buprenorphine
condition
 Low rates of
illicit drug use
during
pregnancy
and at delivery
 Maternal
outcomes similar
in the 2 study
conditions
Jones et al., N Engl J Med, 2010.
37
38
MOTHER Study:
Secondary Analysis Studies
One of the goals of the MOTHER Study was to collect comprehensive data on maternal, fetal, and
neonatal behavior that could be shared with the broader research community
This broad availability of the MOTHER data has allowed MOTHER Principal Investigators and other
researchers to ask a variety of questions about maternal, fetal, and neonatal issues related to maternal
buprenorphine and/or methadone treatment. An Addiction Supplement issue will be published shortly
reporting on these studies.
The following slides present findings from a number of these secondary outcome studies, including:






The extent to which 32-week fetal movement and cardiac measures differ between methadone
and buprenorphine before and after dosing
Differences between buprenorphine- and methadone-maintained pregnant women in
obstetrical and neonatal complications
Liver enzymes and their relationship to buprenorphine and methadone treatment, as well as
HCV status
Differences in NAS signs between medications
Predicting treatment for neonatal abstinence syndrome
Neonatal neurobehavioral effects following buprenorphine v. methadone exposure
MOTHER User’s Guide and Databases can be found at:
http://www.jefferson.edu/jmc/pediatrics/mother/
39
MOTHER Study:
Secondary Analysis Studies
Fetal Cardiac and Movement Parameters at 36 weeks
(N=11)
Primary Outcomes
Methadone
Buprenorphine
n=6
n=5
Z
Mean (SD)
FHR, bpm
133.42 (7.89)
134.58 (7.12)
-0.18
FHR variability
4.43 (0.78)
5.30 (2.16)
-0.37
Accelerations
1.17 (1.17)
2.80 (3.83)
0.0
Motor activity
3.58 (1.18)
5.92 (2.95)
-2.01*
FM duration
8.74 (2.71)
21.53 (13.22)
-2.01*
27.42 (13.97)
18.88 (6.90)
-1.10
FHR-FM coupling, %
*p < .05
 Compared with methadoneexposed fetuses,
buprenorphine-exposed
fetuses have better
indications of fetal wellbeing, including:
– greater FHR variability
– more accelerations
– better FM-FHR coupling
early in the second half of
gestation
 In contrast, FM was most
consistently suppressed in
methadone-exposed fetuses
at the later gestational age
period
Jansson et al., Neurotoxicol Teratol. 2011.
40
MOTHER Study:
Secondary Analysis Studies
p < .01
 Fetuses exposed to buprenorphine were
more likely to have a reactive non-stress
test with more fetal heart rate (FHR)
accelerations than fetuses exposed to
methadone treatment
 Medications did not differ on these
measures immediately prior to dosing
p = .095
►Buprenorphine
dosing has less of a
suppressive effect than does methadone
on mean FHR, FHR variability, and the
ability of the autonomic system to
respond to integrate response to
movement
Salisbury et al., Addiction, 107 (Suppl. 1), 36–44
41
MOTHER Study:
Secondary Analysis Studies
Obstetrical and Neonatal Complications
 Several studies have compared obstetrical outcomes for opioiddependent pregnant women in maintenance treatment with
buprenorphine or methadone
 Results have suggested that obstetrical outcomes are comparable
between the two medications
 However, only two of these studies were randomized controlled trials,
both with small sample sizes
 This study compared obstetrical and neonatal measures between
buprenorphine and methadone for outcomes that were not
presented in the MOTHER primary outcomes paper
Holbrook et al., Addiction, 107 (Suppl. 1), 83–90.
42
MOTHER Study:
Secondary Analysis Studies
Incidence of obstetrical/neonatal complications
Buprenorphine
(n=86)
Methadone
(n=73)
0
4 (5%)
Gestational diabetes
1 (2%)
2 (3%)
Placental abruption
0
3 (4%)
Premature rupture of membranes
≥37 weeks EGA
2 (4%)
0
Head sparing
1 (2%)
1 (1%)
Meconium aspiration
1 (2%)
0
Placenta previa
0
1 (1%)
Non-head sparing
0
1 (1%)
Preeclampsia
0
0
Sepsis
0
0
Premature rupture of membranes
< 37 weeks EGA
• There were few
obstetrical and
neonatal
complications in
the total sample,
as well as in both
the
buprenorphine
and methadone
conditions
Holbrook et al., Addiction, 107 (Suppl. 1), 83–90.
43
MOTHER Study:
Secondary Analysis Studies
Preterm Labor (%)
Incidence of Preterm Labor
in the Two Medication Conditions
20
p < .05
15
10
5
0
■ Methadone ■ Buprenorphine
p < .05
• Maternal methadone
versus buprenorphine
maintenance treatment
was associated with:
 a higher incidence of
preterm labor
 a higher percentage
of respiratory distress
signs in neonates
Holbrook et al., Addiction, 107 (Suppl. 1), 83–90.
44
MOTHER Study:
Secondary Analysis Studies
Liver enzymes, buprenorphine, methadone, and HCV Status
 Possible relationship between buprenorphine treatment and hepatic injury or
dysfunction in opioid-dependent individuals
 Liver enzymes do not show much variation from normal in healthy pregnant
women
 However, rates of HCV infection in pregnant opioid-dependent women have
been reported as high as 93%
 Thus, the extent to which agonist medication, HCV exposure, or both have an
effect on liver enzymes in pregnant opioid-dependent women is unknown
 Liver enzymes assayed:
- aspartate aminotransferase (AST)
- alanine aminotranferase (ALT)
- gamma-glutamyl transferase (GGT)
McNicholas et al., Addiction, 107 (Suppl. 1), 91–97.
45
MOTHER Study:
Secondary Analysis Studies
AST, ALT, and GGT Levels by Trimester
35
30
25
AST
First
20
Second
15
Third
10
Post-partum
5
0
40
35
30
25
20
15
ALT
Trimester
First
■ First
■ Second
■ Third
■ Postpartum
Second
Third
Post-partum
10
5
0
45
40
GGT
 AST, ALT, and GGT decline during the
course of pregnancy, and then return
to baseline during the postpartum
period
 Participants with HCV had higher liver
function levels at all time points
 There was no effect of medication on
ALT or GGT. However, methadonemaintained participants had higher
GGT levels than did buprenorphinemaintained patients over the course of
the study
35
30
25
20
15
10
5
0
Liver function test results are in IU/L
First
Second
Third
Post-partum
All ps < .05
 HCV status did not moderate the
effects of the medication in either
group
McNicholas et al., Addiction, 107 (Suppl. 1), 91–97.
46
MOTHER Study:
Secondary Analysis Studies
• 53% of the total sample required treatment for NAS
• Receipt of NAS treatment for infants was predicted by:
– infant birthweight
– greater maternal nicotine use
• Total medication dose needed to treat NAS was predicted by:
– Maternal use of SSRIs
– higher nicotine use
– fewer days of study medication received also predicted.
 No variables predicted length of treatment for NAS
Kaltenbach et al., Addiction, 107 (Suppl. 1), 45–52.
47
MOTHER Study:
Secondary Analysis Studies
Incidence of NAS signs
 Three signs were observed
significantly more often in the
buprenorphine than in the
methadone condition: sneezing,
loose stools, and nasal stuffiness
 Two signs were observed
significantly more often in the
methadone than in the
buprenorphine condition:
undisturbed tremors and
hyperactive Moro reflex
 Methadone-exposed neonates
had higher mean NAS total
scores than buprenorphineexposed neonates
Gaalema et al., Addiction, 107 (Suppl. 1), 53–62.
48
MOTHER Study:
Secondary Analysis Studies
Methadone-exposed neonates had higher mean scores for: disturbed tremors, undisturbed tremors,
hyperactive Moro reflex, excessive irritability and failure to thrive
Buprenorphine-exposed neonates had higher mean scores
All ps ≤ 0.04
Gaalema et al., Addiction, 107 (Suppl. 1), 53–62.
49
MOTHER Study:
Secondary Analysis Studies
Time to Morphine Treatment Initiation
80
p = .01
Hours
60
40
20
0
Methadone
(n = 41)
Buprenorphine
(n = 27)
►
There was a significant
difference between
medication conditions in
mean time to initiation of
morphine treatment for
those neonates treated for
NAS, with the methadone
condition requiring
morphine treatment
earlier than the
buprenorphine condition
Gaalema et al., Addiction, 107 (Suppl. 1), 53–62.
50
Methadone: NAS
Other Factors Contributing to Severity
 Structural
 The NAS assessment and medication initiation and
weaning protocols
 Non-modifiable
 Genetics
 Other Substances
 Benzodiazepines
 SSRIs
 Cigarette smoking
Jansson and Velez,Curr. Opin Pediatrics, 2012
51
Smoking and Neonatal Abstinence
Syndrome (NAS)
9.8
10
8
NAS score and time to peak NAS score in
neonates of 29 methadone-maintained women
4.8
4
2
► lower
neonatal birth weight, smaller birth length, and
greater NAS severity in neonates of 139 opioidmaintained pregnant women
Heavy
Smoking
(> 20/day)
0
Light Smoking
(< 10/day)
n = 16
Heaving Smoking
(> 20/day)
n = 13
Time to Peak NAS Score
► NAS
symptoms and duration of hospitalization in 65
neonates of methadone-maintained women
113
120
100
80
► NAS
symptoms and unrelated to any NAS treatment in 64
neonates of methadone-maintained women
p < .05
60
40
51
37.8
► duration
20
Light Smoking
(< 10/day)
n = 16
Heavy
Smoking
(> 20/day)
0
Light
Smoking
(< 10/day)
Mean Time to Peak NAS Score
Heavier cigarette smoking has been found to
be related to:
► peak
p < .05
6
Light
Smoking
(< 10/day)
Mean Peak NAS Score
Peak NAS Score
Heaving Smoking
(> 20/day)
n = 13
of NAS treatment in 26 neonates of methadonemaintained pregnant women but not in 12 neonates of
buprenorphine-maintained pregnant women
Choo et al., Drug Alcohol Depend. 2004;75(3):253-60.
Winklbaur et al., Eur Addict Res 2009;15(3):153-6.
Bakstad et al., Eur Addict Res 2009;15(3):128-134.
Miles et al., J Reprod Med 2006;51(7):567-572.
Jansson et al., Drug Alcohol Depend. 2010;109(1-3):198-204.
52
MOTHER Study: Cigarette Smoking
Mean Amount of Morphine (mg)
RESULTS
Average number of cigarettes smoked
in the past 30 days was significantly
positively related to:
Total Amount of Morphine Needed to Treat NAS
6
5
5
4
3
2
3.2
2
1.5
1
0
NonSmoking
Below
Average
Smoking
Average
Smoking
Aboveaverage
Smoking
Number of Days Medicated for NAS
Mean Number of Days
• Total amount of morphine needed to
treat NAS
• Number of days neonate was
medicated for NAS
8.4
8
6.3
6
4
4.6
3.7
2
0
NonSmoking
Neonatal
Mean Number of Days
• Neonatal length of hospital stay
10
Below
Average
Smoking
Length of
Average
Smoking
Hospital Stay
16.2
18
15
12
Aboveaverage
Smoking
13
10.5
8.9
9
6
3
0
Non-Smoking
Below Average
Smoking
Average
Smoking
Above-average
Smoking
OLS and Poisson regression analyses were used to test average number of cigarettes smoked in the past 30 days at α= .05, adjusting for both
Medication Condition and Site. Below-average cigarette smoking was defined as 6 cigarettes/day (-1 SD), average cigarette smoking as 14
cigarettes/day (Mean), and above-average cigarette smoking as 21 cigarettes/day (+1 SD).
Jones et al., under review
53
MOTHER Study: Cigarette Smoking
Average number of cigarettes
smoked in the past 30 days was
significantly negatively related to:
Neonatal Weight at Birth
Mean Birth Weight (gm)
RESULTS
3200
3149
3075
3100
2978
3000
2881
2900
2800
NonSmoking
Below
Average
Smoking
Average
Smoking
Aboveaverage
Smoking
Apgar Score at 1 Minute
Mean Apgar Score
10
8.6
8.4
8
7.7
NonSmoking
Below
Average
Smoking
Average
Smoking
Aboveaverage
Smoking
8
6
4
2
0
Apgar Score at 5 Minutes
Mean Apgar Score
• Neonatal weight at birth
• Apgar score at 1 minute
• Apgar score at 5 minutes
• Maternal weight gain, study entry to
delivery
10
9.5
9.3
9
8.7
NonSmoking
Below
Average
Smoking
Average
Smoking
Aboveaverage
Smoking
8
6
4
2
0
OLS and Poisson regression analyses were used to test average number of cigarettes smoked in the past 30 days at α= .05, adjusting for both
Medication Condition and Site. Below-average cigarette smoking was defined as 6 cigarettes/day (-1 SD), average cigarette smoking as 14
cigarettes/day (Mean), and above-average cigarette smoking as 21 cigarettes/day (+1 SD).
Jones et al., under review
54
MOTHER Study: Cigarette Smoking
A Practical Viewpoint on the Results
Relative to a pregnant woman in opioid agonist treatment who didn’t smoke
during her pregnancy, a pregnant woman in opioid agonist treatment who
smokes a pack of cigarettes a day on average during her pregnancy would
likely face:
 More than triple the total amount of morphine needed to treat her neonate’s NAS
 More than double the number of days required to treat her neonate’s NAS
 Almost double the length of hospital stay for her neonate
 A more than 8% decrease in her neonate’s birth weight
 A decrease of almost 1 point in her neonate’s Apgar scores at 1 minute
 A more than ½ point decrease in her neonate’s Apgar scores at 5 minutes
Jones et al., under review
55
Reducing Cigarette Smoking in
Methadone Treated Pregnant Patients
• Took baseline and then measured
CO 3 times a week.
• Rewards given for reducing by:
• 25% for 3 wks
• 50% for 3 wks
• 75% for 3 wks
• smoking abstinence for 3 wks
% of participants meeting CO
reduction from baseline
• Providing monetary rewards for meeting smoking reduction targets over 12
weeks
Tuten et al., Addiction, 2012
56
MOTHER Study:
Secondary Analysis Studies
Hypertonia
0.4
0.3
0.2
0.1
0
Handling
0.8
0.4
0.6
0.3
0.4
0.2
0.2
0.1
0
0
■ Methadone Mean
Excitability
5
4
3
2
1
0
■ Buprenorphine Mean
Self-Regulation
Arousal
5
4
3
2
1
0
All ps < .04
Stress-Abstinence
6
5
4
3
2
1
0
 Neurobehavioral
functioning improves
during the first month
of life for neonates
exposed to opioidagonist medication in
utero (data not shown)
 Relative to the
methadone condition,
the buprenorphine
condition results in
superior
neurobehavioral
functioning on
several outcomes
Coyle et al., Addiction, 107 (Suppl. 1), 63–73.
57
Buprenorphine v. Methadone:
Summary of Comparisons
Benefits and Risks of Opioid Agonist Pharmacotherapy
Buprenorphine
Methadone
Longer treatment retention


Reduced risk behaviors


Greater birth weight


Recommended for pregnancy


Independent replication
of results


NAS


Fetal behavior


• Both medications show similar
maternal treatment outcomes
• Data support buprenorphine’s
advantage for minimizing NAS
• Fetal behavior appears more
normal with buprenorphine
• Breastfeeding is recommended
for patients who are stable on
either medication
• Longer-term outcomes are
confounded by multiple factors
57
58
Conclusions
 It is feasible to conduct multicenter
randomized controlled trials examining
medications to treat chronic illnesses like
opioid dependence in pregnant women
 In terms of NAS severity, buprenorphine
may have an advantage as a front-line
medication option for managing opioiddependence for pregnant women who are
new to treatment or maintained on
buprenorphine pre-pregnancy
 Having more medications given in the
context of comprehensive services to
treat opioid-dependent pregnant women
should optimize treatment options
59
Pharmacotherapy for Opioid Dependence:
Unresolved Issues
► Cost/reimbursement
within the public sector is
uncertain
► Practitioners
are gaining in experience with inducting
pregnant women onto buprenorphine
► Practitioners
may be reluctant to continue prescribing
buprenorphine during pregnancy
► No
data are available to inform selection of patients
who should be maintained on which medication
► Optimal
duration of time that a patient should be
maintained on either medication is unknown
► Insufficient
data are available regarding the longerterm outcomes for the medications
59
60
Unanswered Questions
 Relative safety and efficacy
of buprenorphine/naloxone?
 Use of methadone and
buprenorphine with co-morbid
alcohol and/or benzodiazepine use?
 Buprenorphine induction?
 NAS
– Tools to measure
– Medications to treat
– Factors exacerbating and
minimizing
 Short- and long-term outcomes
– Growth, learning, development,
behavior
61
For More Information
Hendrée E. Jones, PhD
email: hjones@rti.org
T
H
E
voice: 1-919-485-2664
E
N
D
My heart and greatest joy
The list of references used in preparing this slide set are available upon request.
61
62
Outcomes with Buprenorphine +
Naloxone (N=10)
Maternal
Maternal weight gain (kg)
Cesarean section [yes]
Analgesia during delivery [yes] †
Urine drug screening at delivery [positive] ‡
Days of maternal hospital stay
Began breastfeeding after delivery [yes]
Neonatal
Gestational age at delivery (in weeks)
Preterm (< 37 weeks)
Apgar score at 1 min / 5 min
Head circumference (cm)
Birthweight (gm)
Infant length (cm)
Treated for neonatal abstinence syndrome [yes]
Total amount of morphine for NAS (mg)
Days treated for neonatal abstinence syndrome
Days of infant hospital stay
f (%)
M (SD)
7.8 (3.9)
1 (10%)
6 (67%)
0 (0%)
4.1 (4.5)
3 (30%)
37.5 (3.5)
2 (20%)
8.0 (2.5) / 8.6 (1.3)
32.8 (1.2)
2816.1 (368.3)
46.3 (2.2)
4 (40%)
3.5 (2.6)
6.9 (10.1)
10.1 (9.8)
Debelak et al., Am J Addict, in press.