Medication Assisted Treatment for Opioid Dependence during Pregnancy

1. Medication Assisted Treatment for Opioid Dependence during Pregnancy Jason B. Fields MD DACCO University of Florida Addiction Medicine Fellow and Medical Services Manager

2. How Prevalent is drug and alcohol use in pregnancy? • 12-24% of women use drugs and alcohol during pregnancy • 1 of every 3-4 women expose fetus to alcohol • Alcohol and tobacco > illicit drugs and prescription drugs • Prevalence in public clinic=private practice • Caucasians > African Americans > Hispanic • No significant variation by socioeconomic status

3. Major Women’s Health Issue! Opioid dependence is compounded by multiple risk factors contributing to adverse maternal, neonatal, and long-term developmental sequelae. Improved treatment options should reduce the public health and medical costs associated with the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to $112.6 million in the US alone. Just as the use of methadone in non-pregnant women improves patient outcomes, its use as part of a comprehensive approach to the care of pregnant women improves maternal and neonatal outcomes, as compared with no treatment and with Medication Assisted Withdrawal (MSW).

4. A Complex Clinical Problem Of the 400,000 women admitted to programs in 1999, 4% were pregnant when admitted. Opioids were the primary substance of abuse for 19% of both pregnant and non-pregnant women who entered these programs Increasing prevalence of non-medically used analgesics in women of child bearing age. Self-reported nonmedical use of analgesics increased from 51,900 in 1993 to an average of 109,000 in 2002 to 2004 Children of opioid dependent women might be at risk for poor outcomes not only because of opioid drug exposure, but also because of concomitant alcohol and tobacco exposure and numerous factors related to the caregiving environment.

5. Opioid misuse during pregnancy is a serious and growing concern: High rates of infection Premature delivery Low birth weight, which is an important risk factor for later developmental delay. Comprehensive methadone maintenance treatment that includes prenatal care reduces the risk of obstetrical and fetal complications, in utero growth retardation, and neonatal morbidity and mortality.

6. Benefits of Maintenance with Opioid Agonist Therapy in Pregnancy

7. Pregnant Patients Receive All the Same Benefits as Non-Pregnant Patients on Maintenance Therapy • Reduction in All Cause Mortality • “…the all cause mortality rate for patients receiving methadone maintenance treatment was similar to the mortality rate for the general population whereas the mortality rate of untreated individuals using heroin was more than 15 times higher.” Bell 2000

8. Methadone Maintenance Treatment A full mu-opioid agonist. Methadone is the only medication currently approved for the treatment of opioid addiction in pregnancy (US). Maintenance with methadone during pregnancy produces the same benefits as treatment in the non-pregnant patient. Has been the recommended standard of care over no treatment or medication-assisted withdrawal. But, medically supervised withdrawal is not the standard of care due to the poor outcomes (Jones H, 2008) and the potential catastrophic consequences of relapse. Because the goal of treatment with methadone is to prevent relapse to illicit substance use. A pregnant patient CAN taper off of methadone (opioid agonist therapy) but should not be permitted to experience significant abstinence syndrome. (Luty, J, Nilolaou V, Bearn J. 2004)

9. Methadone Maintenance Treatment MMT is but a single element in the variety of services needed for optimal care of the pregnant opioid dependent patient. This recommendation is based on longer durations of maternal drug abstinence, better obstetrical care compliance, avoidance of associated risk factors, reductions in fetal illicit drug exposure, and enhanced neonatal outcomes (i.e. heavier birth weight). Recommended because when MMT is used within a treatment setting that includes comprehensive care, obstetrical and fetal complications, including neonatal morbidity and mortality, can be reduced (Jarvis and Schnoll 1995; Kaltenbach et al. 1998).

10. Methadone Maintenance Treatment Effective medical maintenance treatment with methadone has the same benefits for pregnant patients as for patients in general. Effective MMT prevents the onset of withdrawal, reduces or eliminates drug craving, and blocks the euphoric effects of illicit self-administered opioids (Dole et al. 1966, Kreek 1988) In addition, methadone substantially reduces fluctuations in maternal serum opioid levels, so it protects the fetus from repeated withdrawal episodes. Because needle use is eliminated, MMT reduces the risk of infectious disease. The mandatory link to prenatal care, frequent contact with program staff, and elimination of the stress of obtaining opioids daily to feel “normal” are additional benefits from MMT (Burns et al. 2006).

11. Acceptance as the Standard of Care Methadone has been accepted since the late 1970s to treat opioid addiction during pregnancy In 1998, a National Institutes of Health consensus panel recommended methadone maintenance as the standard of care for pregnant women with opioid addiction Methadone currently is the only approved opioid medication-assisted treatment for opioid addiction (MAT) in pregnant patients.

12. Standard of Care Methadone maintenance has been the recommended standard of care over no treatment or Medication Assisted Withdrawal (MAW) based on: Longer durations of maternal drug abstinence Better obstetrical care compliance Avoidance of associated risk behaviors Reductions in fetal illicit drug exposure Enhanced neonatal outcomes-heavier birth weight (Kaltenbach 1998).

13. Standard of Care Methadone is the oldest, most widely used medication prescribed during pregnancy, and in comparison to infants born to heroin-abusing mothers, infants from methadone-treated mothers have: Increased fetal growth Reduced fetal mortality Decreased risk of HIV infection Decreased risk of pre-eclampsia Less fetal exposure to rapid and unpredictable cycles of heroin-induced highs and withdrawal Increased likelihood of the infants being discharged to their parents (Finnegan 1991).

14. Pregnancy Specific Benefits of Opioid Maintenance Therapy • Methadone Maintenance Therapy (MMT) is regarded as an established treatment with birth outcomes comparable to a general obstetrical population (Kreek MJ, 2000) • Fewer Pre-term Births • Less Intrauterine Growth Restriction • Fewer Low Birth Weight Infants • Less Maternal Drug Use • Greater reduction with higher dose of methadone • Improved Prenatal Care Compliance (Burns L, 2004; Goler NC, 2008) • There appears “to be no differential effect of either treatment (methadone or buprenorphine)—it was exposure to stable treatment that was important (Gibson 2008).

15. Principles of Opioid Agonist Therapy • Opioids bind the mu opioid receptors in the brain. • The mu receptor generates the effects experienced by the patient/drug user. • Different opioids stimulate the receptor to a greater or lesser degree. • By occupying the mu receptor with a long acting opioid the effects of other opioids are impeded or attenuated. • By dosing regularly and before developing symptoms of abstinence syndrome the mu receptors will be occupied when a trigger or craving is experienced. • A higher dose occupies more receptors longer.

16. Principles of Pharmacotherapy with Methadone • Methadone is the only agonist therapy approved for use in pregnancy. It is supported by 30 years of research. • Methadone is a full agonist so the effect is directly proportionate to the dose. • It takes 24 to 36 hours for the body of a healthy person to eliminate half of the methadone ingested. • A person with impaired liver function or on other medications/intoxicants may require up to 50 hours to eliminate half of the methadone • The opioid “blocker” effect is a result of having the mu opioid receptor occupied with methadone when another opioid is introduced.

17. Diagnosing Opioid Addiction Some women who are opioid addicted do not acknowledge pregnancy readily, or they misinterpret early signs of pregnancy (fatigue, headaches, nausea and vomiting and cramps as opioid withdrawal symptoms). Onset of pregnancy may cause these patients to increase their use of illicit opioids or other substances that do no alleviate their perceived withdrawal symptoms but expose their fetuses to increased serum levels of these substances.

18. Factors in Opioid Dependence and Pregnancy Many women who are opioid addicted confuse the amenorrhea caused by stressful, unhealthy lifestyles with infertility. They might have been sexually active for years without using contraceptives and becoming pregnant. The consensus panel (National Institutes of Health Consensus Developmental Panel, 1998) noted that because methadone normalizes endocrine functions, it is not unusual for women in the early phases of MAT to become pregnant unintentionally, especially if they receive no counseling for this possibility.

19. Diagnosing Opioid and other Addictions Information from their medical and substance abuse histories, PE, drug test reports, and observed signs or symptoms of withdrawal. Indication may be evidence of diseases associated with drug use like hepatitis, bacterial endocarditis, and cellulitis. Poor attendance of prenatal care and unexplained fetal growth abnormalities (IUGR). Using an opioid antagonist to diagnose addiction in pregnant women is absolutely contraindicated as inducing even mild withdrawal can cause premature labor or other adverse fetal effects.

20. Medical and Obstetrical Concerns Pregnant women who abuse substances (including alcohol and nicotine) have a greater than normal risk of medical complications Related to addiction: anemia, poor nutrition, increased blood pressure, hyperglycemia, STDs, hepatitis, preeclampsia. The big concern with opioid withdrawal is premature labor, pregnant women should be educated about the potential adverse effects of substance use on their fetuses

21. Common Medical Complications Among Pregnant Women Who Are Opiate Addicted (many of these from intravenous drug use) Anemia Bacteremia/septicemia Cardiac disease, especially endocarditis Cellulitis Depression and other mental disorders Edema Gestational Diabetes Hepatitis A, B, and C Hypertension/tachycardia Phlebitis Pneumonia Poor dental hygiene STDs Chlamydia Condyloma acuminatum Gonorrhea Herpes HIV/AIDS Syphilis Tetanus Tuberculosis UTIs Cystitis Pyelonephritis Urethritis

22. Hepatitis Rate of vertical perinatal transmission of hepatitis B virus (HBV) is high (70 to 90%), esp if a pregnant woman has active infection (+ Hep B antigen test) in the 3rd trimester or within 5 weeks postpartum. Neonate should receive both Hep B vaccine and Hep B immune globulin Rate of vertical transmission of Hep C is lower, however vaccines exist for Hep A and HBV but not for HCV. Pregnant women with a history of injection drug use are at high risk for HCV infection and should be screened for anti-HCV antibody and HCV RNA testing should be done if anti-HCV antibody is positive.

23. HIV A limited number of studies with small numbers of patients have examined the relationship of HIV, methadone, and immune function. It is difficult to conclude any significant relationship. Women who are opioid addicted and HIV infected receive additional counseling and support during the postpartum period to improve their adherence to antiretroviral therapy and to meet the demands of caring for the newborn.

24. Common Obstetrical Complications Among Women Addicted to Opioids (The fetus is at risk for morbidity and mortality because of episodes of maternal withdrawal compounded by a lack of prenatal care) Abruptio placentae Chorioamnionitis Intrauterine death IUGR Intrauterine passage of meconium Low Apgar Scores Placental insufficiency Amnionitis Postpartum hemorrhage Preeclampsia Premature labor/delivery PROM Septic thrombophlebitis Spontaneous abortion, especially first trimester

25. Methadone Pharmacology Methadone is distributed widely throughout the body with extensive nonspecific tissue binding creating reservoirs that release unchanged methadone back into the blood. Peak plasma levels occur between 2 and 6 hours after a maintenance dose of methadone is ingested, with less than 6% of the ingested dose in the total blood volume at this time. Lower sustained plasma concentrations are present during the remainder of a 24 hour period.

26. Pharmacology Cont The same methadone dosage produces lower blood methadone levels, owing to increased fluid volume, a larger tissue reservoir for methadone, and altered opioid metabolism in both the placenta and the fetus. Women often experience symptoms of withdrawal in later pregnancy and require dosage increases. The daily dose can be increased and administered singly or split into twice-daily doses

27. Dosages relative to Neonatal Abstinence Syndrome Historically, treatment providers have based dosing decisions on the need to avoid or reduce the incidence of NAS (Kaltenbach et al. 1998). This low-dose approach emerged from several 1970s studies (Harper et al. 1977) and has been contradicted by more recent studies (Brown et al. 1998). There is no compelling evidence supporting reduced methadone dosages to avoid NAS.

28. Studies on Methadone Dose and Outcomes One long term follow up study of 27 children who had been exposed to methadone in utero found no cognitive impairment in the preschool years (Kaltenbach et al. 1988). Overall, prenatal exposure to methadone provided as a part of comprehensive treatment does not appear to be associated with developmental or cognitive impairments.

29. On the contrary, higher doses of Methadone have been associated with: Increased weight gain Decreased illegal drug use Improved compliance with prenatal care by pregnant women in MAT Increased birth weight Increased head circumference Prolonged gestation Improved growth of infants born to women in MAT (De Petrillo and Rice 1995) ***Reduced methadone dosages may result in continued substance use and increased risks to both expectant mothers and their fetuses

30. Getting the Prenatal Dose Right: Induction and Stabilization

31. OUTPATIENT Initial dose 30 mg Twice daily assessment for objective signs of withdrawal “Peak” and “Trough” Increase in increments of 5 or 10 mg Patient to record fetal movement regularly Methadone Induction for the Pregnant Patient INPATIENT Permits larger initial dose and more rapid escalation Prenatal assessment conducted concurrently More likely to isolate patient from source of other illicit substances

32. Induction and Stabilization Methadone dosages for pregnant women should be based on the same criteria as those for women who are not pregnant. Women who received methadone before pregnancy should be maintained initially at their pre-pregnancy dosage. If pregnant women have not been maintained on methadone, the consensus panel recommends that they either be inducted in an outpatient setting by standard procedures or be admitted to a hospital (for an average of 3 days) to evaluate their prenatal health status, document physiologic dependence, and initiate methadone maintenance if possible.

33. Induction and Stabilization For pregnant women being inducted in an outpatient setting, a widely accepted protocol is to give initial methadone doses of 10 to 20 mg/day, with exact dosage based on a patient’s opioid use history. A patient should be asked to return for follow-up at the end of the day and the initial dose may be followed by regular adjustments of 5 to 10 mg per day based on therapeutic response. Twice daily observation should continue until the patient is stabilized. If evidence of intoxication or withdrawal emerges, treatment providers should adjust the dosage. Most pregnant women can be stabilized within 48 to 72 hours. In outpatient settings, where fetal monitors usually are unavailable, it is crucial that patients record measures of fetal movement at set intervals.

34. Safe and Effective Induction with Methadone: Outpatient • Safe dose: • “Start low and go slow.” • Respiratory depression develops later than peak effect. • Cross tolerance between opioids is not 100% • Average dose: • 80 to 120mg • Titrate to effect/individualize treatment • Effective dose: • Abolishes abstinence syndrome for at least 24 hours. • Does not cause over–sedation at peak effect (4 hours after dosing.)

35. The Right Dose Throughout Pregnancy(is the dose that stops withdrawal) Increased Blood Volume Larger Tissue Reservoir Methadone Loss to Amniotic Fluid Altered Maternal Metabolism Metabolic Activity of Fetus Patient may require progressive increases throughout pregnancy Split dosing is an option to maintain adequate blood levels with fewer increases (Kaltenbach 1998; Jarvis 1999). Counseling is essential to address cravings, stress, and anxiety

36. Split Dosing Split-dosing methadone regimens are accepted widely for pregnant patients, but little empirical evidence investigation has been done of its effects on fetuses or maternal plasma levels. Although split dosing may improve maternal compliance with treatment and decreased other illicit substance use (cocaine), traveling to an opioid treatment program twice a day or, for unstable or newly admitted patients, qualifying for take-home medication doses may be difficult.

37. Intrapartum &Postpartum Management

38. Intrapartum and Postpartum Management • Provided the prenatal opioid agonist is dosed appropriately for the individual… • Intrapartum analgesic need and response in the methadone maintained patient is similar to non-opioid dependent patients. (Meyer M 2007) • Post-partum pain management is comparable to the non-opioid dependent patient. (Jones H 2008) • MMT patients may tolerate a dose reduction in the immediate or early post-partum period even in the absence of sedation. Advance preparation makes this more successful. (Jones H, 2008; Bogen D, ----)

39. Managing Polysubstance Use A large percentage of pregnant women in MAT-88% in one study-continue to use other substances including alcohol, heroin, cocaine, barbiturates, and tranquilizers (Edelin et al. 1988) It is essential that patients be monitored for use of both licit and illicit drugs and alcohol to manage the perinatal care of both mothers and infants (Kaltenbach et al. 1998) Polysubstance use is a special concern during pregnancy because of the adverse effects of cross-tolerance, drug interactions, and potentiation and the serious maternal and fetal health risks from continued substance use and lack of adequate prenatal care (Svikis et al. 1997a).

40. Ongoing Illicit or Polysubstance Use Can be reduced by higher dose of methadone Does not seem to directly increase the incidence of pregnancy complications, but Does reverse the positive impact of opioid maintenance on birth weight (Kashiwagi et al. 2003) Maternal tobacco use plays a role in timing and onset of Neonatal Abstinence Syndrome-NAS (Choo et al. 2004).

41. Management of Acute Opioid Overdose in Pregnancy Naloxone, a short-acting, pure opioid antagonist, is the pharmacological treatment of choice for opioid overdose but should be given to pregnant patients only as a last resort (Weaver, 2003). Patients should receive naloxone (0.01 mg/kg of body weight) intravenously after an airway is established to ensure adequate respiration. Patients can receive additional naloxone doses every 5 minutes after they regain consciousness. Naloxone’s duration of action is from 30 minutes to 2 hours, whereas that of most opioids is from 6 to 8 hours and that of methadone or other long-acting opioids is from 12 to 48 hours.

42. Management of Acute Opioid Overdose in Pregnancy Symptoms are likely to recur within 30 min to 2 hours and treatment providers should continue administering naloxone IV or IM until the effects of the illicit opioids markedly diminish, which can be 2 to 3 days. Special care is needed to avoid acute opioid withdrawal that harm a fetus. Treatment providers should titrate the naloxone dose against withdrawal symptoms and use a short-acting opioid to reverse acute withdrawal symptoms (Archie, 1998).

43. Managing Withdrawal from Methadone Withdrawal from methadone, called medically supervised withdrawal (MSW) or dose tapering, is not recommended for pregnant women. When it is considered, a thorough assessment is important to determine whether a woman is an appropriate candidate for MSW because the procedure frequently results in relapse to opiate use. Appropriate candidates for MSW include women who: Live where methadone is unavailable Have been stable in MAT and request MSW before delivery Refuse to be maintained on methadone Plan to undergo MSW through a structured treatment program (Archie 1998, Kaltenbach et al. 1998

44. Managing Withdrawal from Methadone A patient who elects to withdraw should do so only under supervision by a physician experienced in perinatal addiction treatment with fetal monitoring. Usually done in the second trimester (consensus panel has found no systematic studies on whether withdrawal should be initiated only during the second trimester) If MSW is undertaken, methadone should be decreased by 1.0 to 2.5 mg/day for inpatients and by 2.5 to 10.0 mg per week for outpatients. Fetal movement should be monitored twice daily in outpatients, and stress tests should be performed at least twice a week; MSW should be discontinued if causes fetal distress or threatens to cause pre-term labor.

45. Postpartum Treatment of Mothers in MAT Methadone should be continued after delivery either at dosages similar to those before pregnancy. For women who began methadone during pregnancy, at approximately ½ the dosages they received in the third trimester. No empirical data support these approaches, and any decrease should be based on signs of over-medication, withdrawal symptoms, or patient blood plasma levels (Kaltenbach et al. 1998)

46. Breastfeeding on Methadone Alex Grey “Nursing”1985 Oil on Linen

47. Breast-Feeding Mothers maintained on methadone can breast-feed if they are not HIV positive, are not abusing substances, and do not have a disease or infection in which breast-feeding is contraindicated (Kaltenbach et al. 1993). Hepatitis C is no longer considered a contraindication for breast-feeding. The AAP has a long-standing recommendation that methadone is compatible with breast-feeding only if mothers receive no more than 20mg in 24 hours. Studies have found minimal transmission of methadone in breast milk, regardless of maternal dose (Geraghty et al. 1997) McCarthy and Posey (2000) found only small amounts of methadone in breast milk of women maintained on daily doses up to 180 mg and argued the 20mg/day limit.

48. Breast-Feeding • Methadone doses of 25 to 180 mg/d → milk concentrations in milk from 27 to 260 ng/ml. • Based on estimated milk intake of 500 ml/d in an infant, average daily methadone ingestion is 0.05 mg. • In an 11 lb baby, the ingested amount is thus less than 1% of the maternal weight-adjusted dose. • Methadone clearance in neonates is slower than adults, but the infant dose will not exceed 5% of the maternal weight-adjusted dose (Glatstein et al. 2008 Canadian Family Physician 54(12): 1689-90. • AAP Recommendations • 1994: doses > 20mg/day contraindicated • 2001: methadone, regardless of dose, removed from the contraindicated list, data supported. • Breastfeeding shouldn’t impact dosing decisions.

49. Perinatal Outcomes Older Studies comparing infants born to women addicted to heroin but not receiving methadone with infants born to women receiving methadone found reduced fetal mortality and greater birth weights of infants maintained on methadone. Another older study by Kalenbach and Finnegan (1987) with 268 infants found that infants born to opiate addicted women on methadone had lower birth weights and smaller head circumferences than those not exposed to drugs, but the former are not growth restricted.

50. Behavioral Assessment Comparisons Researchers (Chasnoff et al. 1984) who used the Brazelton Neonatal Behavioral Assessment Scale to investigate neuro-behavioral characteristics in newborns undergoing opioid withdrawal have found consistent behavior differences between these infants and those born to women not opiate addicted. Infants exposed to opioids were more irritable, exhibited more tremors, and had increased muscle tone. Other studies have shown less responsiveness to visual stimuli and reduced alertness among infants exposed to opioids. Important are the implications for mother-infant interactions. In the consensus panel’s experience, these infants are frequently difficult to nurture, causing poor mother-infant bonding, which Hoegerman and colleagues (1990) suggested might be the most significant aspect of perinatal addiction.