Pharmacological Treatment of Opioid Dependence during Pregnancy: Methadone and Buprenorphine

OverviewKarol 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/mlMethadone dose x=128mg (80-

190mg)Trough level x=310ng/mlNegative UDS 83%

Dose and Blood Plasma Levels

Results25 women had trough plasma levels

< 200ng/mlMethadone dose x=98.6 (35-215mg)Trough plasma level x=118ng/mlNegative 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 23 mg

Madden et al. 1977 N=110 0-20mg >20mg

Harper et al. 1977 N=21 Mean dose =28mg 5-60

Kandall et al. 1983 N=153 50mg 29mg

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

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 Mean dose=38mg 10-100 mg

Stimmel et al. 1982 N=239 <50mg 50mg >50mg

Thakur et al. 1990 N=152 10-40mg 40-60mg >60 mg

10-70 mg

Shaw et al. 1994 N=32 Median dose = 35mg 5-80 mg

Hagopian et al. 1995 N=172 Mean dose = 31mg 10-60 mg

Kaltenbach et al. 1997 N=38 <80mg ≥80 mg 35-135 mg

Brown et al. 1998 N=32 50 mg ≥ 50 mg

Methadone Dose and Neonatal Withdrawal

Mean Dose N NWT LOS <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

Methadone Dose and Neonatal Withdrawal

Mean dose N Mean birth-weight NWT LOS

<80mg 50 2769+/-559 34 (68%) 13.3>80mg 50 2663+/-556 33 (66%) 13.6

Last dose N Mean birth-weight NWT LOS

<80mg 39 2811+/-586 29 (74%) 14.2>80mg 61 2655+/-534 38 (62%) 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%) 9.6+/-11.5

Positive 39 13.3+/-12.8 30(77%) 19.5+/-26.3 p.08 p.09 p.01

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

IFWe recognize that “one size does not fit all”And pharmacotherapy decisions are based

on “effective treatment”