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Pharmacological Treatment of
Opioid Dependence during
Pregnancy: Methadone and
Buprenorphine
Overview
Karol Kaltenbach, PhD
Maternal Addiction Treatment
Education and Research
Thomas Jefferson University
Pharmacological Management
Methadone Maintenance has been
recommended for opioid dependent
pregnant women since the early 1970’s
 1997 NIH Consensus Panel
recommended as standard of care

Methadone Maintenance and
Pregnancy

Effective methadone maintenance
– Prevents the onset of withdrawal for 24
hours
– Reduces or eliminates drug craving
– Blocks the euphoric effects of other
narcotics
Methadone Maintenance and
Pregnancy

In addition, during pregnancy methadone
maintenance
– Prevents erratic maternal opioid levels and
protects the fetus from repeated episodes
of withdrawal
– Decreases risks to fetus of infection from
HIV, hepatitis and sexually transmitted
disease
– Reduces the incidence of obstetrical and
fetal complications
Issues in Methadone and Pregnancy:
Historical and Contemporary
Appropriate dose during pregnancy
 Severity of neonatal abstinence related
to maternal dose

Issues of Dose During Pregnancy




Previous FDA regulations required the lowest
“effective” dose
Dose should be based on the same criteria
used for non-pregnant patients
Original work by Dole and Nyswander
suggests that effective dose is usually in the
range of 80-120mg
Current consensus is 50-150mg, with blood
plasma levels ≥ 200ng/ml
Issues of Dose During Pregnancy
In the late 1970’s recommendations
emerged for pregnant women to be
maintained on low dose, i.e.< 20mg
 Such low dose recommendations are
based on attempts to reduce or
eliminate neonatal abstinence and are
contrary to the therapeutic objectives of
methadone maintenance

Dose and Blood Plasma Levels



Subjects: N=45 pregnant women:
Six stabilized on methadone before they
became pregnant.
Thirty-nine were pregnant at the time of
their admit for stabilization
– Age
x=28yrs (19-40 yrs)
– Methadone dose x=112 mg (35-215mg)
– Gestational age x=26wks (10-38 wks)
Drozdick et al, Am J Obstet Gynecol Vol.187, No 5, 2002
Dose and Blood Plasma Levels

Results:
20 women had trough plasma levels in the
therapeutic range of >200ng/ml
Methadone dose x=128mg (80-190mg)
Trough level
x=310ng/ml
Negative UDS
83%
Dose and Blood Plasma Levels

Results
25 women had trough plasma levels
< 200ng/ml
Methadone dose
x=98.6 (35-215mg)
Trough plasma level x=118ng/ml
Negative UDS
x=40%
Dose and Blood Plasma Levels

Summary of findings
– The need for some pregnant women to be
maintained on higher doses (>80mg) to be
at a therapeutic level
– The idiosyncratic variability of adequate
dose
– The importance of measuring methadone
serum levels in making dosing decisions
for pregnant women
Neonatal Abstinence



Infants prenatally exposed to heroin or
methadone have a high incidence of neonatal
abstinence
Neonatal abstinence (NAS) may be more
severe and/or prolonged with methadone
than heroin
Research indicates that 60-87% of infants
born to methadone maintained mothers
require treatment for NAS
Issues Regarding Relationship of
Maternal Dose and Neonatal Abstinence
Continued debate regarding relationship
between maternal dose and NAS
 Often recommended to reduce maternal
methadone dose to avoid neonatal
abstinence
 A non-therapeutic maternal dose may
promote supplemental drug use and
increase risk to the fetus

Ostrea et al. 1976
N=95
15mg
Madden et al. 1977
N=110
0-20mg >20mg
Harper et al. 1977
N=21
Mean dose =28mg
Kandall et al. 1983
N=153
50mg
Suffet et al. 1984
N=216
Mean dose=29mg
Doberczak et al. 1991
N=21
Mean dose=47mg
20-80
Malpas et al. 1995
N=70
Mean dose=15.4mg
0->21
Mayes et al. 1996
N=68
Mean dose=44mg
15-80
Dashe et al. 2002
23 mg
5-60
29mg
No Relationship between NAS and
Maternal Dose
Blinick et al. 1973
N= 61
80-140 mg
Newman et al. 1974
N=331 40mg-90 mg
Rosen et al. 1976
N=30
Stimmel et al. 1982
N=239 <50mg 50mg >50mg
Thakur et al. 1990
N=152 10-40mg 40-60mg
>60 mg
Shaw et al. 1994
N=32
Hagopian et al. 1995
N=172 Mean dose = 31mg
Kaltenbach et al. 1997
N=38
<80mg ≥80 mg
Brown et al. 1998
N=32
50 mg ≥ 50 mg
Mean dose=38mg
10-100 mg
10-70 mg
Median dose = 35mg 5-80 mg
10-60 mg
35-135 mg
Methadone Dose and Neonatal
Withdrawal

Mean Dose
N
NWT
<20 mg
25
3
7
20-39 mg
20
11
15
>40 mg
20
18
38
Dashe et al. Am J of Obstet Gynecol, 2002
LOS
Methadone Dose and
Neonatal Withdrawal
Mean dose
N
<80mg
>80mg
50
50
Last dose
N
<80mg
>80mg
39
61
Mean birth-weight
2769+/-559
2663+/-556
Mean birth-weight
2811+/-586
2655+/-534
NWT
LOS
34 (68%)
33 (66%)
13.3
13.6
NWT
LOS
29 (74%)
38 (62%)
14.2
12.9
Berghella et al. Am J Obstet Gynecol, 2003
Methadone Dose and
Neonatal Withdrawal
Benzo
N
Highest NAS
NWT
LOS
Negative
61
10.1+/-4.4
37(61%)
Positive
39
13.3+/-12.8
p.08
30(77%) 19.5+/-26.3
p.09
p.01
9.6+/-11.5
Impact of Buprenorphine

May be effective treatment alternative
for some women
– Women who don’t want to be
maintained on methadone
– Women who live in areas where
methadone is not available
– Women for whom methadone
program compliance is difficult
Buprenorphine and NAS



Buprenorphine may produce a NAS that is
milder and of shorter duration than
methadone.
However, need to insure that history is not
repeated and that pharmacotherapy
decisions are based on therapeutic objectives
of treatment.
Buprenorphine should not be the treatment of
choice solely on the basis of reducing
symptoms of NAS.
Methadone and Buprenorphine



Will increase treatment options for women
Will increase effectiveness of treatment
IF
We recognize that “one size does not fit all”
And pharmacotherapy decisions are based
on “effective treatment”