Caring for Infants with Neonatal
Abstinence Syndrome and their
Families
4-year experience from a
Primary Service Area in Maine
Acadia Hospital Grand Rounds
April 13, 2012
Mark S Brown MD MSPH
Eastern Maine Medical Center
Pediatrics and Neonatology
Roadmap
Where are we going today?
 Looking at the scope by the numbers
 Looking at the development of the infrastructure of a
comprehensive NAS Program





Prenatal counseling
Who gets screened
Confounders of withdrawal
Assessment of withdrawal – Scoring system
Treatment



Dropping routine phenobarbital use
Methadone versus morphine
Understanding variation in NAS treatment
 Breast feeding
 Importance of transitions to the community – an aftercare safety
net
 The continued challenge: Can we change their Legacy
 A Role for Infant Mental Health through enhancing
attachment and individualized infant sensitivity?
I HAVE NO
FINANCIAL DISCLOSURES
OR
CONFLICTS OF INTEREST
TO DECLARE
The Headwaters
Narcotic Replacement Therapy during Pregnancy
• Methadone
• Buprenorphine
– Long acting
– Prescribed daily
• Usually in liquid form
• Earn take-homes for up to a week
– No ceiling effect
• Better for those coming into
treatment during pregnancy
– Agonist
– Recommendation to NOT
wean during pregnancy
– Longer acting
• Subutex and Suboxone
– Prescribed for up to 30-day
take-homes
• IV, strips, and sublingual forms
– Ceiling effects on euphoria and
respiratory depression
• Better for those already on treatment
before pregnancy
– Agonist – antagonist
• Tight binding to μ receptor
– Recommendation to NOT
wean during pregnancy
The Downstream Impact
is on Healthcare Resources and Family
Treatment Rate by Prenatal Opioid Exposure
for Newborns Admitted to EMMC
>36 weeks, Nov 2007 - Nov 2011, N = 494
80%
69%
55%
60%
51%
40%
23%
20%
0%
Methadone
Buprenorphine
Prescribed Opiates
Illicit
Length of Stay when Treated
by Prenatal Opioid Exposure
>36 weeks, Nov 2007-Nov 2011, N = 263
30
26.3
20.8
20
19.4
Days
15.1
10
0
Methadone
Buprenorphine
Prescribed
Opiates
Illicit
Treatment of Neonatal
Abstinence Syndrome
• Non-pharmacologic:
–
–
–
–
Higher calorie nutrition to maintain weight gain within tolerance
Minimal stimulation environment
Swaddling/bundling
Rooming in
• Pharmacologic:
– Phenobarbital – sedative not an opiate replacement
• Does not treat gastrointestinal symptoms (cramps, vomiting or
diarrhea)
– Morphine
– Methadone
– Buprenorphine – not FDA approved
– Clonidine – alpha agonist
– NO Paregoric (contains many toxins)
US and UK Surveys about Treatment of NAS:
US N=75/102 and UK N = 215/235
Medications for First Line Treatment of NAS from Prenatal Opiate Exposure
100%
75%
50%
25%
US 2006
UK 2008
Be
nz
o
at
e
al
hy
dr
hl
or
C
Ph
en
ob
ar
bi
ta
l
et
ha
do
ne
M
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on
-m
et
ha
do
ne
op
ia
te
s
0%
EMMC
NICU
Pediatrics
Background
Let’s Look at the
Numbers
What’s the Trickle-down of the Increase in
Replacement Therapy for Mothers?
Annual Admissions of Opioid-Exposed Newborns
to Eastern Maine Medical Center
175
154
150
Discovery House
Opens 9/2007
125
Metro Clinic
Opens 10/2005
100
139
94
Acadia Clinic
75 Opens 2001
75
50
25
159
24
26
2003
2004
50
55
2005
2006
0
2007
2008
2009
2010
2011
Distribution of Opioid-Exposed Newborns Admitted to EMMC
by Opioid Category
Nov 2007 - Nov 2011, N = 568
50%
42%
40%
32%
30%
17%
20%
9%
10%
0%
Methadone
Buprenorphine
Prescribed Opiates
Illicit
Prenatal Methadone and Buprenorphine Exposures
for Newborns Admitted to EMMC
2005-2011
MOTHERS Trial published
Dec 2010
140
Buprenorphine patient limits
go from 30 to 100
120
100
80
Buprenorphine released
Oct 2002
60
40
20
0
2005
2006
2007
Methadone
2008
2009
Buprenorphine
2010
2011
Prematurity Rate (<37 weeks)
for Opioid-Exposed Newborns Admitted to EMMC
Nov 2007 - Nov 2011, N = 111/568
50%
42.3%
40%
30%
21.6%
19.1%
20%
10.5%
10.3%
10%
0%
Methadone
Buprenorphine
Prescribed
Opiates
Illicit
Maine 2008
What Issues Have We Taken
Care Of?
• Who gets screened upon admission to L&D?
• What do we know about confounders to
opiate withdrawal?
• Trying to achieve consistency with our
withdrawal scoring tool
• Challenging “conventional treatment” – a
change from phenobarbital-first to
methadone-first
• Should mothers be encouraged to breast feed
and under what circumstances?
Breast Milk on Day 5 by Prenatal Opioid Exposure
for Newborns Admitted to EMMC, >36 weeks
Nov 2007 - Nov 2011, N = 456
60%
46%
38%
40%
31%
20%
0%
Methadone
Buprenorphine
Prescribed Opiates
Treatment Rate by Prenatal Opioid Exposure and
Feeding Choice on Day 5 for Newborns Admitted to EMMC
>36 weeks, Nov 2007-Nov 2011, N = 494
80%
76%
67%
60%
56%
45%
40%
31%
20%
20%
0%
Methadone
Buprenorphine
Formula day 5 & Treated
Prescribed Opiates
Breast milk day 5 & Treated
Length of Stay when Treated by Prenatal Opioid Exposure and
Feeding Choice on Day 5 for Newborns Admitted to EMMC
> 36 weeks, Nov 2007-Nov 2011, N = 263
30
±
27.3
*
23.9
22.1
20
17.5
Days
15.8
11.2
10
0
Methadone
Buprenorphine
LOS with Formula day 5 & Treated
Prescribed Opiates
LOS with Breast milk day 5 &Treated
What Issues are We Currently
Taking Care of?
• Prenatal Counseling
• Challenging “conventional treatment” – comparing
methadone-first to morphine-first
• Why is there such a response variation to treatment?
• What are the determinants for longer term
developmental outcome?
• What is the feedback from parents about their
experience?
• Working on transitions and aftercare for the
newborn and family – Linking
Prenatal Counseling
• Preparing the parents for experience of the opiate-exposed
newborn
– No one likes surprises – especially unanticipated ones with your baby
• Group meeting
– Acadia, Discovery House, Metro Clinic, Open Door Recovery Center
• Individual or small groups
• Topics covered
–
–
–
–
Don’t wean off opiate replacement medication during pregnancy
Importance of supportive care and attachment for the baby
Length of stay – 5-day observation and criteria for treatment
Helpful hints in getting along with staff – e.g., don’t sleep with baby or
fall asleep with baby, do what you say you will do
– Breast feeding
• Potential for judgment – family and staff
What Issues Are We Taking Care of?
• Prenatal Counseling
• Challenging “conventional treatment” comparing
methadone-first to morphine-first
– This is a double-blinded, randomized protocol
– 22 babies entered 1st year
•
•
•
•
Response to treatment variation
Longer term developmental outcome
Feedback from parents
Transitions and aftercare of Newborn and Family
What Issues Are We Taking Care of?
• Prenatal Counseling
• Challenging “conventional treatment”
comparing methadone-first to morphine-first
• Response to treatment variation
• Longer term developmental outcome
• Feedback from parents
• Transitions and aftercare of Newborn and
Family
Addiction
• There are at least 3 different categories of
factors that contribute to the vulnerability to
develop addiction:
– Environmental factors – cues, external
stressors (e.g., ACEs)
– Drug-induced factors that lead to
neurobiological changes - neuroadaptation
– Genetic factors – these represent
approximately 40 to 60% of the risk to
develop addiction
Opiate Genetics – A SNiP of
Information about NAS Treatment
• Why do some newborns get treated for
withdrawal and others don’t despite same
prenatal exposure and dose?
• Why do some newborns get treated with a 2nd
drug and others don’t?
• What is the source of this wide variation?
• Domains of Opiate Neurobiology on which to
focus
– μ-Opioid receptor
– Membrane transport of opiates into the brain
– Potentiating pleasure pathways such as dopaminergic
“Exploring the source of variation is fertile soil
in which to sow our seeds of ignorance”
Opiate Genetics
Single Nucleotide Polymorphisms
 A single-nucleotide
polymorphism (SNP) is a DNA
point mutation for which alternative
paring occurs
 The sequence variation occurs
when a single nucleotide —
Adenosine, Thymine, Cytosine or
Guanine — is replaced in the
genome and can cause a functional
change in the protein for which it
codes
Opiate Genetics
Single Nucleotide Polymorphisms
 SNP of 118A→G in the opiate receptor
(OPRM1) has been associated with
reduced opiate effectiveness in the
variant
 Correlated with increased rates of opioid
dependence
 SNP of 472G→A catechol-Omethyltransferase (COMT) results in a
4-fold decrease in activity of metabolism
of dopamine transmitter.
 Correlated with the ability to experience reward
Single Nucleotide Polymorphisms and
Variability in Severity of Neonatal
Abstinence Syndrome
EM Wachman1*, MS Brown2, BA Logan3,
NA Heller3, H O Kasaroglu1, T Marino4, JM
Davis1, and MJ Hayes3
1Neonatology,
Tufts Medical Center;
2Neonatology, Eastern Maine Medical Center;
3Psychology, Univ Maine;
4OB/Gyn, Tufts Medical Center
Abstract for Society for Pediatric Research
Boston May 2012
Candidate Genes for NAS
 μ-Opioid Receptor (OPRM1) = Site of Action
 A118G SNP
 Multi-Drug Resistance Gene (MDR1) = Transporter
 G2677T SNP
 C1236T SNP
 C3435T SNP
 Catechol-O-methyltransferase (COMT) = Modulator
 A158G SNP (Val158Met)
Lotsch J, et al. Clin Pharmacokinet, 2004; Yuferov V, et al. Ann NY Acad Sci,
2010; Reyes-Gibby CC, et al. Pain, 2007.
Question
 Are SNPs in the OPRM1, MDR1, and COMT
genes associated with treatment and length of
stay in opiate-exposed newborns?
 N = 26 newborns




GA >36 weeks
Methadone 70%, buprenorphine 30%
Blood or saliva samples for DNA
54% Treated for NAS
OPRM1 – Treatment for NAS
100%
80%
60%
40%
20%
n=6
n=20
*
0%
AA
AG/GG
GENOTYPE
68% vs 18% χ² = 4.34; p<0.05 *
OPRM1 – Length of Hospital Stay
35
30
DAYS
25
20
*
15
10
5
n=6
n=20
0
AA
GENOTYPE
AG / GG
Mean 24.5 vs 8.8 days p=0.006 *
COMT – Length of Hospital Stay
60
50
DAYS
40
30
20
10
*
n=6
n=20
AA
AG/GG
0
GENOTYPE
Mean 34.3 vs 16.9 days p<0.05 *
Conclusions
 SNPs in the OPRM1 and COMT
genes affect the incidence and
severity of NAS
 Infants with the minor allele present
in the OPRM1 A118G and COMT
A158G demonstrated a milder
phenotype vs. homozygotes for the
major allele
What Issues are we Taking Care of?
• Prenatal Counseling
• Challenging “conventional treatment”
comparing methadone-first to morphine-first
• Response to treatment variation
• Longer term developmental outcome
• Feedback from parents
• Transitions and aftercare of Newborn and
Family
What do parents tell us that they are
worried about?
• That they will be judged – “methadone mother”
– By Providers
– By their own family
• Lack of understanding by those in charge of services they need
–
–
–
–
•
•
•
•
WIC
Shelters
Transportation often based on NTP and are not available to EMMC
Barriers to frequent hospital visitations
Babies will be stigmatized – “methadone baby”
Birth defects during pregnancy
Is my baby going to be normal?
Terrified of losing baby to DHHS even though they have done the
“right things”
• Knowing how to do the NAS scoring ‘right’
• Feeling that they can never do enough according to some
nursing staff
What works well for them?
• Prenatal groups at narcotic treatment programs
• Participation in research about infant
development
• Public Health Nursing in the home
• Advanced notice of CAPE involvement
• Maine Families
• Gas cards, taxi vouchers, housing
• Some providers that are very respectful – being
listened to and validated concerns
What Issues are we Taking Care
of?
• Prenatal Counseling
• Challenging “conventional treatment” comparing
methadone-first to morphine-first
• Response to treatment variation
• Longer term developmental outcome
• Feedback from parents
• Transitions and aftercare of Newborn and
Family – Penquis District Linking Group
Penquis District Linking Project
• Began community-based meetings in November 2010
• Goal has been:
– “To link families of substance-exposed newborns – aged
from prenatal to preschool age in Penobscot and
Piscataquis counties – to a well coordinated system of care
to optimize their social developmental and medical well
being.”
• Conference planned in the Fall 2012
• Seeking funding for Coordinator and focus groups
What Issues do we Need to
Take of?
• Formalize the transitions work with parents
– Synchronizing mother and infant to each other allow the mother to
appropriately respond to the infant’s needs within the context of
the mother’s own sphere of limitations.
• Continue to expand Linking Project for aftercare of
Newborn and Family – funding, coordinator
• Update NAS scoring
• Move the inpatient treatment to an outpatient setting
• Extend long-term developmental assessments to learn
more about permutations that impact the newborn’s
developmental plasticity
Lessons
Learned
• Support the mother’s recovery
• Build trust of the parent(s) and their support
– The health care setting is often a black hole of
judgment and criticism for those in recovery
– Consistency, consistency
• Caregivers, treatment
– Predictability – plan of care, length of treatment,
endpoints
– Accountability – do what you say you will do
– Informal networks
• Variation in parental and newborn opiate genetics
account for half of the variation in addiction and
newborn response to treatment
• Ultimate focal point is to enhance attachment to
improve family outcomes
Roadmap
Where have we been?
 Looking at the scope by the numbers
 Looking at the development of the infrastructure
of a comprehensive NAS Program





Prenatal counseling
Who gets screened
Confounders of withdrawal
Assessment of withdrawal – Scoring system
Treatment



Dropping routine phenobarbital use
Methadone versus morphine
Understanding variation in NAS treatment
 Breast feeding
 Importance of transitions to the community – an aftercare safety
net
 The continued challenge: Can we change their Legacy
 A Role for Infant Mental Health through enhancing
attachment and individualized infant sensitivity?
The Window of the “Learning Moment”
for the Mother is the Cornerstone for
Attachment
Key Resources
• Maine Office of Substance Abuse
2010 data
– http://www.maine.gov/dhhs/osa/
– http://www.maine.gov/dhhs/osa/data/p
ubrpts.htm
• CDC Website with Information
about ACEs
– http://www.cdc.gov/ace/index.htm