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Medication Assisted Treatment for Opioid Dependence during Pregnancy

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Presentation on theme: "Medication Assisted Treatment for Opioid Dependence during Pregnancy"— Presentation transcript:

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) Postpartum hemorrhage Preeclampsia Premature labor/delivery PROM Septic thrombophlebitis Spontaneous abortion, especially first trimester Abruptio placentae Chorioamnionitis Intrauterine death IUGR Intrauterine passage of meconium Low Apgar Scores Placental insufficiency Amnionitis

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 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 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

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 Canadian Family Physician 54(12): 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.

51 Developmental Sequelae
Research findings on developmental sequelae associated with in utero methadone exposure are diverse but most studies suggest that infants through 2 year-olds function well within the normal developmental range. They do not differ in cognitive function from a population that was not drug exposed and was of comparable socioeconomic and racial background (Kaltenbach 1996). Another study by Lifeschitz and associates (1985) found no significant developmental differences between children of mothers maintained on methadone and children of mothers using heroin or no opioids, when sociodemographic, biological, and other health factors were considered. Other data have suggested that maternal drug use is not the most important factor in how opioid-exposed infants and children develop but that family characteristics and functioning play a significant role (Johnson et al. 1987).

52 Developmental Sequelae
One long-term follow-up study of 27 children who had been exposed to methadone in utero found no cognitive impairment in preschool years (Kaltenbach et al. 1998). Overall, prenatal exposure to methadone provided as part of comprehensive treatment does not appear to be associated with developmental or cognitive impairments (Kaltenbach 1996).

53 Neonatal Abstinence Syndrome (NAS)
Exposure to opiates like heroin and methadone in utero can result in NAS characterized by: Hyperirritablity of the CNS Dysfunction in the autonomic nervous system Dysfunction in the GI tract, vomiting Dysfunction in the respiratory system, respiratory distress fever When left untreated, NAS can result in serious illness (e.g. diarrhea, feeding difficulties, weight loss, and seizures). Methadone-associated NAS can require prolonged hospitalization, pharmacologic intervention, and monitoring With appropriate pharmacotherapy, NAS can be treated effectively.

54 NAS Infants prenatally exposed to opioids have a high incidence of NAS, characterized by hyperactivity of the central and autonomic nervous systems that is reflected in changes in the GI tract and respiratory system. Infants with NAS often suck frantically on their fists or thumbs but may have extreme difficulty feeding because their sucking reflex is uncoordinated. Withdrawal symptoms may begin from minutes or hours after birth to 2 weeks later, but most appear within 72 hours, not related to dose of methadone. Preterm infants usually have milder symptoms and delayed onset. Buprenorphine NAS less severe than methadone NAS

55 Factors that influence NAS
Types of substances used by the mothers Timing and dosages of methadone before delivery Characteristics of labor, type and amount of anesthesia or analgesic during labor Infant maturity and nutrition, metabolic rate of the infant’s liver, and presence of intrinsic disease in infants.

56 Characteristics of NAS
NAS may be mild or transient, delayed in onset or incremental in severity, or biphasic in its course, including acute neonatal withdrawal signs followed by improvement and then onset of subacute withdrawal (Kaltenbach et al. 1998). Other conditions may mimic NAS, such as hypoglycemia, hypocalcemia, sepsis, and neurologic illnesses. To rule out such conditions, infants should have a CBC with diff, electrolyte and calcium levels, comprehensive neurologic consultation and head ultrasound if indicated. NAS can be more severe or prolonged with methadone’s longer half-life, with appropriate pharmacotherapy, NAS can be treated without any severe neonatal effects.

57 Abstinence Scoring An abstinence scoring system should be used to monitor opioid-exposed newborns to assess the onset, progression, and resolution of symptoms. The NAS Score (Finnegan and Kaltenbach 1992 used widely to estimate NAS severity Determine whether pharmacotherapy is needed Monitor the optimum response to therapy All infants of mothers with an opioid use history should be scored every 4 hours. Control is achieved when the average NAS Score is less than 8, infants exhibit rhythmic feeding and sleep cycles, and have optimal weight gains.

58 Methadone Dose and Maternal / Infant Outcomes Measured (Study 1):
For methadone-exposed pregnancies, compare maternal and infant outcomes by Methadone dose at delivery Timing of conversion to methadone Retrospective cohort study De-identified data abstracted from hospital delivery records (MOMI) – N=224 with delivery dose N=215 with conversion time

59 Outcomes: Maternal & Fetal

60 Methadone Dose Distribution
Quartiles < 60 mg 60-79 mg 80-99 mg > 100 mg

61 Timing of Methadone Conversion

62 Infant Outcome by Methadone Dose
p = ns p=.06 p = ns p=.01 p=0.04* p=.3 p = ns * Linear-by-linear Association (exact significance) Multinomial Logistic Regression: dose <60 mg/d lower odds of SGA

63 Outcomes & Limitations
No association with any maternal outcomes Methadone dose Timing of conversion No association with infant outcomes and timing of conversion Source of data – medical records review No measure of adherence to treatment No data on other drug use Observations from hospital setting - no early miscarriages or abortions

64 Dosage of Methadone and NAS
In a retrospective review of pregnancies that were maintained on methadone therapy in one hospital, 100 mother/neonate pairs on methadone therapy were identified. Women who received an average methadone dose of greater than 80 mg were similar to women maintained on dosages of less than or equal to 80 mg in: Having infants with similar NAS Scores Needs for neonatal treatment for withdrawal Similar duration of withdrawal when it occurred in the neonate. The authors concluded that maternal methadone dosage does not correlate with neonatal withdrawal; therefore maternal benefits of effective methadone dosing are not offset by neonatal harm.

65 Methadone Dosage and NAS
The relationship between maternal methadone dosage and NAS has been difficult to establish, and the consensus panel believes no compelling evidence shows that methadone reduction avoids NAS. Although a number of investigators have reported significant relationships between neonatal withdrawal and maternal methadone dosage, MOST have found no such relationship.

66 Methadone Dosage and NAS
Another study with maternal maintenance dosage found that NAS was related to the mother’s dose of methadone (McCarthy 2005). Opiate dependent pregnant patients receiving mean methadone doses of 132 mg had less illicit drug use at delivery, but their neonates had more severe NAS than expectant mothers receiving mean doses of 62 mg of methadone. The conclusion of this study and another study (Jones et al. 2008) is that pregnant women should receive appropriate methadone doses to treat their addiction, but concerns regarding greater NAS severity associated with larger doses of methadone should not be the primary factor in determining dose.

67 Buprenorphine Classified as a category C drug by the FDA and is not FDA approved to treat pregnant women Several studies have found it safe and effective in this group (Fischer et al. 2000; Lacroix et al. 2004) Even though it is a category C drug, buprenorphine may be used with pregnant patients in the US under certain circumstances

68 Methadone vs. Buprenorphine
Opioid maintained patients who become pregnant should be maintained on the current agent Suboxone can be changed directly to Subutex Even though it is a category C drug, buprenorphine may be used with pregnant patients in the US under certain circumstances Buprenorphine should only be initiated when Patient cannot tolerate methadone Methadone program is not accessible Patient is adamant about avoiding methadone Patient is capable of informed consent

69 Principles of Pharmacotherapy with Buprenorphine (Subutex)
Antagonist / High receptor affinity Highest receptor affinity and receptor occupancy: 95% occupancy at 16 mg (Greenwald et al, 2003) Blockade or attenuate effect of other opioids Rapid onset of action and risk of acute opioid reversal Partial receptor agonist / Low Intrinsic Activity Lower physical dependence Limited development of tolerance Ceiling effect on respiratory depression Long Acting / Slow dissociation from receptor Long duration of action Milder withdrawal

70 Buprenorpine Not FDA approved for use in pregnancy/Category C (widely used in Europe) Pharmacokinetics of buprenorphine not well understood in pregnancy or in the fetus. Typical dosing is 8mg to 24mg daily and generally requires few adjustments in pregnancy Highly receptor bound so less affected by increased metabolic rate and larger blood/tissue volume. Recommended buprenorphine monotherapy only (Subutex), no benefit to divided dosing. A partial mu-opioid agonist and kappa-opioid antagonist, effectively treats opioid dependence. Is low intrinsic receptor efficacy results in less-than-maximal opioid effect a diminished risk of overdose, as compared with methadone. In non-pregnant adults, the effects of abrupt withdrawal of buprenorphine are minimal relative to the effects of withdrawal of full mu-opioid agonists.

71 Buprenorphine: Pharmacological advantages led to prospective open-label and controlled studies of its use in prenatal treatment. The results of some of these studies suggested that neonates exposed to buprenorphine might be less likely to require treatment for NAS than those exposed to methadone. These studies have had inconsistent results with respect to NAS outcomes. Improved pregnancy outcomes seen with methadone appear to be duplicated on buprenorphine.

72 Buprenorphine There have been 31 published reports of buprenorphine, a partial-mu opioid agonist, exposure during pregnancy that were reviewed and summarized (Jones et al. 2008). Overall, the studies report approximately 522 neonates prenatally exposed to buprenorphine, with a wide range of therapeutic doses from 0.4 to 24 mg sublingual tablets/day. Generally, the pregnancies were uneventful, without physical teratogenic effects, and with low rates of prematurity, suggesting that buprenorphine is relatively safe and effective for this population.

73 Buprenorphine Despite significant variability in the instruments and scoring methods used, the literature suggests that buprenorphine exposure is also associated with NAS, half the cases of which require pharmacotherapy. The pregnancy, birth and NAS outcomes are also confounded by other drug use in 86% of the reports.

74 Buprenorphine Although considerable individual variability exists, the NAS timing observed to date has an apparent onset within the first 12 to 48 hours, peaks within approx 66 to 96 hours, and lasts approx 120 to 168 hours A few infants exhibited withdrawal 6 to 10 weeks after delivery (NAS medication and regimen related?) To date, only one report found a correlation between buprenorphine dose and the severity of the NAS (Marquet et al. 2002). Other recent reports, including one with a large sample size (Lejeune et al. 2006) have reported no correlation. Overall, buprenorphine associated NAS was found to be less intense than that associated with methadone (Johnson et al. 2003a)

75 MOTHER Project Given the calls to increase representation of pregnant women in medication research, the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project was initiated. A multicenter, randomized, controlled trial comparing buprenorphine with methadone for the treatment of opioid-dependent pregnant patients. Prior to this only 2 randomized, double-blind studies have been conducted comparing methadone with buprenorphine (Fisher et al. 2006; Jones et al. 2005).

76 New Study! Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure, Jones et. Al 2010, New England Journal of Medicine. A double blind, double dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at 8 international sites. Primary outcomes were: The number of neonates requiring treatment for NAS The peak NAS score The total amount of morphine needed to treat NAS The length of the hospital stay for neonates Neonatal head circumference

77 Results: A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed the buprenorphine group Required significantly less morphine (mean dose, 1.1 mg vs mg) Had a significantly shorter hospital stay (10.0 days vs days) Had a significantly shorter duration of treatment for the NAS (4.1 days vs. 9.9 days) There were no significant differences between the groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events.


79 Measured Neonatal Study Outcomes
Secondary Neonatal Outcomes Number of days during which medication was given for NAS Weight and length at birth Preterm birth (< 37 weeks gestation) Gestational age at delivery 1 and 5 minute APGAR scores Primary Neonatal Outcomes Number of neonates requiring treatment for NAS Peak NAS score Total amount of morphine needed for treatment of NAS Length of Hospital Stay Head circumference

80 Measured Maternal Outcomes
Cesarean section Weight gain Abnormal fetal presentation during delivery Anesthesia during delivery Results of drug screening at delivery Medical complications at delivery Study discontinuation Amount of voucher money earned for drug-negative tests Number of prenatal obstetrical visits

81 Primary Outcomes with no significant differences:
The percentage of neonates requiring NAS treatment did not differ significantly between groups (57% vs. 47%). The groups did not differ significantly with respect to the peak NAS score (12.8 vs. 11.0). There was not a significant difference in the infant’s head circumference (33.0 vs. 33.8).

82 Primary Outcomes with significant differences:
The mean total dose amount of morphine needed for the treatment of NAS averaged 10.4 mg in the methadone group and 1.1 mg in the buprenorphine group. On average, neonates exposed to buprenorphine required 89% less morphine than did neonates exposed to methadone. The average amount of days for the infant’s stay in the hospital was 17.5 vs 10.0 days, so infants born to mother’s on buprenorphine spent on average 43% less time in the hospital.


84 Secondary Outcomes with significant differences:
One of the 7 neonatal outcomes differed in that neonates exposed to buprenorphine spent, on average, 58% less time in the hospital receiving medication for NAS than did those exposed to methadone (4.1 days vs. 9.9 days). There were no significant differences in any of the nine maternal secondary outcomes.

85 In Summary: In this randomized, double-blind trial:
Infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment of NAS. Buprenorphine infants had significantly shorter period of NAS treatment. Buprenorphine infants had a significantly shorter hospital stay than did infants with prenatal exposure to methadone. The superiority of buprenorphine over methadone did not extend to differences in the number of neonates requiring NAS treatment, peak NAS score, head circumference, any other neonatal outcome, or any maternal outcome.

86 In Summary: Methadone has been the recommended standard of care for opioid-dependent pregnant women, and this double blind study provides critical data on the outcomes of methadone treatment. Findings support the safety and usefulness of methadone treatment for opioid dependence during pregnancy, and shows that the treatment of opioid-dependent pregnant women with buprenorphine results in a clinically meaningful reduction in the severity of NAS in their neonates, as compared with methadone. Also, findings that there was no significant differences between the treatment groups in rates of opioid use during treatment is consistent with observations in previous randomized trials involving non-pregnant patients that methadone and buprenorphine cause similar reductions in illicit opioid use AND both medications, in the context of comprehensive care, do not differ markedly in their effect on maternal treatment outcomes at delivery.

87 In Summary: Findings are consistent with the use of buprenorphine as an alternative to methadone for the treatment of opioid dependency during pregnancy. Although there were no significant differences in the overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy. In selecting a course of treatment, clinicians should take into account the possibility of reduced adherence and ceiling effect of this medication as compared with methadone.

88 Breast-Feeding During Buprenorphine
Research has indicated that only small amounts of buprenorphine and buprenorphine-naloxone pass into breast milk, with little or no effect on infants (Johnson et al. 2001). Studies show buprenorphine is likely to be poorly absorbed by infants via the oral route. The consensus panel for TIP 43 recommends that women maintained on buprenorphine be encouraged to breast-feed because of benefits to infants and mother-child interaction.

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