1. Drug Treatment Issues in Drug-Dependent, Pregnant Women Hendrée E. Jones, Ph.D. Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

2. APA May 5, 2004 Disclosure During this presentation at the annual APA meeting, Dr. Jones will be discussing the uses of commercial products not yet approved for this purpose by the FDA. She has no actual or potential conflict of interest in regards to this program.

3. APA May 5, 2004 Presentation Goals Use of medication to treat opioid dependence during pregnancy Clinical trial of methadone and buprenorphine during pregnancy Behavioral interventions enhance maternal outcomes

4. APA May 5, 2004 Studies of Medication During Pregnancy Controversial Some say unethical Stigma associated with medication treatment for pregnant women is severe

5. APA May 5, 2004 Goals of Opioid Agonist Treatment Cessation of opioid use Stabilize intrauterine environment Increased prenatal care compliance Enhanced pregnancy outcomes

6. APA May 5, 2004 Methadone is effective during pregnancy Methadone is recommended for the treatment of opioid-dependent women Over 30 years of experience and research Not appear to have teratogenic potential

7. APA May 5, 2004 Neonatal Abstinence Syndrome (NAS)  Neuralgic excitability (hyperactivity, irritability, sleep disturbance)  Gastrointestinal dysfunction (uncoordinated sucking/swallowing, vomiting)  Autonomic Signs (fever, sweating, nasal stuffiness)

8. APA May 5, 2004 The 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 up to 12 months

9. APA May 5, 2004 Buprenorphine A derivative of thebaine Marketed as Subutex or Suboxone Full Agonist Full Antagonist Heroin Methadone Morphine Naltrexone Naloxone Buprenorphine Nalmefene

10. APA May 5, 2004 Buprenorphine Birth outcomes improved with agonist therapy (e.g., methadone) Withdrawal associated with agonist therapy can require hospitalization Buprenorphine reported to produce less physical dependence in adults

11. APA May 5, 2004 Case Reports and Open-Label Studies Since 1995, 23 reports of prenatal exposure to buprenorphine 22 reports from Europe and 1 from U.S. Number of cases ranged from 1 to 153 (median=6) TOTAL 338 babies

12. APA May 5, 2004 Outline Use of medication to treat opioid dependence during pregnancy Clinical trial of methadone and buprenorphine during pregnancy Behavioral interventions enhance mother and child outcomes

13. APA May 5, 2004 Randomized Controlled Study –Double-blind (staff and patient) –Double-dummy (two medications) –Two groups: Methadone or Buprenorphine –Flexible dosing  Methadone 40-100 mg  Buprenorphine 4-24 mg

14. APA May 5, 2004 Setting: Center for Addiction & Pregnancy Interdisciplinary Approach –Psychiatry –Obstetrics –Pediatrics –Nursing

15. APA May 5, 2004 Criteria Inclusion: – 18 - 40 years of age – Gestational age 16 - 30 weeks – Opioid dependent (DSM-IV, SCID I) – Recent opioid use – Opioid positive urine

16. APA May 5, 2004 Criteria 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)

17. APA May 5, 2004 Primary Outcome Measures Infant Neonatal Abstinence Syndrome (NAS) Length of Hospital Stay (LOS)

18. APA May 5, 2004 Selected Secondary Outcome Measures Maternal –Days of treatment –Prenatal care visits –Illicit drug use Infant –Physical birth parameters

19. APA May 5, 2004 Patient Flow Number screened 1490 Not Qualify Initially 1433 Qualify and sign consent 57 Randomized 30 Buprenorphine 15 Methadone 15 Buprenorphine 9 Methadone 11

20. APA May 5, 2004 Induction 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

21. APA May 5, 2004 Maternal Outcome Drug Use During Pregnancy % opioid +15.616.7 % cocaine +11.215.2 % amphetamine + 0.0 0.0 % barbiturates + 0.0 0.0 % benzo + 0.4 2.5 % THC+ 7.5 0.0 Methadone N=11 Buprenorphine N=9

22. APA May 5, 2004 % African-American63.688.9 EGA (weeks)23.622.8 Education (yrs)10.010.3 % Employed 0.0 0.0 Age (yrs)30.330.0 Methadone N=11 Buprenorphine N=9 Maternal Characteristics

23. APA May 5, 2004 Maternal Outcomes Days in Treatment 99.9115.6 Prenatal care visits3.4 3.6 LOS mom2.2 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 delivery38.8 38.8 Ave. dose at delivery (mg) 79.1 18.7 Methadone N=11 Buprenorphine N=9

24. APA May 5, 2004 % Treated45.520.0 Birth Weight (gm)* 3001.8 3530.4 LOS baby 8.1 6.8 % NICU treatment18.010.0 APGAR 1 8.3 8.1 APGAR 5 8.9 8.7 Length (cm)*49.652.8 Head Cir. (cm)*33.234.9 %Tox + (Baby)* 0.020.0 Birth Outcomes Methadone N=11 Buprenorphine N=9 deliveries (10 babies) * data safety monitoring board recommended removing twin data from these variables

25. APA May 5, 2004 Limitations 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

26. APA May 5, 2004 Conclusions 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

27. APA May 5, 2004 Bottom 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 More medication options will improve the treatment of pregnant women

28. APA May 5, 2004 Issues Pregnant, Drug- Dependent Women Face Multigenerational drug use Lack of education Maladaptive behaviors poor self-control trust issues Legal Parenting Unstable housing Victimization and violence physical sexual emotional Severe stigma Other psychiatric issues

29. APA May 5, 2004 Presentation Goals Use of medication to treat opioid dependence during pregnancy Clinical trial of methadone and buprenorphine during pregnancy Behavioral Interventions enhance maternal outcomes

30. APA May 5, 2004 Types of Behavioral Interventions Examined at CAP Contingency Management –Rewards for drug-abstinence include housing, gift certificates, goods and services Community Reinforcement Approach Motivational Interviewing

31. APA May 5, 2004 Relationships as Barriers to Treatment Female drug use starts and continues in context of male romantic relationships Level of partner support impacts outcomes among pregnant methadone-maintained women (Jeremy, 1984; Marcus, 1984)

32. APA May 5, 2004 Women’s Treatment Retention * Mean relationship of 4 yrs + Drug using partners -less employed - less supportive of woman’s treatment -more legal involvement -more dental and medical needs * P<0.05; Data adapted from Drug and Alcohol Dependence (2003)

33. APA May 5, 2004 Partner Treatment 2 group randomized design Control-- receive weekly support group Intervention -- –Methadone or detox + aftercare –MI type counseling –abstinent contingent vouchers 1, 3, and 6 month follow-up interviews

34. APA May 5, 2004 Partner Results 35 years old 73% unemployed 59% African-American 72% used cocaine 94% believed they were the father of the baby

35. APA May 5, 2004 * *p<.05 Intervention Increases Drug Abstinence in Male Partners

36. APA May 5, 2004 * *p<.05 Intervention Increases Drug Abstinence in Women

37. APA May 5, 2004 Intervention Increases Partner Support of the Woman *p<.05 *

38. APA May 5, 2004 Conclusions Interventions are available to engage and retain male partners Treating the male partner is associated with enhanced treatment outcomes for pregnant opioid-dependent women

39. APA May 5, 2004 Take Home Message Pregnancy is area where most certainty is desired, but there is often the least data More medication options will improve the treatment of pregnant women Engaging and treating the male drug using partners can improve the outcomes of women in drug treatment

40. APA May 5, 2004 Acknowledgements Rolley “Ed” Johnson Patients and infants NIDA R01 DA12220 and DA13496 Co-Investigators Staff at Center for Addiction and Pregnancy Staff at BPRU