1. Pharmacological Treatment of Opioid Dependence during Pregnancy: Methadone and Buprenorphine Overview Karol Kaltenbach, PhD Maternal Addiction Treatment Education and Research Thomas Jefferson University

2. Pharmacological Management n Methadone Maintenance has been recommended for opioid dependent pregnant women since the early 1970’s n 1997 NIH Consensus Panel recommended as standard of care

3. Methadone Maintenance and Pregnancy n Effective methadone maintenance –Prevents the onset of withdrawal for 24 hours –Reduces or eliminates drug craving –Blocks the euphoric effects of other narcotics

4. 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

5. Issues in Methadone and Pregnancy: Historical and Contemporary n Appropriate dose during pregnancy n Severity of neonatal abstinence related to maternal dose

6. Issues of Dose During Pregnancy n Previous FDA regulations required the lowest “effective” dose n Dose should be based on the same criteria used for non-pregnant patients n Original work by Dole and Nyswander suggests that effective dose is usually in the range of 80-120mg n Current consensus is 50-150mg, with blood plasma levels ≥ 200ng/ml

7. Issues of Dose During Pregnancy n In the late 1970’s recommendations emerged for pregnant women to be maintained on low dose, i.e.< 20mg n Such low dose recommendations are based on attempts to reduce or eliminate neonatal abstinence and are contrary to the therapeutic objectives of methadone maintenance

8. Dose and Blood Plasma Levels n Subjects: N=45 pregnant women : n Six stabilized on methadone before they became pregnant. n 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

9. Dose and Blood Plasma Levels n 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%

10. Dose and Blood Plasma Levels n 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%

11. Dose and Blood Plasma Levels n 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

12. Neonatal Abstinence n Infants prenatally exposed to heroin or methadone have a high incidence of neonatal abstinence n Neonatal abstinence (NAS) may be more severe and/or prolonged with methadone than heroin n Research indicates that 60-87% of infants born to methadone maintained mothers require treatment for NAS

13. Issues Regarding Relationship of Maternal Dose and Neonatal Abstinence n Continued debate regarding relationship between maternal dose and NAS n Often recommended to reduce maternal methadone dose to avoid neonatal abstinence n A non-therapeutic maternal dose may promote supplemental drug use and increase risk to the fetus

14. Ostrea et al. 1976N=9515mg 23 mg Madden et al. 1977N=1100-20mg >20mg Harper et al. 1977N=21Mean dose =28mg 5-60 Kandall et al. 1983N=15350mg 29mg Suffet et al. 1984N=216Mean dose=29mg Doberczak et al. 1991N=21Mean dose=47mg 20-80 Malpas et al. 1995 N=70Mean dose=15.4mg0->21 Mayes et al. 1996N=68Mean dose=44mg15-80 Dashe et al. 2002

15. No Relationship between NAS and Maternal Dose Blinick et al. 1973N= 6180-140 mg Newman et al. 1974N=33140mg-90 mg Rosen et al. 1976N=30Mean dose=38mg10-100 mg Stimmel et al. 1982N=239 50mg Thakur et al. 1990N=15210-40mg 40-60mg >60 mg 10-70 mg Shaw et al. 1994N=32Median dose = 35mg5-80 mg Hagopian et al. 1995N=172Mean dose = 31mg 10-60 mg Kaltenbach et al. 1997N=38<80mg ≥80 mg35-135 mg Brown et al. 1998N=3250 mg ≥ 50 mg

16. Methadone Dose and Neonatal Withdrawal n Mean Dose N NWT LOS <20 mg25 3 7 20-39 mg20 11 15 >40 mg 20 18 38 Dashe et al. Am J of Obstet Gynecol, 2002

17. 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

18. 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

19. Impact of Buprenorphine n 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

20. Buprenorphine and NAS n Buprenorphine may produce a NAS that is milder and of shorter duration than methadone. n However, need to insure that history is not repeated and that pharmacotherapy decisions are based on therapeutic objectives of treatment. n Buprenorphine should not be the treatment of choice solely on the basis of reducing symptoms of NAS.

21. Methadone and Buprenorphine n Will increase treatment options for women n Will increase effectiveness of treatment n IF We recognize that “one size does not fit all” And pharmacotherapy decisions are based on “effective treatment”