Medication Assisted Medication Assisted Treatment for Opioid Treatment for Opioid Dependence during Dependence during

PregnancyPregnancy

Jason B. Fields MDJason B. Fields MDDACCODACCO

University of Florida Addiction Medicine Fellow University of Florida Addiction Medicine Fellow and and

Medical Services ManagerMedical Services Manager

How Prevalent is drug and How Prevalent is drug and alcohol use in pregnancy?alcohol use in pregnancy?

12-24% of women use drugs and alcohol during pregnancy12-24% of women use drugs and alcohol during pregnancy

1 of every 3-4 women expose fetus to alcohol1 of every 3-4 women expose fetus to alcohol

Alcohol and tobacco > illicit drugs and prescription Alcohol and tobacco > illicit drugs and prescription drugsdrugs

Prevalence in public clinic=private practicePrevalence in public clinic=private practice

Caucasians > African Americans > HispanicCaucasians > African Americans > Hispanic

No significant variation by socioeconomic statusNo significant variation by socioeconomic status

Major Women’s Health Major Women’s Health Issue!Issue!

Opioid dependence is compounded by multiple Opioid dependence is compounded by multiple risk factors contributing to adverse maternal, risk factors contributing to adverse maternal, neonatal, and long-term developmental sequelae.neonatal, and long-term developmental sequelae.

Improved treatment options should reduce the Improved treatment options should reduce the public health and medical costs associated with public health and medical costs associated with the treatment of neonates exposed to opioids, the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to which in 2009 was estimated at $70.6 million to $112.6 million in the US alone.$112.6 million in the US alone.

Just as the use of methadone in non-pregnant Just as the use of methadone in non-pregnant women improves patient outcomes, its use as women improves patient outcomes, its use as part of a comprehensive approach to the care of part of a comprehensive approach to the care of pregnant women improves maternal and pregnant women improves maternal and neonatal outcomes, as compared with no neonatal outcomes, as compared with no treatment and with Medication Assisted treatment and with Medication Assisted Withdrawal (MSW). Withdrawal (MSW).

A Complex Clinical A Complex Clinical ProblemProblem

Of the 400,000 women admitted to programs in 1999, 4% Of the 400,000 women admitted to programs in 1999, 4% were pregnant when admitted.were pregnant when admitted.

Opioids were the primary substance of abuse for 19% of Opioids were the primary substance of abuse for 19% of both pregnant and non-pregnant women who entered these both pregnant and non-pregnant women who entered these programsprograms

Increasing prevalence of non-medically used analgesics in Increasing prevalence of non-medically used analgesics in women of child bearing age.women of child bearing age.

Self-reported nonmedical use of analgesics increased from Self-reported nonmedical use of analgesics increased from 51,900 in 1993 to an average of 109,000 in 2002 to 200451,900 in 1993 to an average of 109,000 in 2002 to 2004

Children of opioid dependent women might be at risk for Children of opioid dependent women might be at risk for poor outcomes not only because of opioid drug exposure, poor outcomes not only because of opioid drug exposure, but also because of concomitant alcohol and tobacco but also because of concomitant alcohol and tobacco exposure and numerous factors related to the caregiving exposure and numerous factors related to the caregiving environment. environment.

Opioid misuse during Opioid misuse during pregnancy is a serious and pregnancy is a serious and

growing concern:growing concern: High rates of infectionHigh rates of infection Premature deliveryPremature delivery Low birth weight, which is an important Low birth weight, which is an important

risk factor for later developmental delay.risk factor for later developmental delay. Comprehensive methadone maintenance Comprehensive methadone maintenance

treatment that includes prenatal care treatment that includes prenatal care reduces the risk of obstetrical and fetal reduces the risk of obstetrical and fetal complications, in utero growth complications, in utero growth retardation, and neonatal morbidity and retardation, and neonatal morbidity and mortality. mortality.

Benefits of Maintenance with Benefits of Maintenance with Opioid Agonist Therapy in PregnancyOpioid Agonist Therapy in Pregnancy

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

Methadone Maintenance Methadone Maintenance TreatmentTreatment A full mu-opioid agonist. A full mu-opioid agonist.

Methadone is the only medication currently approved for the Methadone is the only medication currently approved for the treatment of opioid addiction in pregnancy (US).treatment of opioid addiction in pregnancy (US). Maintenance with methadone during pregnancy produces Maintenance with methadone during pregnancy produces

the same benefits as treatment in the non-pregnant the same benefits as treatment in the non-pregnant patient.patient.

Has been the recommended standard of care over no Has been the recommended standard of care over no treatment or medication-assisted withdrawal.treatment or medication-assisted withdrawal.

ButBut, medically supervised withdrawal is not the standard of , medically supervised withdrawal is not the standard of care due to the poor outcomes (Jones H, 2008) and the care due to the poor outcomes (Jones H, 2008) and the potential catastrophic consequences of relapse.potential catastrophic consequences of relapse.

BecauseBecause the goal of treatment with methadone is to prevent the goal of treatment with methadone is to prevent relapse to illicit substance use.relapse to illicit substance use.

A pregnant patient CAN taper off of methadone (opioid A pregnant patient CAN taper off of methadone (opioid agonist therapy) but should not be permitted to experience agonist therapy) but should not be permitted to experience significant abstinence syndrome. (Luty, J, Nilolaou V, Bearn significant abstinence syndrome. (Luty, J, Nilolaou V, Bearn J. 2004)J. 2004)

Methadone Maintenance Methadone Maintenance TreatmentTreatment

MMT is but a single element in the variety of MMT is but a single element in the variety of services needed for optimal care of the pregnant services needed for optimal care of the pregnant opioid dependent patient.opioid dependent patient.

This recommendation is based on longer durations This recommendation is based on longer durations of maternal drug abstinence, better obstetrical care of maternal drug abstinence, better obstetrical care compliance, avoidance of associated risk factors, compliance, avoidance of associated risk factors, reductions in fetal illicit drug exposure, and reductions in fetal illicit drug exposure, and enhanced neonatal outcomes (i.e. heavier birth enhanced neonatal outcomes (i.e. heavier birth weight).weight).

Recommended because when MMT is used within a Recommended because when MMT is used within a treatment setting that includes comprehensive treatment setting that includes comprehensive care, obstetrical and fetal complications, including care, obstetrical and fetal complications, including neonatal morbidity and mortality, can be reduced neonatal morbidity and mortality, can be reduced (Jarvis and Schnoll 1995; Kaltenbach et al. 1998).(Jarvis and Schnoll 1995; Kaltenbach et al. 1998).

Methadone Maintenance Methadone Maintenance TreatmentTreatment Effective medical maintenance treatment with methadone Effective medical maintenance treatment with methadone

has the same benefits for pregnant patients as for patients has the same benefits for pregnant patients as for patients in general.in general.

Effective MMT prevents the onset of withdrawal, reduces Effective MMT prevents the onset of withdrawal, reduces or eliminates drug craving, and blocks the euphoric effects or eliminates drug craving, and blocks the euphoric effects of illicit self-administered opioids (Dole et al. 1966, Kreek of illicit self-administered opioids (Dole et al. 1966, Kreek 1988)1988)

In addition, methadone substantially reduces fluctuations In addition, methadone substantially reduces fluctuations in maternal serum opioid levels, so it protects the fetus in maternal serum opioid levels, so it protects the fetus from repeated withdrawal episodes. from repeated withdrawal episodes.

Because needle use is eliminated, MMT reduces the risk of Because needle use is eliminated, MMT reduces the risk of infectious disease.infectious disease.

The mandatory link to prenatal care, frequent contact with The mandatory link to prenatal care, frequent contact with program staff, and elimination of the stress of obtaining program staff, and elimination of the stress of obtaining opioids daily to feel “normal” are additional benefits from opioids daily to feel “normal” are additional benefits from MMT (Burns et al. 2006).MMT (Burns et al. 2006).

Acceptance as the Standard Acceptance as the Standard of Careof Care

Methadone has been accepted since the Methadone has been accepted since the late 1970s to treat opioid addiction during late 1970s to treat opioid addiction during pregnancypregnancy

In 1998, a National Institutes of Health In 1998, a National Institutes of Health consensus panel recommended methadone consensus panel recommended methadone maintenance as the standard of care for maintenance as the standard of care for pregnant women with opioid addictionpregnant women with opioid addiction

Methadone currently is the only approved Methadone currently is the only approved opioid medication-assisted treatment for opioid medication-assisted treatment for opioid addiction (MAT) in pregnant opioid addiction (MAT) in pregnant patients.patients.

Standard of CareStandard of Care Methadone maintenance has been the Methadone maintenance has been the

recommended standard of care over no recommended standard of care over no treatment or Medication Assisted Withdrawal treatment or Medication Assisted Withdrawal (MAW) based on:(MAW) based on: Longer durations of maternal drug Longer durations of maternal drug

abstinenceabstinence Better obstetrical care complianceBetter obstetrical care compliance Avoidance of associated risk behaviorsAvoidance of associated risk behaviors Reductions in fetal illicit drug exposureReductions in fetal illicit drug exposure Enhanced neonatal outcomes-heavier birth Enhanced neonatal outcomes-heavier birth

weight (Kaltenbach 1998). weight (Kaltenbach 1998).

Standard of CareStandard of Care Methadone is the oldest, most widely used Methadone is the oldest, most widely used

medication prescribed during pregnancy, medication prescribed during pregnancy, and in comparison to infants born to and in comparison to infants born to heroin-abusing mothers, infants from heroin-abusing mothers, infants from methadone-treated mothers have:methadone-treated mothers have: Increased fetal growthIncreased fetal growth Reduced fetal mortalityReduced fetal mortality Decreased risk of HIV infectionDecreased risk of HIV infection Decreased risk of pre-eclampsiaDecreased risk of pre-eclampsia Less fetal exposure to rapid and unpredictable Less fetal exposure to rapid and unpredictable

cycles of heroin-induced highs and withdrawalcycles of heroin-induced highs and withdrawal Increased likelihood of the infants being Increased likelihood of the infants being

discharged to their parents (Finnegan 1991). discharged to their parents (Finnegan 1991).

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).

Principles of Opioid Agonist Principles of Opioid Agonist TherapyTherapy

Opioids bind the mu opioid receptors in the brain.Opioids bind the mu opioid receptors in the brain. The mu receptor generates the effects The mu receptor generates the effects

experienced by the patient/drug user.experienced by the patient/drug user. Different opioids stimulate the receptor to a Different opioids stimulate the receptor to a

greater or lesser degree.greater or lesser degree.By occupying the mu receptor with a long acting By occupying the mu receptor with a long acting

opioid the effects of other opioids are impeded or opioid the effects of other opioids are impeded or attenuated.attenuated. By dosing regularly and before developing By dosing regularly and before developing

symptoms of abstinence syndrome the mu symptoms of abstinence syndrome the mu receptors will be occupied when a trigger or receptors will be occupied when a trigger or craving is experienced. craving is experienced.

A higher dose occupies A higher dose occupies moremore receptors receptors longerlonger..

Principles of Principles of Pharmacotherapy with Pharmacotherapy with

MethadoneMethadone Methadone is the only agonist therapy approved for Methadone is the only agonist therapy approved for

use in pregnancy. It is supported by 30 years of use in pregnancy. It is supported by 30 years of research.research.

Methadone is a full agonist so the effect is directly Methadone is a full agonist so the effect is directly proportionate to the dose.proportionate to the dose.

It takes 24 to 36 hours for the body of a healthy person It takes 24 to 36 hours for the body of a healthy person to eliminate half of the methadone ingested.to eliminate half of the methadone ingested. A person with impaired liver function or on other A person with impaired liver function or on other

medications/intoxicants may require up to 50 hours medications/intoxicants may require up to 50 hours to eliminate half of the methadoneto eliminate half of the methadone

The opioid “blocker” effect is a result of having the mu The opioid “blocker” effect is a result of having the mu opioid receptor occupied with methadone when opioid receptor occupied with methadone when another opioid is introduced. another opioid is introduced.

Diagnosing Opioid Diagnosing Opioid AddictionAddiction

Some women who are opioid addicted do not Some women who are opioid addicted do not acknowledge pregnancy readily, or they acknowledge pregnancy readily, or they misinterpret early signs of pregnancy misinterpret early signs of pregnancy (fatigue, headaches, nausea and vomiting and (fatigue, headaches, nausea and vomiting and cramps as opioid withdrawal symptoms).cramps as opioid withdrawal symptoms).

Onset of pregnancy may cause these patients Onset of pregnancy may cause these patients to increase their use of illicit opioids or other to increase their use of illicit opioids or other substances that do no alleviate their substances that do no alleviate their perceived withdrawal symptoms but expose perceived withdrawal symptoms but expose their fetuses to increased serum levels of their fetuses to increased serum levels of these substances.these substances.

Factors in Opioid Dependence Factors in Opioid Dependence and Pregnancyand Pregnancy

Many women who are opioid addicted confuse Many women who are opioid addicted confuse the amenorrhea caused by stressful, unhealthy the amenorrhea caused by stressful, unhealthy lifestyles with infertility.lifestyles with infertility.

They might have been sexually active for years They might have been sexually active for years without using contraceptives and becoming without using contraceptives and becoming pregnant.pregnant.

The consensus panel (National Institutes of The consensus panel (National Institutes of Health Consensus Developmental Panel, 1998) Health Consensus Developmental Panel, 1998) noted that because methadone normalizes noted that because methadone normalizes endocrine functions, it is not unusual for endocrine functions, it is not unusual for women in the early phases of MAT to become women in the early phases of MAT to become pregnant unintentionally, especially if they pregnant unintentionally, especially if they receive no counseling for this possibility.receive no counseling for this possibility.

Diagnosing Opioid and Diagnosing Opioid and other Addictionsother Addictions

Information from their medical and substance Information from their medical and substance abuse histories, PE, drug test reports, and abuse histories, PE, drug test reports, and observed signs or symptoms of withdrawal.observed signs or symptoms of withdrawal.

Indication may be evidence of diseases Indication may be evidence of diseases associated with drug use like hepatitis, associated with drug use like hepatitis, bacterial endocarditis, and cellulitis.bacterial endocarditis, and cellulitis.

Poor attendance of prenatal care and Poor attendance of prenatal care and unexplained fetal growth abnormalities unexplained fetal growth abnormalities (IUGR).(IUGR).

Using an opioid antagonist to diagnose Using an opioid antagonist to diagnose addiction in pregnant women is addiction in pregnant women is absolutely absolutely contraindicatedcontraindicated as inducing even mild as inducing even mild withdrawal can cause premature labor or withdrawal can cause premature labor or other adverse fetal effects. other adverse fetal effects.

Medical and Obstetrical Medical and Obstetrical ConcernsConcerns

Pregnant women who abuse substances Pregnant women who abuse substances (including alcohol and nicotine) have a (including alcohol and nicotine) have a greater than normal risk of medical greater than normal risk of medical complicationscomplications

Related to addiction: anemia, poor Related to addiction: anemia, poor nutrition, increased blood pressure, nutrition, increased blood pressure, hyperglycemia, STDs, hepatitis, hyperglycemia, STDs, hepatitis, preeclampsia.preeclampsia.

The big concern with opioid withdrawal is The big concern with opioid withdrawal is premature labor, pregnant women should premature labor, pregnant women should be educated about the potential adverse be educated about the potential adverse effects of substance use on their fetuseseffects of substance use on their fetuses

Common Medical Complications Common Medical Complications Among Pregnant Women Who Are Among Pregnant Women Who Are

Opiate Addicted Opiate Addicted (many of these from (many of these from intravenous drug use)intravenous drug use) AnemiaAnemia

Bacteremia/septicemia Bacteremia/septicemia Cardiac disease, Cardiac disease,

especially endocarditisespecially endocarditis CellulitisCellulitis Depression and other Depression and other

mental disordersmental disorders EdemaEdema Gestational DiabetesGestational Diabetes Hepatitis A, B, and CHepatitis A, B, and C Hypertension/tachycardiaHypertension/tachycardia PhlebitisPhlebitis PneumoniaPneumonia Poor dental hygienePoor dental hygiene

STDsSTDs ChlamydiaChlamydia Condyloma Condyloma

acuminatumacuminatum GonorrheaGonorrhea HerpesHerpes HIV/AIDSHIV/AIDS SyphilisSyphilis

TetanusTetanus TuberculosisTuberculosis UTIsUTIs

CystitisCystitis PyelonephritisPyelonephritis UrethritisUrethritis

HepatitisHepatitis Rate of vertical perinatal transmission of hepatitis Rate of vertical perinatal transmission of hepatitis

B virus (HBV) is high (70 to 90%), esp if a pregnant B virus (HBV) is high (70 to 90%), esp if a pregnant woman has active infection (+ Hep B antigen test) woman has active infection (+ Hep B antigen test) in the 3in the 3rdrd trimester or within 5 weeks postpartum. trimester or within 5 weeks postpartum.

Neonate should receive both Hep B vaccine and Neonate should receive both Hep B vaccine and Hep B immune globulinHep B immune globulin

Rate of vertical transmission of Hep C is lower, Rate of vertical transmission of Hep C is lower, however vaccines exist for Hep A and HBV but not however vaccines exist for Hep A and HBV but not for HCV. for HCV.

Pregnant women with a history of injection drug Pregnant women with a history of injection drug use are at high risk for HCV infection and should be use are at high risk for HCV infection and should be screened for anti-HCV antibody and HCV RNA screened for anti-HCV antibody and HCV RNA testing should be done if anti-HCV antibody is testing should be done if anti-HCV antibody is positive. positive.

HIVHIV

A limited number of studies with small A limited number of studies with small numbers of patients have examined the numbers of patients have examined the relationship of HIV, methadone, and relationship of HIV, methadone, and immune function. It is difficult to conclude immune function. It is difficult to conclude any significant relationship. any significant relationship.

Women who are opioid addicted and HIV Women who are opioid addicted and HIV infected receive additional counseling and infected receive additional counseling and support during the postpartum period to support during the postpartum period to improve their adherence to antiretroviral improve their adherence to antiretroviral therapy and to meet the demands of caring therapy and to meet the demands of caring for the newborn. for the newborn.

Common Obstetrical Common Obstetrical Complications Among Women Complications Among Women

Addicted to Opioids Addicted to Opioids (The fetus is at risk for (The fetus is at risk for morbidity and mortality because of episodes of morbidity and mortality because of episodes of

maternal withdrawal compounded by a lack of prenatal maternal withdrawal compounded by a lack of prenatal care)care) Abruptio placentaeAbruptio placentae

ChorioamnionitisChorioamnionitis Intrauterine deathIntrauterine death IUGRIUGR Intrauterine passage Intrauterine passage

of meconiumof meconium Low Apgar ScoresLow Apgar Scores Placental Placental

insufficiencyinsufficiency AmnionitisAmnionitis

Postpartum Postpartum hemorrhagehemorrhage

PreeclampsiaPreeclampsia Premature Premature

labor/deliverylabor/delivery PROMPROM Septic Septic

thrombophlebitisthrombophlebitis Spontaneous Spontaneous

abortion, especially abortion, especially first trimesterfirst trimester

Methadone Methadone PharmacologyPharmacology

Methadone is distributed widely throughout Methadone is distributed widely throughout the body with extensive nonspecific tissue the body with extensive nonspecific tissue binding creating reservoirs that release binding creating reservoirs that release unchanged methadone back into the blood.unchanged methadone back into the blood.

Peak plasma levels occur between 2 and 6 Peak plasma levels occur between 2 and 6 hours after a maintenance dose of hours after a maintenance dose of methadone is ingested, with less than 6% of methadone is ingested, with less than 6% of the ingested dose in the total blood volume the ingested dose in the total blood volume at this time. at this time.

Lower sustained plasma concentrations are Lower sustained plasma concentrations are present during the remainder of a 24 hour present during the remainder of a 24 hour period.period.

Pharmacology ContPharmacology Cont

The same methadone dosage produces lower The same methadone dosage produces lower blood methadone levels, owing to increased blood methadone levels, owing to increased fluid volume, a larger tissue reservoir for fluid volume, a larger tissue reservoir for methadone, and altered opioid metabolism methadone, and altered opioid metabolism in both the placenta and the fetus.in both the placenta and the fetus.

Women often experience symptoms of Women often experience symptoms of withdrawal in later pregnancy and require withdrawal in later pregnancy and require dosage increases.dosage increases.

The daily dose can be increased and The daily dose can be increased and administered singly or split into twice-daily administered singly or split into twice-daily dosesdoses

Dosages relative to Dosages relative to Neonatal Abstinence Neonatal Abstinence

SyndromeSyndrome Historically, treatment providers have Historically, treatment providers have

based dosing decisions on the need to based dosing decisions on the need to avoid or reduce the incidence of NAS avoid or reduce the incidence of NAS (Kaltenbach et al. 1998).(Kaltenbach et al. 1998).

This low-dose approach emerged from This low-dose approach emerged from several 1970s studies (Harper et al. 1977) several 1970s studies (Harper et al. 1977) and has been contradicted by more recent and has been contradicted by more recent studies (Brown et al. 1998).studies (Brown et al. 1998).

There is no compelling evidence There is no compelling evidence supporting reduced methadone dosages supporting reduced methadone dosages to avoid NAS.to avoid NAS.

Studies on Methadone Dose Studies on Methadone Dose and Outcomesand Outcomes

One long term follow up study of 27 One long term follow up study of 27 children who had been exposed to children who had been exposed to methadone in utero found no cognitive methadone in utero found no cognitive impairment in the preschool years impairment in the preschool years (Kaltenbach et al. 1988).(Kaltenbach et al. 1988).

Overall, prenatal exposure to Overall, prenatal exposure to methadone provided as a part of methadone provided as a part of comprehensive treatment does not comprehensive treatment does not appear to be associated with appear to be associated with developmental or cognitive developmental or cognitive impairments. impairments.

On the contrary, higher doses On the contrary, higher doses of Methadone have been of Methadone have been

associated with:associated with: Increased weight gainIncreased weight gain Decreased illegal drug useDecreased illegal drug use Improved compliance with prenatal care by Improved compliance with prenatal care by

pregnant women in MAT pregnant women in MAT Increased birth weightIncreased birth weight Increased head circumferenceIncreased head circumference Prolonged gestationProlonged gestation Improved growth of infants born to women in Improved growth of infants born to women in

MAT (De Petrillo and Rice 1995)MAT (De Petrillo and Rice 1995)

***Reduced methadone dosages may result in continued substance use ***Reduced methadone dosages may result in continued substance use and increased risks to both expectant mothers and their fetusesand increased risks to both expectant mothers and their fetuses

Getting the Prenatal Dose Right: Induction and Stabilization

OUTPATIENTOUTPATIENT

Initial dose 30 mgInitial dose 30 mg

Twice daily assessment Twice daily assessment for objective signs of for objective signs of withdrawalwithdrawal ““Peak” and “Trough”Peak” and “Trough”

Increase in increments Increase in increments of 5 or 10 mgof 5 or 10 mg

Patient to record fetal Patient to record fetal movement regularlymovement regularly

Methadone Induction for the Methadone Induction for the Pregnant PatientPregnant Patient

INPATIENTINPATIENT

Permits larger initial Permits larger initial dose and more rapid dose and more rapid escalationescalation

Prenatal assessment Prenatal assessment conducted concurrentlyconducted concurrently

More likely to isolate More likely to isolate patient from source of patient from source of other illicit substancesother illicit substances

Induction and Induction and StabilizationStabilization

Methadone dosages for pregnant women should be Methadone dosages for pregnant women should be based on the same criteria as those for women who based on the same criteria as those for women who are not pregnant.are not pregnant.

Women who received methadone before pregnancy Women who received methadone before pregnancy should be maintained initially at their pre-should be maintained initially at their pre-pregnancy dosage.pregnancy dosage.

If pregnant women have not been maintained on If pregnant women have not been maintained on methadone, the consensus panel recommends that methadone, the consensus panel recommends that they either be inducted in an outpatient setting by they either be inducted in an outpatient setting by standard procedures or be admitted to a hospital standard procedures or be admitted to a hospital (for an average of 3 days) to evaluate their prenatal (for an average of 3 days) to evaluate their prenatal health status, document physiologic dependence, health status, document physiologic dependence, and initiate methadone maintenance if possible.and initiate methadone maintenance if possible.

Induction and Induction and StabilizationStabilization

For pregnant women being inducted in an outpatient For pregnant women being inducted in an outpatient setting, a widely accepted protocol is to give initial setting, a widely accepted protocol is to give initial methadone doses of 10 to 20 mg/day, with exact methadone doses of 10 to 20 mg/day, with exact dosage based on a patient’s opioid use history.dosage based on a patient’s opioid use history.

A patient should be asked to return for follow-up at A patient should be asked to return for follow-up at the end of the day and the initial dose may be followed the end of the day and the initial dose may be followed by regular adjustments of 5 to 10 mg per day based on by regular adjustments of 5 to 10 mg per day based on therapeutic response.therapeutic response.

Twice daily observation should continue until the Twice daily observation should continue until the patient is stabilized. If evidence of intoxication or patient is stabilized. If evidence of intoxication or withdrawal emerges, treatment providers should withdrawal emerges, treatment providers should adjust the dosage.adjust the dosage.

Most pregnant women can be stabilized within 48 to Most pregnant women can be stabilized within 48 to 72 hours. In outpatient settings, where fetal monitors 72 hours. In outpatient settings, where fetal monitors usually are unavailable, it is crucial that patients usually are unavailable, it is crucial that patients record measures of fetal movement at set intervals. record measures of fetal movement at set intervals.

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.)

The Right Dose Throughout The Right Dose Throughout

PregnancyPregnancy (is the dose that (is the dose that stops withdrawal)stops withdrawal)

Increased Blood Increased Blood VolumeVolume

Larger Tissue Larger Tissue ReservoirReservoir

Methadone Loss to Methadone Loss to Amniotic FluidAmniotic Fluid

Altered Maternal Altered Maternal MetabolismMetabolism

Metabolic Activity Metabolic Activity of Fetusof Fetus

Patient may require Patient may require progressive increases progressive increases throughout pregnancythroughout pregnancy

Split dosing is an Split dosing is an option to maintain option to maintain adequate blood levels adequate blood levels with fewer increases with fewer increases (Kaltenbach 1998; (Kaltenbach 1998; Jarvis 1999).Jarvis 1999).

Counseling is essential Counseling is essential to address cravings, to address cravings, stress, and anxietystress, and anxiety

Split DosingSplit Dosing Split-dosing methadone regimens are accepted Split-dosing methadone regimens are accepted

widely for pregnant patients, but little empirical widely for pregnant patients, but little empirical evidence investigation has been done of its evidence investigation has been done of its effects on fetuses or maternal plasma levels.effects on fetuses or maternal plasma levels.

Although split dosing may improve maternal Although split dosing may improve maternal compliance with treatment and decreased other compliance with treatment and decreased other illicit substance use (cocaine), traveling to an illicit substance use (cocaine), traveling to an opioid treatment program twice a day or, for opioid treatment program twice a day or, for unstable or newly admitted patients, qualifying unstable or newly admitted patients, qualifying for take-home medication doses may be for take-home medication doses may be difficult.difficult.

Intrapartum &Postpartum Management

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, ----)

Managing Polysubstance Managing Polysubstance UseUse

A large percentage of pregnant women in MAT-88% A large percentage of pregnant women in MAT-88% in one study-continue to use other substances in one study-continue to use other substances including alcohol, heroin, cocaine, barbiturates, and including alcohol, heroin, cocaine, barbiturates, and tranquilizers (Edelin et al. 1988)tranquilizers (Edelin et al. 1988)

It is essential that patients be monitored for use of It is essential that patients be monitored for use of both licit and illicit drugs and alcohol to manage the both licit and illicit drugs and alcohol to manage the perinatal care of both mothers and infants perinatal care of both mothers and infants (Kaltenbach et al. 1998)(Kaltenbach et al. 1998)

Polysubstance use is a special concern during Polysubstance use is a special concern during pregnancy because of the adverse effects of cross-pregnancy because of the adverse effects of cross-tolerance, drug interactions, and potentiation and tolerance, drug interactions, and potentiation and the serious maternal and fetal health risks from the serious maternal and fetal health risks from continued substance use and lack of adequate continued substance use and lack of adequate prenatal care (Svikis et al. 1997a). prenatal care (Svikis et al. 1997a).

Ongoing Illicit or Ongoing Illicit or Polysubstance UsePolysubstance Use

Can be reduced by higher dose of Can be reduced by higher dose of methadonemethadone

Does not seem to directly increase the Does not seem to directly increase the incidence of pregnancy complications, butincidence of pregnancy complications, but

Does reverse the positive impact of opioid Does reverse the positive impact of opioid maintenance on birth weight (Kashiwagi maintenance on birth weight (Kashiwagi et al. 2003)et al. 2003)

Maternal tobacco use plays a role in Maternal tobacco use plays a role in timing and onset of Neonatal Abstinence timing and onset of Neonatal Abstinence Syndrome-NAS (Choo et al. 2004).Syndrome-NAS (Choo et al. 2004).

Management of Acute Management of Acute Opioid Overdose in Opioid Overdose in

PregnancyPregnancy Naloxone, a short-acting, pure opioid antagonist, Naloxone, a short-acting, pure opioid antagonist,

is the pharmacological treatment of choice for is the pharmacological treatment of choice for opioid overdose but should be given to pregnant opioid overdose but should be given to pregnant patients only as a last resort (Weaver, 2003).patients only as a last resort (Weaver, 2003).

Patients should receive naloxone (0.01 mg/kg of Patients should receive naloxone (0.01 mg/kg of body weight) intravenously after an airway is body weight) intravenously after an airway is established to ensure adequate respiration. established to ensure adequate respiration. Patients can receive additional naloxone doses Patients can receive additional naloxone doses every 5 minutes after they regain consciousness. every 5 minutes after they regain consciousness.

Naloxone’s duration of action is from 30 minutes Naloxone’s duration of action is from 30 minutes to 2 hours, whereas that of most opioids is from to 2 hours, whereas that of most opioids is from 6 to 8 hours and that of methadone or other long-6 to 8 hours and that of methadone or other long-acting opioids is from 12 to 48 hours.acting opioids is from 12 to 48 hours.

Management of Acute Management of Acute Opioid Overdose in Opioid Overdose in

PregnancyPregnancy Symptoms are likely to recur within 30 min Symptoms are likely to recur within 30 min

to 2 hours and treatment providers should to 2 hours and treatment providers should continue administering naloxone IV or IM continue administering naloxone IV or IM until the effects of the illicit opioids markedly until the effects of the illicit opioids markedly diminish, which can be 2 to 3 days.diminish, which can be 2 to 3 days.

Special care is needed to avoid acute opioid Special care is needed to avoid acute opioid withdrawal that harm a fetus. Treatment withdrawal that harm a fetus. Treatment providers should titrate the naloxone dose providers should titrate the naloxone dose against withdrawal symptoms and use a against withdrawal symptoms and use a short-acting opioid to reverse acute short-acting opioid to reverse acute withdrawal symptoms (Archie, 1998). withdrawal symptoms (Archie, 1998).

Managing Withdrawal from Managing Withdrawal from MethadoneMethadone

Withdrawal from methadone, called medically Withdrawal from methadone, called medically supervised withdrawal (MSW) or dose tapering, is not supervised withdrawal (MSW) or dose tapering, is not recommended for pregnant women.recommended for pregnant women.

When it is considered, a thorough assessment is When it is considered, a thorough assessment is important to determine whether a woman is an important to determine whether a woman is an appropriate candidate for MSW because the appropriate candidate for MSW because the procedure frequently results in relapse to opiate use.procedure frequently results in relapse to opiate use.

Appropriate candidates for MSW include women who:Appropriate candidates for MSW include women who: Live where methadone is unavailableLive where methadone is unavailable Have been stable in MAT and request MSW before deliveryHave been stable in MAT and request MSW before delivery Refuse to be maintained on methadoneRefuse to be maintained on methadone Plan to undergo MSW through a structured treatment Plan to undergo MSW through a structured treatment

program (Archie 1998, Kaltenbach et al. 1998program (Archie 1998, Kaltenbach et al. 1998

Managing Withdrawal Managing Withdrawal from Methadonefrom Methadone

A patient who elects to withdraw should do so only under A patient who elects to withdraw should do so only under supervision by a physician experienced in perinatal supervision by a physician experienced in perinatal addiction treatment with fetal monitoring.addiction treatment with fetal monitoring.

Usually done in the second trimester (consensus panel Usually done in the second trimester (consensus panel has found no systematic studies on whether withdrawal has found no systematic studies on whether withdrawal should be initiated only during the second trimester)should be initiated only during the second trimester)

If MSW is undertaken, methadone should be decreased by 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 1.0 to 2.5 mg/day for inpatients and by 2.5 to 10.0 mg per week for outpatients.week for outpatients.

Fetal movement should be monitored twice daily in Fetal movement should be monitored twice daily in outpatients, and stress tests should be performed at least outpatients, and stress tests should be performed at least twice a week; MSW should be discontinued if causes fetal twice a week; MSW should be discontinued if causes fetal distress or threatens to cause pre-term labor.distress or threatens to cause pre-term labor.

Postpartum Treatment of Postpartum Treatment of Mothers in MATMothers in MAT

Methadone should be continued after delivery Methadone should be continued after delivery either at dosages similar to those before either at dosages similar to those before pregnancy.pregnancy.

For women who began methadone during For women who began methadone during pregnancy, at approximately ½ the dosages pregnancy, at approximately ½ the dosages they received in the third trimester.they received in the third trimester.

No empirical data support these approaches, No empirical data support these approaches, and any decrease should be based on signs of and any decrease should be based on signs of over-medication, withdrawal symptoms, or over-medication, withdrawal symptoms, or patient blood plasma levels (Kaltenbach et al. patient blood plasma levels (Kaltenbach et al. 1998)1998)

Breastfeeding on Methadone

Alex Grey“Nursing”1985Oil on Linen

Breast-FeedingBreast-Feeding Mothers maintained on methadone can breast-feed if they Mothers maintained on methadone can breast-feed if they

are not HIV positive, are not abusing substances, and do are not HIV positive, are not abusing substances, and do not have a disease or infection in which breast-feeding is not have a disease or infection in which breast-feeding is contraindicated (Kaltenbach et al. 1993).contraindicated (Kaltenbach et al. 1993).

Hepatitis C is no longer considered a contraindication for Hepatitis C is no longer considered a contraindication for breast-feeding.breast-feeding.

The AAP has a long-standing recommendation that The AAP has a long-standing recommendation that methadone is compatible with breast-feeding only if methadone is compatible with breast-feeding only if mothers receive no more than 20mg in 24 hours.mothers receive no more than 20mg in 24 hours.

Studies have found minimal transmission of methadone in Studies have found minimal transmission of methadone in breast milk, regardless of maternal dose (Geraghty et al. breast milk, regardless of maternal dose (Geraghty et al. 1997)1997)

McCarthy and Posey (2000) found only small amounts of McCarthy and Posey (2000) found only small amounts of methadone in breast milk of women maintained on daily methadone in breast milk of women maintained on daily doses up to 180 mg and argued the 20mg/day limit.doses up to 180 mg and argued the 20mg/day limit.

Breast-Feeding Breast-Feeding Methadone doses of 25 to 180 mg/d → milk Methadone doses of 25 to 180 mg/d → milk

concentrations in milk from 27 to 260 ng/ml.concentrations in milk from 27 to 260 ng/ml. Based on estimated milk intake of 500 ml/d in an infant, Based on estimated milk intake of 500 ml/d in an infant,

average daily methadone ingestion is 0.05 mg.average daily methadone ingestion is 0.05 mg. In an 11 lb baby, the ingested amount is thus less than In an 11 lb baby, the ingested amount is thus less than

1% of the maternal weight-adjusted dose.1% of the maternal weight-adjusted dose. Methadone clearance in neonates is slower than adults, Methadone clearance in neonates is slower than adults,

but the infant dose will not exceed 5% of the maternal but the infant dose will not exceed 5% of the maternal weight-adjusted dose (Glatstein et al. 2008 Canadian weight-adjusted dose (Glatstein et al. 2008 Canadian Family Physician 54(12): 1689-90.Family Physician 54(12): 1689-90.

AAP RecommendationsAAP Recommendations 1994: doses > 20mg/day contraindicated1994: doses > 20mg/day contraindicated 2001: methadone, regardless of dose, removed from 2001: methadone, regardless of dose, removed from

the contraindicated list, data supported.the contraindicated list, data supported. Breastfeeding shouldn’t impact dosing decisions.Breastfeeding shouldn’t impact dosing decisions.

Perinatal OutcomesPerinatal Outcomes Older Studies comparing infants born to Older Studies comparing infants born to

women addicted to heroin but not receiving women addicted to heroin but not receiving methadone with infants born to women methadone with infants born to women receiving methadone found reduced fetal receiving methadone found reduced fetal mortality and greater birth weights of mortality and greater birth weights of infants maintained on methadone.infants maintained on methadone.

Another older study by Kalenbach and Another older study by Kalenbach and Finnegan (1987) with 268 infants found Finnegan (1987) with 268 infants found that infants born to opiate addicted women that infants born to opiate addicted women on methadone had lower birth weights and on methadone had lower birth weights and smaller head circumferences than those not smaller head circumferences than those not exposed to drugs, but the former are not exposed to drugs, but the former are not growth restricted.growth restricted.

Behavioral Assessment Behavioral Assessment ComparisonsComparisons

Researchers (Chasnoff et al. 1984) who used the Researchers (Chasnoff et al. 1984) who used the Brazelton Neonatal Behavioral Assessment Scale to Brazelton Neonatal Behavioral Assessment Scale to investigate neuro-behavioral characteristics in investigate neuro-behavioral characteristics in newborns undergoing opioid withdrawal have found newborns undergoing opioid withdrawal have found consistent behavior differences between these infants consistent behavior differences between these infants and those born to women not opiate addicted. and those born to women not opiate addicted.

Infants exposed to opioids were more irritable, Infants exposed to opioids were more irritable, exhibited more tremors, and had increased muscle tone.exhibited more tremors, and had increased muscle tone.

Other studies have shown less responsiveness to visual Other studies have shown less responsiveness to visual stimuli and reduced alertness among infants exposed to stimuli and reduced alertness among infants exposed to opioids. opioids.

Important are the implications for mother-infant Important are the implications for mother-infant interactions. In the consensus panel’s experience, these interactions. In the consensus panel’s experience, these infants are frequently difficult to nurture, causing poor infants are frequently difficult to nurture, causing poor mother-infant bonding, which Hoegerman and mother-infant bonding, which Hoegerman and colleagues (1990) suggested might be the most colleagues (1990) suggested might be the most significant aspect of perinatal addiction.significant aspect of perinatal addiction.

Developmental SequelaeDevelopmental Sequelae Research findings on developmental sequelae associated Research findings on developmental sequelae associated

with in utero methadone exposure are diverse but most with in utero methadone exposure are diverse but most studies suggest that infants through 2 year-olds function studies suggest that infants through 2 year-olds function well within the normal developmental range. They do well within the normal developmental range. They do not differ in cognitive function from a population that not differ in cognitive function from a population that was not drug exposed and was of comparable was not drug exposed and was of comparable socioeconomic and racial background (Kaltenbach socioeconomic and racial background (Kaltenbach 1996). 1996).

Another study by Lifeschitz and associates (1985) found Another study by Lifeschitz and associates (1985) found no significant developmental differences between no significant developmental differences between children of mothers maintained on methadone and children of mothers maintained on methadone and children of mothers using heroin or no opioids, when children of mothers using heroin or no opioids, when sociodemographic, biological, and other health factors sociodemographic, biological, and other health factors were considered. were considered.

Other data have suggested that maternal drug use is not Other data have suggested that maternal drug use is not the most important factor in how opioid-exposed infants the most important factor in how opioid-exposed infants and children develop but that family characteristics and and children develop but that family characteristics and functioning play a significant role (Johnson et al. 1987).functioning play a significant role (Johnson et al. 1987).

Developmental SequelaeDevelopmental Sequelae

One long-term follow-up study of 27 One long-term follow-up study of 27 children who had been exposed to children who had been exposed to methadone in utero found no cognitive methadone in utero found no cognitive impairment in preschool years impairment in preschool years (Kaltenbach et al. 1998).(Kaltenbach et al. 1998).

Overall, prenatal exposure to methadone Overall, prenatal exposure to methadone provided as part of comprehensive provided as part of comprehensive treatment does not appear to be treatment does not appear to be associated with developmental or associated with developmental or cognitive impairments (Kaltenbach 1996).cognitive impairments (Kaltenbach 1996).

Neonatal Abstinence Neonatal Abstinence Syndrome (NAS)Syndrome (NAS)

Exposure to opiates like heroin and methadone in utero Exposure to opiates like heroin and methadone in utero can result in NAS characterized by:can result in NAS characterized by: Hyperirritablity of the CNS Hyperirritablity of the CNS Dysfunction in the autonomic nervous systemDysfunction in the autonomic nervous system Dysfunction in the GI tract, vomitingDysfunction in the GI tract, vomiting Dysfunction in the respiratory system, respiratory Dysfunction in the respiratory system, respiratory

distressdistress feverfever

When left untreated, NAS can result in serious illness When left untreated, NAS can result in serious illness (e.g. diarrhea, feeding difficulties, weight loss, and (e.g. diarrhea, feeding difficulties, weight loss, and seizures).seizures).

Methadone-associated NAS can require prolonged Methadone-associated NAS can require prolonged hospitalization, pharmacologic intervention, and hospitalization, pharmacologic intervention, and monitoringmonitoring

With appropriate pharmacotherapy, NAS can be treated With appropriate pharmacotherapy, NAS can be treated effectively.effectively.

NASNAS Infants prenatally exposed to opioids have a high Infants prenatally exposed to opioids have a high

incidence of NAS, characterized by hyperactivity of the incidence of NAS, characterized by hyperactivity of the central and autonomic nervous systems that is reflected central and autonomic nervous systems that is reflected in changes in the GI tract and respiratory system.in changes in the GI tract and respiratory system.

Infants with NAS often suck frantically on their fists or Infants with NAS often suck frantically on their fists or thumbs but may have extreme difficulty feeding because thumbs but may have extreme difficulty feeding because their sucking reflex is uncoordinated.their sucking reflex is uncoordinated.

Withdrawal symptoms may begin from minutes or hours Withdrawal symptoms may begin from minutes or hours after birth to 2 weeks later, but most appear within 72 after birth to 2 weeks later, but most appear within 72 hours, hours, not related to dose of methadone.

Preterm infants usually have milder symptoms and Preterm infants usually have milder symptoms and delayed onset.delayed onset.

Buprenorphine NAS less severe than methadone NAS

Factors that influence Factors that influence NASNAS

Types of substances used by the mothersTypes of substances used by the mothers Timing and dosages of methadone before Timing and dosages of methadone before

deliverydelivery Characteristics of labor, type and amount Characteristics of labor, type and amount

of anesthesia or analgesic during laborof anesthesia or analgesic during labor Infant maturity and nutrition, metabolic Infant maturity and nutrition, metabolic

rate of the infant’s liver, and presence of rate of the infant’s liver, and presence of intrinsic disease in infants.intrinsic disease in infants.

Characteristics of NASCharacteristics of NAS NAS may be mild or transient, delayed in onset or NAS may be mild or transient, delayed in onset or

incremental in severity, or biphasic in its course, incremental in severity, or biphasic in its course, including acute neonatal withdrawal signs followed by including acute neonatal withdrawal signs followed by improvement and then onset of subacute withdrawal improvement and then onset of subacute withdrawal (Kaltenbach et al. 1998).(Kaltenbach et al. 1998).

Other conditions may mimic NAS, such as hypoglycemia, Other conditions may mimic NAS, such as hypoglycemia, hypocalcemia, sepsis, and neurologic illnesses.hypocalcemia, sepsis, and neurologic illnesses.

To rule out such conditions, infants should have a CBC To rule out such conditions, infants should have a CBC with diff, electrolyte and calcium levels, comprehensive with diff, electrolyte and calcium levels, comprehensive neurologic consultation and head ultrasound if indicated.neurologic consultation and head ultrasound if indicated.

NAS can be more severe or prolonged with methadone’s NAS can be more severe or prolonged with methadone’s longer half-life, with appropriate pharmacotherapy, NAS longer half-life, with appropriate pharmacotherapy, NAS can be treated without any severe neonatal effects.can be treated without any severe neonatal effects.

Abstinence ScoringAbstinence Scoring An abstinence scoring system should be used to An abstinence scoring system should be used to

monitor opioid-exposed newborns to assess the monitor opioid-exposed newborns to assess the onset, progression, and resolution of symptoms.onset, progression, and resolution of symptoms.

The NAS Score (Finnegan and Kaltenbach 1992 The NAS Score (Finnegan and Kaltenbach 1992 used widely toused widely to estimate NAS severityestimate NAS severity Determine whether pharmacotherapy is neededDetermine whether pharmacotherapy is needed Monitor the optimum response to therapyMonitor the optimum response to therapy

All infants of mothers with an opioid use history All infants of mothers with an opioid use history should be scored every 4 hours.should be scored every 4 hours.

Control is achieved when the average NAS Score Control is achieved when the average NAS Score is less than 8, infants exhibit rhythmic feeding and is less than 8, infants exhibit rhythmic feeding and sleep cycles, and have optimal weight gains.sleep cycles, and have optimal weight gains.

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) – 1999-2005 N=224 with delivery dose N=215 with conversion time

Outcomes: Maternal & Fetal Outcomes (n=252) %

Fewer than 7 OB visits 8.3

Meconium staining 8.7

Abnormal fetal heart rate/rhythm or distress

15.1

Chorioamnionitis 6.0

Still born 0.8

Outcome (n=252)

Birth weight (g), mean (sd) 2788 (690)

Gestational age (wks), mean (sd) 37.4 (3.3)

Preterm birth, % 27.4

Small for gestational age, % 26.3

NICU admission 55.6

NICU admission for NAS, % ** 41.3

NICU admit other reason 14.3

In-hospital death rate, % 1.6

Methadone Dose Distribution

Quartiles

< 60 mg

60-79 mg

80-99 mg

> 100 mg

Timing of Methadone Conversion

0

5

10

15

20

25

30

35

BeforePregnancy

1st Trimester 2nd Trimester 3rd Trimester

Conversion to methadone

Per

cent

N=215

Infant Outcome by Methadone Dose

* Linear-by-linear Association (exact significance)Multinomial Logistic Regression: dose <60 mg/d lower odds of SGA

p=.01

p=.3

p=.06

0

10

20

30

40

50

60

70

SGA Preterm Admit to NICU NAS

Pe

rce

nt

<60 mg/d 60-79 mg/d 80-99 mg/d > 100 mg/d

p=0.04*p = ns

p = nsp = ns

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

Dosage of Methadone Dosage of Methadone and NASand NAS In a retrospective review of pregnancies that were In a retrospective review of pregnancies that were

maintained on methadone therapy in one hospital, 100 maintained on methadone therapy in one hospital, 100 mother/neonate pairs on methadone therapy were mother/neonate pairs on methadone therapy were identified.identified.

Women who received an average methadone dose of Women who received an average methadone dose of greater than 80 mg were similar to women maintained greater than 80 mg were similar to women maintained on dosages of less than or equal to 80 mg in:on dosages of less than or equal to 80 mg in: Having infants with similar NAS ScoresHaving infants with similar NAS Scores Needs for neonatal treatment for withdrawalNeeds for neonatal treatment for withdrawal Similar duration of withdrawal when it occurred in Similar duration of withdrawal when it occurred in

the neonate.the neonate. The authors concluded that maternal methadone dosage The authors concluded that maternal methadone dosage

does not correlate with neonatal withdrawal; therefore does not correlate with neonatal withdrawal; therefore maternal benefits of effective methadone dosing are not maternal benefits of effective methadone dosing are not offset by neonatal harm.offset by neonatal harm.

Methadone Dosage and Methadone Dosage and NASNAS

The relationship between maternal The relationship between maternal methadone dosage and NAS has been methadone dosage and NAS has been difficult to establish, and the consensus difficult to establish, and the consensus panel believes no compelling evidence panel believes no compelling evidence shows that methadone reduction avoids shows that methadone reduction avoids NAS.NAS.

Although a number of investigators have Although a number of investigators have reported significant relationships between reported significant relationships between neonatal withdrawal and maternal neonatal withdrawal and maternal methadone dosage, MOST have found no methadone dosage, MOST have found no such relationship.such relationship.

Methadone Dosage and Methadone Dosage and NASNAS

Another study with maternal maintenance Another study with maternal maintenance dosage found that NAS was related to the dosage found that NAS was related to the mother’s dose of methadone (McCarthy 2005).mother’s dose of methadone (McCarthy 2005).

Opiate dependent pregnant patients receiving Opiate dependent pregnant patients receiving mean methadone doses of 132 mg had less illicit mean methadone doses of 132 mg had less illicit drug use at delivery, but their neonates had drug use at delivery, but their neonates had more severe NAS than expectant mothers more severe NAS than expectant mothers receiving mean doses of 62 mg of methadone.receiving mean doses of 62 mg of methadone.

The conclusion of this study and another study The conclusion of this study and another study (Jones et al. 2008) is that pregnant women (Jones et al. 2008) is that pregnant women should receive appropriate methadone doses to should receive appropriate methadone doses to treat their addiction, but concerns regarding treat their addiction, but concerns regarding greater NAS severity associated with larger greater NAS severity associated with larger doses of methadone should not be the primary doses of methadone should not be the primary factor in determining dose. factor in determining dose.

BuprenorphineBuprenorphine

Classified as a category C drug by the Classified as a category C drug by the FDA and is not FDA approved to treat FDA and is not FDA approved to treat pregnant womenpregnant women

Several studies have found it safe and Several studies have found it safe and effective in this group (Fischer et al. effective in this group (Fischer et al. 2000; Lacroix et al. 2004)2000; Lacroix et al. 2004)

Even though it is a category C drug, Even though it is a category C drug, buprenorphine may be used with buprenorphine may be used with pregnant patients in the US under pregnant patients in the US under certain circumstancescertain circumstances

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

Principles of Principles of Pharmacotherapy with Pharmacotherapy with

Buprenorphine (Subutex)Buprenorphine (Subutex) Antagonist / High receptor affinityAntagonist / High receptor affinity Highest receptor affinity and receptor occupancy: Highest receptor affinity and receptor occupancy:

95% occupancy at 16 mg (Greenwald et al, 2003)95% occupancy at 16 mg (Greenwald et al, 2003) Blockade or attenuate effect of other opioidsBlockade or attenuate effect of other opioids Rapid onset of action and risk of acute opioid reversalRapid onset of action and risk of acute opioid reversal

Partial receptor agonist / Low Intrinsic ActivityPartial receptor agonist / Low Intrinsic Activity Lower physical dependenceLower physical dependence Limited development of toleranceLimited development of tolerance Ceiling effect on respiratory depressionCeiling effect on respiratory depression

Long Acting / Slow dissociation from receptorLong Acting / Slow dissociation from receptor Long duration of actionLong duration of action Milder withdrawalMilder withdrawal

BuprenorpineBuprenorpine Not FDA approved for use in pregnancy/Category C Not FDA approved for use in pregnancy/Category C

(widely used in Europe)(widely used in Europe) Pharmacokinetics of buprenorphine not well understood Pharmacokinetics of buprenorphine not well understood

in pregnancy or in the fetus.in pregnancy or in the fetus. Typical dosing is 8mg to 24mg daily and generally Typical dosing is 8mg to 24mg daily and generally

requires few adjustments in pregnancyrequires few adjustments in pregnancy Highly receptor bound so less affected by increased Highly receptor bound so less affected by increased

metabolic rate and larger blood/tissue volume. metabolic rate and larger blood/tissue volume. Recommended buprenorphine monotherapy only Recommended buprenorphine monotherapy only

(Subutex), no benefit to divided dosing.(Subutex), no benefit to divided dosing. A partial mu-opioid agonist and kappa-opioid antagonist, A partial mu-opioid agonist and kappa-opioid antagonist,

effectively treats opioid dependence.effectively treats opioid dependence. Is low intrinsic receptor efficacy results in less-than-Is low intrinsic receptor efficacy results in less-than-

maximal opioid effect a diminished risk of overdose, as maximal opioid effect a diminished risk of overdose, as compared with methadone.compared with methadone.

In non-pregnant adults, the effects of abrupt withdrawal In non-pregnant adults, the effects of abrupt withdrawal of buprenorphine are minimal relative to the effects of of buprenorphine are minimal relative to the effects of withdrawal of full mu-opioid agonists.withdrawal of full mu-opioid agonists.

Buprenorphine:Buprenorphine: Pharmacological advantages led to Pharmacological advantages led to

prospective open-label and controlled studies prospective open-label and controlled studies of its use in prenatal treatment.of its use in prenatal treatment.

The results of some of these studies The results of some of these studies suggested that neonates exposed to suggested that neonates exposed to buprenorphine might be less likely to require buprenorphine might be less likely to require treatment for NAS than those exposed to treatment for NAS than those exposed to methadone.methadone.

These studies have had inconsistent results These studies have had inconsistent results with respect to NAS outcomes.with respect to NAS outcomes.

Improved pregnancy outcomes seen with Improved pregnancy outcomes seen with methadone appear to be duplicated on methadone appear to be duplicated on buprenorphine.buprenorphine.

BuprenorphineBuprenorphine There have been 31 published reports of There have been 31 published reports of

buprenorphine, a partial-mu opioid agonist, buprenorphine, a partial-mu opioid agonist, exposure during pregnancy that were reviewed and exposure during pregnancy that were reviewed and summarized (Jones et al. 2008).summarized (Jones et al. 2008).

Overall, the studies report approximately 522 Overall, the studies report approximately 522 neonates prenatally exposed to buprenorphine, with neonates prenatally exposed to buprenorphine, with a wide range of therapeutic doses from 0.4 to 24 mg a wide range of therapeutic doses from 0.4 to 24 mg sublingual tablets/day. sublingual tablets/day.

Generally, the pregnancies were uneventful, Generally, the pregnancies were uneventful, without physical teratogenic effects, and with low without physical teratogenic effects, and with low rates of prematurity, suggesting that buprenorphine rates of prematurity, suggesting that buprenorphine is relatively safe and effective for this populationis relatively safe and effective for this population..

BuprenorphineBuprenorphine

Despite significant variability in the Despite significant variability in the instruments and scoring methods instruments and scoring methods used, the literature suggests that used, the literature suggests that buprenorphine exposure is also buprenorphine exposure is also associated with NAS, half the cases associated with NAS, half the cases of which require pharmacotherapy.of which require pharmacotherapy.

The pregnancy, birth and NAS The pregnancy, birth and NAS outcomes are also confounded by outcomes are also confounded by other drug use in 86% of the reports.other drug use in 86% of the reports.

BuprenorphineBuprenorphine Although considerable individual variability exists, the NAS Although considerable individual variability exists, the NAS

timing observed to date has an apparent onset within the timing observed to date has an apparent onset within the first 12 to 48 hours, peaks within approx 66 to 96 hours, first 12 to 48 hours, peaks within approx 66 to 96 hours, and lasts approx 120 to 168 hoursand lasts approx 120 to 168 hours

A few infants exhibited withdrawal 6 to 10 weeks after A few infants exhibited withdrawal 6 to 10 weeks after delivery (NAS medication and regimen related?)delivery (NAS medication and regimen related?)

To date, only one report found a correlation between To date, only one report found a correlation between buprenorphine dose and the severity of the NAS (Marquet buprenorphine dose and the severity of the NAS (Marquet et al. 2002). Other recent reports, including one with a et al. 2002). Other recent reports, including one with a large sample size (Lejeune et al. 2006) have reported no large sample size (Lejeune et al. 2006) have reported no correlation.correlation.

Overall, buprenorphine associated NAS was found to be Overall, buprenorphine associated NAS was found to be less intense than that associated with methadone (Johnson less intense than that associated with methadone (Johnson et al. 2003a)et al. 2003a)

MOTHER ProjectMOTHER Project Given the calls to increase representation of Given the calls to increase representation of

pregnant women in medication research, the pregnant women in medication research, the Maternal Opioid Treatment: Human Maternal Opioid Treatment: Human Experimental Research (MOTHER) project was Experimental Research (MOTHER) project was initiated.initiated.

A multicenter, randomized, controlled trial A multicenter, randomized, controlled trial comparing buprenorphine with methadone for comparing buprenorphine with methadone for the treatment of opioid-dependent pregnant the treatment of opioid-dependent pregnant patients.patients.

Prior to this only 2 randomized, double-blind Prior to this only 2 randomized, double-blind studies have been conducted comparing studies have been conducted comparing methadone with buprenorphine (Fisher et al. methadone with buprenorphine (Fisher et al. 2006; Jones et al. 2005).2006; Jones et al. 2005).

New Study! New Study! Neonatal Abstinence Syndrome after Methadone or Neonatal Abstinence Syndrome after Methadone or

Buprenorphine Exposure, Jones et. Al 2010, New Buprenorphine Exposure, Jones et. Al 2010, New England Journal of Medicine.England Journal of Medicine.

A double blind, double dummy, flexible-dosing, A double blind, double dummy, flexible-dosing, randomized, controlled study in which buprenorphine randomized, controlled study in which buprenorphine and methadone were compared for use in the and methadone were compared for use in the comprehensive care of 175 pregnant women with comprehensive care of 175 pregnant women with opioid dependency at 8 international sites.opioid dependency at 8 international sites.

Primary outcomes were:Primary outcomes were: The number of neonates requiring treatment for The number of neonates requiring treatment for

NASNAS The peak NAS scoreThe peak NAS score The total amount of morphine needed to treat NASThe total amount of morphine needed to treat NAS The length of the hospital stay for neonatesThe length of the hospital stay for neonates Neonatal head circumferenceNeonatal head circumference

Results:Results: A comparison of the 131 neonates whose A comparison of the 131 neonates whose

mothers were followed to the end of pregnancy mothers were followed to the end of pregnancy according to treatment group (with 58 exposed according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) to buprenorphine and 73 exposed to methadone) showed the buprenorphine group showed the buprenorphine group Required significantly less morphine (mean dose, 1.1 Required significantly less morphine (mean dose, 1.1

mg vs. 10.4 mg)mg vs. 10.4 mg) Had a significantly shorter hospital stay (10.0 days vs. Had a significantly shorter hospital stay (10.0 days vs.

17.5 days)17.5 days) Had a significantly shorter duration of treatment for the Had a significantly shorter duration of treatment for the

NAS (4.1 days vs. 9.9 days)NAS (4.1 days vs. 9.9 days) There were no significant differences between There were no significant differences between

the groups in other primary or secondary the groups in other primary or secondary outcomes or in the rates of maternal or neonatal outcomes or in the rates of maternal or neonatal adverse events. adverse events.

Measured Neonatal Study Measured Neonatal Study OutcomesOutcomes

Primary Neonatal Primary Neonatal OutcomesOutcomes

Number of neonates Number of neonates requiring treatment requiring treatment for NASfor NAS

Peak NAS scorePeak NAS score Total amount of Total amount of

morphine needed for morphine needed for treatment of NAStreatment of NAS

Length of Hospital Length of Hospital StayStay

Head circumferenceHead circumference

Secondary Neonatal Secondary Neonatal OutcomesOutcomes

Number of days during Number of days during which medication was which medication was given for NASgiven for NAS

Weight and length at Weight and length at birthbirth

Preterm birth (< 37 Preterm birth (< 37 weeks gestation)weeks gestation)

Gestational age at Gestational age at deliverydelivery

1 and 5 minute APGAR 1 and 5 minute APGAR scoresscores

Measured Maternal Measured Maternal OutcomesOutcomes

Cesarean sectionCesarean section Weight gainWeight gain Abnormal fetal presentation during Abnormal fetal presentation during

deliverydelivery Anesthesia during deliveryAnesthesia during delivery Results of drug screening at deliveryResults of drug screening at delivery Medical complications at deliveryMedical complications at delivery Study discontinuationStudy discontinuation Amount of voucher money earned for Amount of voucher money earned for

drug-negative testsdrug-negative tests Number of prenatal obstetrical visitsNumber of prenatal obstetrical visits

Primary Outcomes with no Primary Outcomes with no significant differences:significant differences:

The percentage of neonates The percentage of neonates requiring NAS treatment did not requiring NAS treatment did not differ significantly between groups differ significantly between groups (57% vs. 47%).(57% vs. 47%).

The groups did not differ The groups did not differ significantly with respect to the peak significantly with respect to the peak NAS score (12.8 vs. 11.0).NAS score (12.8 vs. 11.0).

There was not a significant There was not a significant difference in the infant’s head difference in the infant’s head circumference (33.0 vs. 33.8).circumference (33.0 vs. 33.8).

Primary Outcomes with Primary Outcomes with significant differences:significant differences:

The mean total dose amount of morphine The mean total dose amount of morphine needed for the treatment of NAS averaged needed for the treatment of NAS averaged 10.4 mg in the methadone group and 1.1 mg 10.4 mg in the methadone group and 1.1 mg in the buprenorphine group.in the buprenorphine group.

On average, neonates exposed to On average, neonates exposed to buprenorphine required 89% less morphine buprenorphine required 89% less morphine than did neonates exposed to methadone.than did neonates exposed to methadone.

The average amount of days for the infant’s The average amount of days for the infant’s stay in the hospital was 17.5 vs 10.0 days, so stay in the hospital was 17.5 vs 10.0 days, so infants born to mother’s on buprenorphine infants born to mother’s on buprenorphine spent on average 43% less time in the spent on average 43% less time in the hospital. hospital.

Secondary Outcomes with Secondary Outcomes with significant differences:significant differences:

One of the 7 neonatal outcomes One of the 7 neonatal outcomes differed in that neonates exposed to differed in that neonates exposed to buprenorphine spent, on average, buprenorphine spent, on average, 58% less time in the hospital 58% less time in the hospital receiving medication for NAS than receiving medication for NAS than did those exposed to methadone (4.1 did those exposed to methadone (4.1 days vs. 9.9 days). days vs. 9.9 days).

There were no significant There were no significant differences in any of the nine differences in any of the nine maternal secondary outcomes. maternal secondary outcomes.

In Summary:In Summary: In this randomized, double-blind trial:In this randomized, double-blind trial:

Infants who had prenatal exposure to buprenorphine Infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment required significantly less morphine for the treatment of NAS.of NAS.

Buprenorphine infants had significantly shorter period Buprenorphine infants had significantly shorter period of NAS treatment.of NAS treatment.

Buprenorphine infants had a significantly shorter Buprenorphine infants had a significantly shorter hospital stay than did infants with prenatal exposure hospital stay than did infants with prenatal exposure to methadone. to methadone.

The superiority of buprenorphine over methadone did not The superiority of buprenorphine over methadone did not extend to differences in the number of neonates requiring extend to differences in the number of neonates requiring NAS treatment, peak NAS score, head circumference, NAS treatment, peak NAS score, head circumference, any other neonatal outcome, or any maternal outcome.any other neonatal outcome, or any maternal outcome.

In Summary:In Summary: Methadone has been the recommended standard of care for opioid-Methadone has been the recommended standard of care for opioid-

dependent pregnant women, and this double blind study provides dependent pregnant women, and this double blind study provides critical data on the outcomes of methadone treatment.critical data on the outcomes of methadone treatment.

Findings support the safety and usefulness of methadone Findings support the safety and usefulness of methadone treatment for opioid dependence during pregnancy, and shows treatment for opioid dependence during pregnancy, and shows that the treatment of opioid-dependent pregnant women with that the treatment of opioid-dependent pregnant women with buprenorphine results in a clinically meaningful reduction in the buprenorphine results in a clinically meaningful reduction in the severity of NAS in their neonates, as compared with methadone. severity of NAS in their neonates, as compared with methadone.

Also, findings that there was no significant differences between the Also, findings that there was no significant differences between the treatment groups in rates of opioid use during treatment is treatment groups in rates of opioid use during treatment is consistent with observations in previous randomized trials consistent with observations in previous randomized trials involving non-pregnant patients that methadone and involving non-pregnant patients that methadone and buprenorphine cause similar reductions in illicit opioid use AND buprenorphine cause similar reductions in illicit opioid use AND both medications, in the context of comprehensive care, do not both medications, in the context of comprehensive care, do not differ markedly in their effect on maternal treatment outcomes at differ markedly in their effect on maternal treatment outcomes at delivery. delivery.

In Summary:In Summary: Findings are consistent with the use of buprenorphine as Findings are consistent with the use of buprenorphine as

an alternative to methadone for the treatment of opioid an alternative to methadone for the treatment of opioid dependency during pregnancy.dependency during pregnancy.

Although there were no significant differences in the Although there were no significant differences in the overall rates of NAS among infants exposed to overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that NAS among neonates with this complication suggest that it should be considered a first-line treatment option in it should be considered a first-line treatment option in pregnancy.pregnancy.

In selecting a course of treatment, clinicians should take In selecting a course of treatment, clinicians should take into account the possibility of reduced adherence and into account the possibility of reduced adherence and ceiling effect of this medication as compared with ceiling effect of this medication as compared with methadone. methadone.

Breast-Feeding During Breast-Feeding During BuprenorphineBuprenorphine

Research has indicated that only small amounts Research has indicated that only small amounts of buprenorphine and buprenorphine-naloxone of buprenorphine and buprenorphine-naloxone pass into breast milk, with little or no effect on pass into breast milk, with little or no effect on infants (Johnson et al. 2001).infants (Johnson et al. 2001).

Studies show buprenorphine is likely to be Studies show buprenorphine is likely to be poorly absorbed by infants via the oral route.poorly absorbed by infants via the oral route.

The consensus panel for TIP 43 recommends The consensus panel for TIP 43 recommends that women maintained on buprenorphine be that women maintained on buprenorphine be encouraged to breast-feed because of benefits encouraged to breast-feed because of benefits to infants and mother-child interaction.to infants and mother-child interaction.