Download Methadone in Pregnancy - Zero Exposure Project

Medication Assisted Treatment for
Opioid Dependence during
Pregnancy
Jason B. Fields MD
DACCO
University of Florida Addiction Medicine Fellow and
Medical Services Manager
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
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).
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.
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.
Benefits of Maintenance with
Opioid 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 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)
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).
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).
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.
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).
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).
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 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.
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.
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.
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.
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.
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
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
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.
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.
Common Obstetrical Complications Among
Women Addicted to Opioids (The fetus is at risk for
morbidity and mortality because of episodes of maternal withdrawal
compounded by a lack of prenatal care)








Abruptio placentae
Chorioamnionitis
Intrauterine death
IUGR
Intrauterine passage of
meconium
Low Apgar Scores
Placental insufficiency
Amnionitis






Postpartum hemorrhage
Preeclampsia
Premature labor/delivery
PROM
Septic thrombophlebitis
Spontaneous abortion,
especially first trimester
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.
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
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.
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.
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
Getting the Prenatal Dose Right: Induction and
Stabilization
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
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.
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.
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 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
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.
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 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).
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).
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.
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).
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
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.
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)
Breastfeeding on Methadone
Alex Grey
“Nursing”
1985
Oil on Linen
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 breastfeeding.
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.
Breast-Feeding






Methadone doses of 25 to 180 mg/d → milk concentrations in milk
from 27 to 260 ng/ml.
Based on estimated milk intake of 500 ml/d in an infant, average
daily methadone ingestion is 0.05 mg.
In an 11 lb baby, the ingested amount is thus less than 1% of the
maternal weight-adjusted dose.
Methadone clearance in neonates is slower than adults, but the infant
dose will not exceed 5% of the maternal weight-adjusted dose
(Glatstein et al. 2008 Canadian Family Physician 54(12): 1689-90.
AAP Recommendations
 1994: doses > 20mg/day contraindicated
 2001: methadone, regardless of dose, removed from the
contraindicated list, data supported.
Breastfeeding shouldn’t impact dosing decisions.
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.
Behavioral Assessment Comparisons




Researchers (Chasnoff et al. 1984) who used the Brazelton
Neonatal Behavioral Assessment Scale to investigate neurobehavioral 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.
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).
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).
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.
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
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.
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.
Abstinence Scoring




An abstinence scoring system should be used to monitor opioidexposed 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.
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)
%
Outcome (n=252)
Fewer than 7 OB visits
8.3
Birth weight (g), mean (sd)
2788 (690)
Meconium staining
8.7
Gestational age (wks), mean (sd)
37.4 (3.3)
Abnormal fetal heart
rate/rhythm or distress
15.1
Chorioamnionitis
6.0
Still born
0.8
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
35
30
Percent
25
20
15
10
5
0
Before
Pregnancy
N=215
1st Trimester
2nd Trimester
Conversion to methadone
3rd Trimester
Infant Outcome by Methadone Dose
<60 mg/d
60-79 mg/d
80-99 mg/d
> 100 mg/d
70
p = ns
60
Percent
50
40
p=.06
p = ns
p=.01
p=0.04*
p=.3
p = ns
30
20
10
0
SGA
Preterm
Admit to NICU
NAS
* Linear-by-linear Association (exact significance)
Multinomial Logistic Regression: dose <60 mg/d lower odds of SGA
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 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.
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.
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.
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
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 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
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.
Buprenorphine:




Pharmacological advantages led to prospective openlabel 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.
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.
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.
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)
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).
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
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. 10.4 mg)
Had a significantly shorter hospital stay (10.0 days vs. 17.5 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.
Measured Neonatal Study Outcomes
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
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
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
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).
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.
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.
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.
In Summary:



Methadone has been the recommended standard of care for opioiddependent 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 opioiddependent 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.
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.
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 motherchild interaction.