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John McCarthy, M.D.
Medical Director, BAART/Bi-Valley Medical
Clinic, Sacramento
Associate Professor of Psychiatry, UC Davis
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Open Letter to the Media and Policy Makers
Regarding Alarmist and Inaccurate Reporting
on Prescription Opiate Use by Pregnant
Women
March 11, 2013
National Advocates for Pregnant Women, 15
West 36th Street, Suite 901, New York, NY
10018
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Between 2000-2009 antepartum opiate use
increased five fold in pregnant women
(Patrick et al JAMA 2012)
Neonatal abstinence increased nearly three
fold. (Patrick et al)
Most of this increase reflects prescription
opiate abuse/addiction.
The average age on admission to Bi-Valley
programs went from 42 to under 30 years in
the space of about 5 years. About 40% of
young admissions are women
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Fetal and neonatal mortality from untreated heroin
addiction was 10% (Fricker and Segal, 1978)
Fetal and neonatal demise from maternal heroin
addiction was 4 times general population: 12 stillbirths
and 25 neonatal deaths among 792 cases. Autopsy: focal
CNS hemorrhages from fetal hypoxia during opiate
withdrawal (Rementeria and Nunag 1973)
During severe withdrawal, oxygen supply goes down,
oxygen demand goes up
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Is it to protect the fetus from methadone? Meaning
use low doses and/or reduced doses and have the
mother tough it out or even relapse to drug use.
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Or is it to protect the fetus from withdrawal?
Meaning treat maternal withdrawal with dose
increases to protect the fetus from intrauterine
abstinence and have a mother who is not chronically
sick.
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A recent meta-analysis of the relationship of methadone dose
to neonatal abstinence syndrome (NAS) reviewed 67 studies
(Cleary: 2010).
The last research study of human fetal opiate abstinence was
in 1975 (Zuspan)
The first summary of intrauterine abstinence syndrome (IAS):
2011 McCarthy (J Maternal Fetal Neonatal Medicine)
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Zuspan et al, reporting on the effects of a 1973 FDA
mandate that forced a 21-day withdrawal on all pregnant
women, documented one fetal death during withdrawal
which they attributed to this process “since violent
intrauterine movements preceded the still birth”
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They reported knowledge of four similar deaths.
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They then used serial amniotic fluid amine assays to monitor the
fetus during withdrawal. After methadone decreases of 5 and 3 mg,
epinephrine and norepinephrine values were 8–10 times higher than
baseline.
Because of the evidence of fetal stress, the dose was increased and
fetal catecholamine levels improved. Maternal catecholamine levels
were normal, indicating a purely fetal stress response.
The authors recommended against detoxification during pregnancy,
unless a scientific means is available to monitor fetal homeostasis.
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Cleary et al in a meta-analysis of 67 studies
of methadone dose and NAS found 4 different
approaches to dosing
1. withdrawal
2. maintenance on low doses
3. maintenance as needed and then reduced
doses
4. dose increases as needed to treat maternal
withdrawal
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Methadone is metabolized by hepatic enzymes (3A4,
2D6) for which there is significant genetic diversity
causing diversity in metabolic rates. The ½ life can
vary between 18-36 hrs.
Pregnancy accelerates methadone metabolism. It
converts women into rapid metabolizers.
CYP3A is consistently and significantly increased in
all stages of pregnancy. It may occur before the
woman is aware she is pregnant. Genetic testing is
now available.
The fetus is exposed only to the serum, not the oral
dose. If methadone is cleared rapidly then the dose
can be quite high (415mg, 70mg q4h) and yet fetal
exposure quite low, (e.g 90mg TID with trough
methadone below detection)
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May expose the fetus to daily episodes of
‘oversedation’ and withdrawal
An ultrasound study of single and split doses by
Whittmann and Segal found significant fetal
behavioral abnormalities on single dose
regimens, including percent of time spent
breathing, number of rotational body
movements, and longest period of fetal activity
prior to the AM dose.
These changes normalized on a BID regimen.
Cardiac parameters have also been shown to
normalize on BID regimen
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Reduces or eliminates fetal methadone peaks
and troughs which are not physiologic for the
fetus
May allow maintenance on lower doses
By reducing maternal withdrawal stress, it
makes for a healthier pregnancy
Reduces maternal anxiety about withdrawal
Reduces risks of relapse
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Average and mean dose 152mg/day, divided
between 3-6 times a day.
Drug of choice on admission 71%
prescription opiates (hydocodone or
oxycodone), 29% heroin
Average serum level 288ng/ml (therapeutic
range for trough levels is 200-600ng/ml)
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Mean gestational age 38.2 weeks (r 23-42)
Full term (N=51/62) 82%
Mean weight 2903 grms (6lb 8oz) (r 5643883)
Full term weight (N=51) 3119gm
92% of infant toxicology screens were
negative for illicit drugs
80% of neonates were nursed
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29% were treated for NAS (N=18/62)
The literature reports 50-80% of babies
exposed to methadone need treatment
LOS in hospital 10 days. Rx’d 22 days; not
Rx’d 3.8 days
25 female babies only 4 treated (16%) 37
male babies, 14 treated (38%)
Seiko in England reports a rate of treatment of
11%: the lowest rate of treatment ever reported.
Abrahams in Vancouver reports a treatment rate of
30%
Do neonates go into withdrawal from the mother?
(Maternal Absence Syndrome)
Do NICU environments exacerbate NAS?
How necessary are NICUs for NAS management?
Can NAS scoring be done with the mother present?
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Dutch War Baby syndrome
Fetal Origins Hypothesis (Barker)
Maternal stress increases fetal exposure to
stress hormones, adrenalin, corticosteroids,
which have been shown to have long term
adverse developmental consequences for the
child.
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Both mu opiate receptor agonists
Both cause continue physical dependence and
withdrawal risks
Both long acting with theoretical once a day
dosing. But multi-dosing regimens are necessary
in many patients
Both effective treatments for opiate addiction
Both may have beneficial psychotropic effects,
e.g. anti-anxiety, anti-depressant, anti-psychotic
effects that are not well understood or clarified
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Methadone is full opiate agonist; bup is a partial
agonist with a ceiling effect on respiratory
depression making bup safer in misuse or
overdose situations
Bup is an opiate antagonist (narcan like) when
other opiates are present. It can cause severe
precipitated withdrawal. Methadone has no such
risks and is therefore safer for induction.
Methadone is more effective in retaining patients
in treatment, at least for more severe addictions
Methadone has more side effects, e.g weight
gain, sweating, sedation
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Although there are some studies that suggest
bup has a milder withdrawal, there is no evidence
that there is any greater success with continued
recovery off the medication
At low doses (like what a fetus is exposed to)
both methadone and buprenorphine are full
opiate agonists! Withdrawal symptoms may be
similar.
Brain recovery involves endorphin and opiate
receptor synthesis and a physical recovery
process that may be unrelated to either
methadone or buprenorphine
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Bup seems to be more abusable, especially by IV
route.
Addition of naloxone (Suboxone) of questionable
efficacy in preventing abuse (Australian study),
but that is at least the political justification.
Buprenorphine is an easier treatment modality
for the patient to access because regulations are
minimal compared to methadone.
But treatment intensity and perhaps effectiveness
is better with methadone because of the added
structure and counseling.