Overview of Neonatal Abstinence Syndrome (NAS), a drug withdrawal syndrome resulting from sudden discontinuation of prolonged fetal exposure in utero. Topics include epidemiology, health care expenditures, pathophysiology, clinical presentation, management, and long-term outcomes.

1. S A R A N O B L E , M S 3
SCHOOL OF MEDICINCE, UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO
NEONATAL ABSTINENCE
SYNDROME (NAS)

2. NEONATAL ABSTINENCE SYNDROME
• A drug withdrawal syndrome, the end result of sudden
discontinuation of prolonged fetal exposure in utero
• Substances Associated with NAS
• Opiates
• Morphine
• Heroin
• Methadone
• Buprenorphine
• Prescription opioid analgesics
• Other Substances
• Antidepressants
• Anxiolytics
• Methamphetamines
• Inhalants

3. EPIDEMIOLOGY
• Since 2000, increasing incidence of NAS has been
responsible for a substantial and growing portion of
resources dedicated to neonates
• Increased use of opiods during pregnancy
• Increased simultaneous use of multiple opiods
• Increased use of non-opioid illicit substances during pregnancy
• Concurrent use of multiple licit or illicit substances during
pregnancy
Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated health care
expenditures: United States, 2000-2009. JAMA. 2012;307(18): 1934–1940
Tolia, VN, Patrick, SW, Bennett, MM, et al. Increasing incidence of the neonatal abstinence synfrome in U.S. neontal ICUs. NEJM. 2015;372: 2118-26.

4. EPIDEMIOLOGY
0
1
2
3
4
5
6
2000 2003 2006 2009
Rateper1000HospitalBirths
Rates of Maternal Opioid Use & NAS in U.S., 2000-2009
Maternal Opioid Use
NAS
Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated health care
expenditures: United States, 2000-2009. JAMA. 2012;307(18): 1934–1940

5. HEALTHCARE EXPENDITURES
• Hospital charges and length of stay for NAS births
are ~fives times higher vs. all other births in U.S.
Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated health care
expenditures: United States, 2000-2009. JAMA. 2012;307(18): 1934–1940
3.3
3.2
3.2
3.1
16.4
15.3
15.9
15.8
0 5 10 15 20
2009
2006
2003
2000
Length of Stay (days)
NAS Neonates Non-NAS Neonates
$9,500
$8,200
$7,300
$6,600
$53,400
$44,600
$47,900
$39,400
$0 $20,000 $40,000 $60,000
2009
2006
2003
2000
Hospital Charges ($)

6. HEALTHCARE EXPENDITURES
Tolia, VN, Patrick, SW, Bennett, MM, et al. Increasing incidence of the neonatal abstinence synfrome in U.S. neontal ICUs. NEJM. 2015;372: 2118-26.

7. PATHOPHYSIOLOGY: OPIATES IN UTERO
• Opiates are easily transferable across the placenta
• Low molecular weight
• Water soluble and lipophobic
• Transmission across placenta increases with advancing
gestational age
• Opioid withdrawal in neonate is more complex vs. adult
• Immature neurologic development, yet the density and affinity
of μ-receptors in neonates are as good as those in adults
• Immature neurologic processing
• Complex materno-feto-placental pharmacokinetics
• Prolonged opioid half-life in fetus

8. PATHOPHYSIOLOGY: OPIATE NAS
Kocherlakora, P. Neonatal Abstinence Syndrome.
Pediatrics. 2014;134(2): e547-e561.

9. PATHOPHYSIOLOGY: NON-OPIATE NAS
• SSRIs, SSNIs
 excess serotonin and noradrenaline
• TCAs
 cholinergic rebound phenomenon
• Benzodiazepines
 increased GABA release
• Methamphetamine
 decreased dopamine, seratonin, other monoamines
• Inhalants
 dopamine, glutamate, GABA pathways

10. CLINICAL FEATURES
Neurological Excitability Autonomic Instability GI Dysfunction
• Hyperirritability
• High-pitched
inconsolable crying
• Agitation/Restlessness
 Exoriations
• Difficulty sleeping
• Tremors
• Exaggerated Moro reflex
• Hypertonia
• Excessive motor activity
• Myoclonic jerks
• Uncontrolled, constant
sucking
• Seizures (2-11%)
• Apnea
• Bradycardia
• Tachypnea
• Nasal flaring
• Nasal stuffiness
• Temperature instablity
• Sweating
• Sneezing
• Mottling
• Yawning
• Diarrhea  electrolyte
disturbances,
dehydration, perianal
skin excoriation
• Hyperphagia
(may require up to 150 kcal/kg/d)
• Regurgitation
• Vomiting
• Poor feeding
• Poor weight gain/FTT

11. CLINICAL TIMELINE
• Onset and duration of NAS withdrawal is dependent on
substance type, amount, pharmacologic properties,
duration of exposure, accumulation of exposure, time
of last dose, and multiplicity of substances
Substance Frequency Onset Duration
OPIOIDS
Heroin 40-80% 24-48 h 8-10 d
Methadone 13-94% 48-72 h Up to 30+ d
Buprenorphine 22-67% 36-60 h Up to 28+ d
Prescription Opioids 5-20% 36-72 h 10-30 d
NON-OPIOIDS
SSRIs 20-30% 24-48 h 2-6 d
TCAs 20-50% 24-48 h 2-6 d
Methamphetamines 2-49% 24 h 7-10 d
Inhalants 48% 24-48 h 2-7 d

12. RISK FACTORS FOR INCREASED SEVERITY
• Definite Risk Factors
• Term
• Good birth weight
• Polydrug abuse
• Combination with benzodiazepines
• μ-opioid receptor (OPRM1 118 AA) positive
• Catechol-O-methyltransferase (COMT 158 AA) positive
• Probable Risk Factors
• Male gender
• Methadone
• Smoking
• Combination with SSRIs

13. DIAGNOSIS
• NAS is a clinical diagnosis
• Testing to confirm substance
• Meconium toxicology
• More sensitive, can detect from 20 weeks gestation
• Urine toxicology
• Cheaper than mec tox
• More selective testing methods required to detect synthetic
substances
• $$$$
• Hair and umbilical cord analyses
• Detect even minor and remote exposures

14. NON-PHARMACOLOGICAL MANAGEMENT
• Swaddling
• Demand feeding, small volume feeds
• Avoid waking
• Minimal stimulation: dim lighting, low noise level
• Pacifiers
• Breastfeeding (if MOC on methadone, no other illicit drugs)
• Holding, cuddling, manual rocking
• Kangaroo care (skin-to-skin contact)
• Water beds may help calm, but not rocking beds
• Music therapy
• Massage therapy
• Maternal participation
Kocherlakora, P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-e561.
Velez, M. & Jansson, L.M. Non-pharmacologic care of the opioid dependent mother and her newborn. J Addict Med. 2008;2(3): 113-120.

15. PHARMACOLOGICAL MANAGEMENT
• Hospitals should have a NAS treatment protocol in
place to guide treatment
• Medications are required only when:
• supportive therapy fails to control the signs and symptoms
• withdrawal scores remain high
• serious signs are observed, such as seizures
• withdrawal is associated with severe dehydration because of
diarrhea and/or vomiting
Kocherlakora, P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-e561.

16. PHARMACOLOGICAL MANAGEMENT
Kocherlakora, P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-e561.
Medication Mechanism of Action Dose t1/2 Advantages Disadvantages
Morphine Natural μ-receptor
agonist
0.05‒0.2 mg/kg/dose q3‒4h
Inc. by 0.05 mg/kg
Max: 1.3 mg/kg/day
9h Tx of choice
in opioid NAS
No alcohol
Short t1/2
Sedation
Apnea
Constipation
Frequent dosing
Methadone Synthetic complete
μ-receptor agonist
N-methyl-d-aspartate
antagonist
0.05‒0.1 mg/kg/dose q12h
Inc. by 0.05 mg/kg q48h
Max: 1 mg/kg/d
26h BID dosing Longer duration of
treatment
Alcohol 8%
Frequent follow-up
needed (variable t1/2)
Phenobarbital GABA agonist Loading: 16 mg/kg
Maintenance:
1‒4 mg/kg/dose q12h
45‒
100h
Tx of choice
in non-opioid
NAS
Possible hyperactivity
High treatment failure
Alcohol 15%
Drug-drug interactions
Sedation
Monitor level
Clonidine α-adrenergic receptor
agonist
Intial: 0.5‒1 mg/kg
Maintenance:
0.5‒1.25 mg/kg/dose
q4‒6h
44‒
72h
Non-narcotic
No sedation
No alcohol
Shorter
duration of
treatment
Hypotension
Abrupt discontinuation
may cause rebound
tachycardia and
hypertension
Monitor level
Buprenorphine Semi-synthetic, SL
partial μ-receptor agonist
κ-receptor antagonist
Dose: 4‒5 mg/kg/dose q8h
Max: 60 mg/kg/d
12h Shorter
duration of
treatment
Alcohol 30%
Adjuvant medications
required

17. PHARMACOLOGICAL MANAGEMENT
Medication Usage in Neonates with NAS, 2004-2013
Tolia, VN, Patrick, SW, Bennett, MM, et al. Increasing incidence of the neonatal abstinence synfrome in U.S. neontal ICUs. NEJM. 2015;372: 2118-26.

18. • Modified Finnegan is
most commonly used
scoring tool
• Scoring should occur
after feedings, when
awake
• Scores q3-4h should
represent status of
infant at time of
assessment and during
preceding interval
ASSESSMENT OF
SEVERITY
Modified Finnegan NAS Scoring
Continuous
High-Pitched Cry
Crying excessively, difficult to console (25-50% of
time)
Crying continuously, inconsoleable (>50% of time)
2
3
Difficulty Sleeping <3 hour sleep duration after feeding
<2 hour sleep duration after feeding
<1 hour sleep duration after feeding
1
2
3
Moro Reflex Hyperactive Moro reflex
Markedly hyperactive Moro reflex
2
3
Tremors Mild tremors, disturbed
Moderate-severe tremors, disturbed
Mild tremors, undisturbed
Moderate-severe tremors, undisturbed
1
2
3
4
Muscle Tone Increased muscle tone 2
Myotonic
Jerks/Convulsions
Myotonic jerks
Generalized convulsion
3
5
Excoriation Specify location; do not score if scabbed over/healing 1
Autonomic Instability Fever 100.4 to 101F
Fever >101F
Frequent yawning (≥3 in an interval)
Sweating (exclude environmental factors)
Nasal stuffiness (exclude if attributed to illness)
Sneezing (≥3 in an interval)
Mottling
Tachypnea (RR >60) without retractions
Tachypnea (RR >50) with retractions
Nasal flaring
1
2
1
1
1
1
1
1
2
2
GI Dysfunction Excessive sucking/rooting
Poor feeding (slow, inadequate amount, inefficienct)
Regurgitation
Projectile vomiting
Loose stools without watery ring
Watery stools with watery ring
1
2
2
3
2
3
UHS intranet.
Jansson, L.M., Velez, M., & Harrow, C. The opioid
exposed newborn: Assessment and pharmacological
management. Journal of Opioid Management.
2009;5(1): 47-55.

19. • Updated May 2015
• Obtain urine and mec
toxicology, social work
consult, non-pharm
interventions
• Initiate
pharmacological
management if 3
consecutive Finn score
≥8 or average of 2 or 2
consecutive scores ≥12
UHS NAS
GUIDELINES
Neonatal Abstinence Syndrome (NAS) Guidelines
START
1. Suspected or known infants of substance
abusing mothers.
2. Infants manifesting typical signs and symptoms
of withdrawal.
3. Infants born to mothers with high risk factors.
No
Routine newborn
care
Signs of
withdrawal
1. Collect first urine and meconium samples.
2. Obtain social work consult.
3. Commence Finnegan scoring within 2 hours
of birth and continue every 3 hours.
4. Initiate non-pharmacologic interventions
(e.g. swaddling, minimal stimulation, etc.)
Yes
Scores < 8 for minimum period of observation
as determined by opiate half-life:
Short half-life=3 days
Long half-life=5-7 days
**May consider earlier discharge for
asymptomatic infants with confirmed negative
meconium toxicology screen.
Minimum Period of
Observation:
1. Short half-life (e.g.
morphine, codeine, & heroin),
require monitoring for
minimum of 3 days (72 hours).
2. Long half-life (e.g.
methadone, buprenorphine)
require monitoring for
minimum of 5-7 days (120-168
hours).
Eligible for discharge: Identify
PCP, provide education to
primary care giver, and ensure
community resources in place.
3consecutivescores ≥ 8orthe
average of two scores or two
consecutivescores are≥ 12?
Initiate treatment
as per protocol
and continue
supportive care.
Maternal Risk Factors:
1. Absent, late or no prenatal care
2. Previously documented or admitted
history of drug use
3. Previous unexplained late fetal demise
4. Precipitous labor
5. Placental abruption
6. Hypertensive episodes
7. Severe mood swings
8. Cerebrovascular Accidents
9. Myocardial infarction
10. Repeated spontaneous abortion
11. Alcohol and/or cigarette use
Exclusions
1. Infants < 36 weeks
2. Medically unstable
3. Possible alternative
diagnosis (e.g. sepsis)
Yes
Continue
monitoring
NoYes
Initiation Doses:
Category Score NMS
0 0-7 none
I 8-12 0.10ml
II 13-16 0.20ml
III 17-20 0.30ml
IV 21-24 0.40ml
V ≥ 25 0.50ml
NMS=Neonatal Morphine
Solution (0.4mg/1ml)
Score stable on
current NMS
dose.
Yes
If2consecutivescores ≥ Category I,
despite rescoring, escalate score as
per protocol.
After 48 hours of Category 0 scores,
wean NMS by 0.05ml every 24
hours as long as scores remain in
NoYes
After discontinuation
of NMS, scores
remain in Category 0
for 48-72 hours.
Stop NMS when scores remain
in Category 0 for 24-48 hours at
dose of 0.05ml.
Escalation Doses:
Category Score NMS
I 8-12 previous dose+0.05ml
II 13-16 previous dose+0.10ml
III 17-20 previous dose+0.15ml
IV 21-24 previous dose+0.20ml
V ≥ 25 previous dose+0.25ml
** Re-escalation doses are in general half
of the initial escalation doses (e.g. increase
NMS by 0.025 ml for 2 consecutive
Category I scores, 0.05ml for 2 consecutive
Category II scores, and so on).
Approved by Pediatric
Subcommittee May 2015
Approved by P&T
Committee June 2015
Yes
UHS Intranet.

20. A P R I L 2 0 1 2 • C N N N E W S R E P O RT
NAS AT EAST TENNESSEE CHILDREN’S HOSPITAL

21. LONG-TERM OUTCOMES
• Research regarding long-term outcomes of opioid
exposure and NAS is inconclusive
• Some research indicates NAS may result in motor
deficits, shorter attention spans, and poorer social
engagement that persist into toddlerhood; however,
other studies do not find significant differences after
controlling for SES and environmental factors
• Recent research suggests prenatal exposure to opioids
is associated with:
• Delayed or alternal maturation of neuronal connective tracts
• Smaller neuroanatomic volumes
Kocherlakora, P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-e561.
Logan BA, Brown MS, Hayes MJ. Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes. Clinical obstetrics and gynecology.
2013:56(1):186-192.

22. CONSIDERATIONS FOR FOLLOW-UP
• Neurodevelopmental Assessment
• Motor deficits, cognitive delays, relative microencephaly
• Psycho-Behavioral Assessment
• Hyperactivity, impulsivity, ADHD, school absence, school failure
• Ophthalmologic Assessment
• Nystagmus, strabismus, refractive errors, other visual defects
• Growth & Nutritional Assessment
• Failure to thrive, short stature
• Family Support Assessment
• Exclude continued maternal substance abuse, child abuse,
discuss optimal home environment with parents/caregivers
Kocherlakora, P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-e561.

23. REFERENCES
• CNN News. Video: Hospital seeing more babies born exposed to prescription drugs. 30 April 2012. Last accessed
3/21/16 at http://www.cnn.com/2012/04/28/health/drug-babies/
• Hayes MJ & Brown MS. Epidemic of prescription opiate abuse and neonatal abstinence. JAMA 2012; 307(18):
1974-5.
• Jansson LM, Velez M, & Harrow C. The opioid exposed newborn: Assessment and pharmacological management.
Journal of Opioid Management. 2009;5(1): 47-55.
• Kocherlakora P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-e561.
• Logan BA, Brown MS, Hayes MJ. Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes. Clinical
obstetrics and gynecology. 2013:56(1):186-192.
• Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome
and associated health care expenditures: United States, 2000-2009. JAMA. 2012;307(18): 1934–1940.
• Substance Abuse and Mental Health Services Administration. Center for Behavioral Health Statistics and Quality.
Results from the 2012 National Survey on Drug Use and Health: summary of national findings.
• Texas Department of State Health Services. Recovery, Restoration, Resilience: Mommies and Babies Overcoming
Neonatal Abstinence Sydrome. Presented at the Behavioral Health Institute. Austin, Texas. July 2015. Web.
• Tolia VN, Patrick SW, Bennett MM, et al. Increasing incidence of the neonatal abstinence synfrome in U.S.
neontal ICUs. NEJM. 2015;372: 2118-26.
• Velez M & Jansson LM. Non-pharmacologic care of the opioid dependent mother and her newborn. J Addict Med.
2008;2(3): 113-120.