Neonatal Drug Withdrawal
Neonatal Drug Withdrawal
 This is a nationwide problem. In Indiana, this is a problem in all
counties.
 The classic drugs of abuse that cause neonatal withdrawal are
opioids such as heroin and morphine. Prescription pain
medications such as oxycodone (Percocet), hydromorphone
(Dilaudid), and propoxyphene (Darvon) are a relatively new
issue.
 Selective serotonin reuptake inhibitors (SSRIs) have become a
problem because of their frequent prescription to pregnant
women with depression.
 Stimulant drugs, such as cocaine and amphetamine, cause
symptoms in neonates, though probably due to drug effects or
injury, as opposed to classic withdrawal syndromes.
Neonatal Drug Withdrawal
 Summary of the Neonatal Drug Withdrawal Clinical Report
from the The Committee on Drugs and The Committee on
Fetus and Newborn published in Pediatrics 2012;129;e 540.
 Cost of the Neonatal Abstinence Syndrome
Neonatal Drug Withdrawal
Pediatrics 2012;129;e 540
 Maternal use of certain drugs can cause transient neonatal
signs consistent with withdrawal or acute toxicity or
sustained signs consistent with a lasting drug effect.
 Additionally, our use of narcotics and/or benzodiazepines
to provide analgesia or sedation for hospitalized infants
puts that population at risk for signs of withdrawal.
2009 National Survey on Drug
Use and Health
 Surveyed population 12 years or older.
 8.7%, 23.7%, and 27.7%, respectively, reported recent use of
illicit drugs, binge or heavy alcohol ingestion and use of tobacco
products.
 4.5% of pregnant women 15-44 years of age reported recent
use of illicit drugs (marijuana, cocaine, hallucinogens, heroin,
methamphetamines, and nonmedical use of prescription
drugs).
 Binge or heavy drinking in the first trimester was reported by
11.9% and recent tobacco use by 15.3%.
 In the 15-17 year old range, the use of illicit drugs and smoking
were higher in pregnant women than in those not pregnant.
Discharge Data from Agency for Health Care
Research and the Florida Department of Health
 Using ICD-9 code 779.5 for neonatal withdrawal syndrome
the number of infants coded at discharge increased from
7653 in 1995 to 11, 937 in 2008.
 In Florida, the number of newborns discharged with ICD-9
code 779.5 increased from 0.4 to 4.4/1000 live births from
1995 to 2009.
 Part of this increase, though exactly how much is not
known, is thought to be from the more liberal use of
prescription opiates in pregnant women to help with pain
from a number of etiologies.
Neonatal Drug Withdrawal
 By far, the most common neonatal drug withdrawal comes
from intrauterine opioid exposure. The typical clinical
findings associated with opioid withdrawal are called the
neonatal abstinence syndrome (NAS).
 Withdrawal signs develop in 55-94% of neonates exposed
to opioids in utero.
 Neonatal withdrawal signs have also been described in
infants exposed to benzodiazepines, barbiturates, and
alcohol.
Cocaine and Other Stimulants
 A true abstinence syndrome after exposure to CNS
stimulants such as cocaine and amphetamine has not
been defined.
 The neurobehavioral abnormalities that occur frequently
2-3 days after birth in neonates with intrauterine exposure
include irritability, hyperactivity, tremors, high-pitched
cry, and excessive sucking.
 Since cocaine and its metabolites may be detected in
exposed infants for up to 7 days after birth, the signs may
relate more to drug effect than withdrawal.
Selective Serotonin Reuptake
Inhibitors (SSRIs)
 This class of antidepressant medications became available
for widespread use in 1988. They are now the most
frequently used drugs to treat depression.
 Included are such well known names as Prozac
(fluoxetine), Zoloft (sertraline, Lexaprol (escitalopram),
and Paxil (paroxetine).
 SSRIs block the reuptake of serotonin into the presynaptic
neuron, thereby increasing the concentration of serotonin
in the presynaptic cleft available to bind to serotonin
receptors on the postsynaptic neuron.
SSRIs
 Third-trimester use of SSRIs can produce neonatal signs that
include continuous crying, irritability, jitteriness, shivering,
fever, tremors, hypertonia, tachypnea, feeding difficulty, sleep
disturbance, hypoglycemia, and seizures.
 The onset of signs varies from several hours to several days
after birth. Signs typically resolve within 1-2 weeks.
 Again, it is unknown whether this is a withdrawal syndrome or
serotonin syndrome (serotonin overload). Clinical course is
frequently one of a slow resolution of signs, which may be more
consistent with a hyperserotonergic condition rather than
withdrawal.
 Only paroxetine (Paxil) produces a ratio of infant to maternal
plasma concentration that is consistently low (<0.1) with breast
feeding.
Opioids
 Opioids are a class of natural, endogenous, and synthetic
compounds that activate primarily mu-opiod receptors in the
CNS to produce supraspinal analgesia.
 Morphine is a natural opioid and is extracted from the opium
poppy. Codeine, heroin, hydromorphone, fentanyl, and
methadone are all synthetic opioids.
 Opioids acutely inhibit the release of noradrenaline at the
synaptic terminals. With chronic opioid exposure, tolerance
develops and the rate of noradrenaline release increases toward
normal.
 Abrupt cessation of exogenous opioids results in a supranormal
release of noradrenaline and produces the autonomic and
behavioral signs characteristic of opioid withdrawal.
Opioid Abuse in Pregnancy
 Opioids are small lipophilic compounds that freely cross the
placenta and blood-brain barrier.
 Maternal detoxification is associated with increased risk of fetal
distress and fetal loss.
 Maintenance programs with methadone for pregnant women
sustain opioid concentrations in the mother and fetus in ranges
that minimize opioid craving, suppress abstinence
symptomatology, block heroin-induced euphoria, and prevent
fetal stress.
 Unfortunately, because of its addictive properties, the use of
methadone makes detoxification after delivery unlikely and
produces a longer course of NAS than with heroin exposure.
Buprenorphine
 Because of the negative aspects of methadone use synthetic opioids
have been developed as alternatives.
 Buprenorphine, a partial mu-receptor agonist, was approved in 2002
by the FDA for the treatment of opioid dependence.
 Buprenorphine alone (Subutex) or in combination with naloxone
(Suboxone) has been used as a first-line treatment of heroin addiction
and as a replacement drug for methadone. Neither methadone or
buprenorphine is approved by the FDA for use in pregnancy.
 There is some data that buprenorphine may produce less withdrawal
in neonates and that the withdrawal, when it occurs, is shorter.
However, the data is not extensive.
 Conversion from methadone to buprenorphine during pregnancy
requires hospitalization for it to be done safely (for the mother and
fetus).
Opioid Withdrawal
Opioid Withdrawal
 Since the opioid receptors are concentrated in the CNS
and GI tract, you get the signs and symptoms seen in the
previous chart.
 Excess environmental stimuli and hunger exacerbate the
perceived severity of NAS. Hence, frequent feeds and a
quiet room are part of the treatment of withdrawal.
 Signs of neonatal withdrawal often begin in the first 24
hours after birth with heroin. In methadone, the
withdrawal tends to begin between 24 and 72 hours.
However, for both opioids, withdrawal has been reported
to take up to 5-7 days to develop.
Opioid Withdrawal
 For buprenorphine, withdrawal onset peaks at 40 hours, is at its
worst at 70 hours.
 The different time courses reflect variations in the half-lives of
drug elimination.
 The incidence and severity of NAS are greater in infants
exposed to methadone compared with infants exposed to
heroin or buprenorphine. However, up to 50% of infants
exposed to buprenorphine may withdraw.
 Daily maternal methadone dose has not been consistently
correlated with the incidence or severity of NAS. Maternal
methadone metabolism is probably a more important
determinant than the actual daily dose.
Opioid Withdrawal
 Preterm infants do not withdraw as frequently or as
severely. It is not known whether that is due to the less
mature nervous system or being exposed to a lower total
dose of narcotic.
Screening for Neonatal
Withdrawal
 Maternal history is important – you have to ask early on in
the pregnancy, every pregnancy. Dr. James Nocon/IPN
have great resources for screening mothers.
 Two semiobjective scoring systems are available for
neonates, the Lipsitz tool and the modified Finnegan’s
Neonatal Abstinence Scoring Tool. Currently, the modified
Finnegan’s is the most commonly used.
 The appropriate length of hospitalization for observation
in a term infant is variable, and depends on the drug used
and the maternal metabolism. For a drug such as
methadone with a prolonged half-life, the infant should be
observed for 5-7 days.
Breast Feeding
 Breastfeeding has been associated with less severe NAS presents later and less often requires drug intervention.
 Breast feeding, safety-wise, requires that the mother be in
a supervised drug treatment program and that the mother
be HIV and Hepatitis C negative.
 Methadone is excreted into breast milk, but at a low level.
Dose range has been estimated at from 0.01 to 0.15
mg/day in the first 30 days of life.
 If possible, and safe, breast feeding probably does reduce
NAS risk.
Pharmacologic Therapy of NAS
 The optimal screening scores for the initiation of pharmacologic
therapy by any published abstinence scoring system are
unknown.
 If nonpharmacologic treatment fails, then the drugs of choice
are oral morphine or methadone (94% first choice in UK, 83%
first choice in US).
 Paragoric is no longer used because it contains a multiple other
opioids as well as camphor, anise oil, alcohol, and benzoic acid.
 Tincture of opium contains a 25 fold higher concentration of
morphine than currently available oral morphine preparations
making accidental overdose a concern.
 When a second drug is needed, phenobarbital is most
commonly picked.
Long Term Outcome
 The long term neurodevelopmental outcome of infants
who withdraw is really not known. It is very difficult to
tease out the drug effects from the family/social issues.
 In most cases, what data there is, tends to be reassuring.
Whether it is looking at infants who seize secondary to
opioid withdrawal or drug toxicity from cocaine, most of
the infants appear to do OK over time. That is probably
related to the fact that neurotransmitter levels recover
over time.
Aquired Opioid and/or
Benzodiazepine Dependency
 This section is a new addition.
 Discusses the drug dependency generated in sick
neonates from the use of opioids and benzodiazepines.
ECMO patients are heavily represented in this patient
population.
 Most of the data comes from Peds ICUs, not NICUs.
 Drug infusions, such as with fentanyl and midazolam, are
especially good at generating dependency. Withdrawal
signs and symptoms from the two drugs overlap, making
it hard to separate the two in weaning.
Aquired Opioid and/or
Benzodiazepine Dependency
 For those infants who receive prolonged cumulative exposure
to these two classes of drugs, the AAP offers some guidelines.
 Each clinical unit needs to establish its own dose levels above
which withdrawal is likely. As a rule for fentanyl infusions, a
cumulative fentanyl exposure of >2 mg/kg or >7 days duration
predicts a likelihood of dependency of over 50%, but less than
100%. These infants should go into a weaning schedule over
weeks.
 Infants who do not reach the cumulative exposure to either
opioids or benzodiazepines can be weaned rapidly. In such
cases, many of the infants will not withdraw (BUT, some will). If
withdrawal occurs after a rapid wean, it is usually within 24
hours of the last dose.
Aquired Opioid and/or
Benzodiazepine Dependency
 As previously mentioned, withdrawal from
benzodiazepines overlaps the signs and symptoms of
NAS.
 Once weaning has been established, iv benzodiazepines
can be converted to oral lorazepam. The weaning
duration will be proportional to the length of treatment
with the iv benzodiazepine.
Clinical Highlights/Summary
 Every nursery (my version) should develop a protocol that
defines indications and procedures for screening for maternal
substance abuse. Additionally, a standardized plan should be in
place for evaluating and treating infants at risk for or showing
signs of withdrawal or drug effect.
 Infants with known intrauterine exposure to opioids and
benzodiazepines should be observed in the hospital for 4-7
days. Outpatient follow-up should be early.
 Breastfeeding, if safely possible, may help reduce the risk of
withdrawal.
 Finally, there is still a lot we do not know about the effects of
drug dependency and drug exposure in neonates.
Jennifer McKee, Pharm D
Neonatal Abstinence Syndrome and Associated
Health Care Expenditures
JAMA, May 9, 2012;307(18);1934-1940.
 This article was a retrospective cross-sectional analysis of
national samples using several large databases. Authors were
from the University of Michigan.
 Infants with NAS were identified from a cross-sectional analysis
of pediatric discharges in 2000, 2003, 2006, and 2009 using the
Healthcare Cost and Utilization Project’s Kids’ Inpatient
Database (KID). The database samples 80% of pediatric
discharges and 10% of uncomplicated births.
 Using the KID, NAS patients were identified using the ICD-9-CM
code of 779.5 (drug withdrawal syndrome in a newborn).
 Using another database, the Nationwide Inpatient Sample
(NIS), delivering mothers were identified by common delivery
diagnosis related groups.
Neonatal Abstinence Syndrome and
Associated Health Care Expenditures
JAMA, May 9, 2012;307(18);1934-1940.
 Iatrogenic NAS was looked for by searching NICU
discharge data for the diagnoses of very low birth weight,
PVL, IVH, NEC , spontaneous bowel perforation, or BPD.
 Data would probably have been more accurate if search
included pulmonary hypertension, ECMO, and congenital
heart disease.
Conclusions
 Between 2000 and 2009 total hospital charges for NAS
were estimated to have increased from 190 to 720 million
dollars (includes inflation).
 The CDC found that the sales and deaths related to opiate
pain relievers quadrupled between 1999 and 2008.
 The majority of costs related to NAS are shouldered by
Medicaid.
 We are no better at getting infants with NAS home than
we were in 2000.
Based on national data comparing 50
states and the District of Columbia,
Indiana ranks…
28th in preterm births* (12.4%) * less
than 37 completed weeks gestation
29th in low birth weight* (8.3%) * less
than 2,500 grams
18th in deliveries via cesarean section
(30%)
39th on 1st trimester entry into
prenatal care (63.3%)
39th in infant mortality (7.8)
36th in percent of babies who are ever
breastfed (70.5%)
Indiana received a grade of C on the
March of Dimes 2011 Premature Birth
Report Cards