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11/22/2017 Neonatal opioid withdrawal

Neonatal opioid withdrawal

Neonatal opioid withdrawal

Author Section Editor Deputy Editor

Lori A Sielski, MD Joseph A Garcia- Melanie S Kim, MD
Prats, MD


Last literature review version 19.3: Fri Sep 30 00:00:00

GMT 2011 | This topic last updated: Thu Sep 08
00:00:00 GMT 2011 (More)
INTRODUCTION A newborn infant born to a mother
addicted to opioids is at risk for drug withdrawal. At delivery,
the discontinuation of opioids from the maternal circulation
can lead to a constellation of withdrawal symptoms known as
the neonatal abstinence syndrome (NAS).

The term opioid refers to natural and synthetic substances

with morphine-like activity. Opiate refers to a subclass of
opioids consisting of alkaloid compounds extracted from
opium, including morphine, codeine, heroin, and methadone.

The clinical manifestations and management of neonatal

opioid withdrawal will be reviewed here. Opioid abuse during
pregnancy and neonatal exposure to other drugs of abuse are
reviewed separately.

(See "Smoking and pregnancy" and "Alcohol intake and

pregnancy" and "Substance use in pregnancy" and "Infants of
mothers with substance abuse".)

EPIDEMIOLOGY In one study from California, the reported

prevalence of maternal opioid drug use at the time of delivery
was one percent [1]. In this study of 30,000 women in 1992,
the prevalence rates based upon ethnicity were 2.5, 1.6, 1.3,
and 1.1 in black, white, Asian, and Hispanic mothers,

Among infants with prenatal exposure to opioids, withdrawal

will occur in 42 to 94 percent [2-7]. There appears to be a
dose-response relationship because several studies have
shown an increased risk of neonatal withdrawal and severity
of symptoms as the cumulative maternal doses of opioids
increase during the last trimester of pregnancy [3,8-11].
However, in contrast, one large retrospective report of 330
women treated with methadone found no correlation between
maternal methadone dose and rate of NAS [12].

A recent retrospective study of 232 infants born to opioid

dependent mothers identified perinatal risk factors for
neonatal withdrawal. The data suggest that timing of delivery,
mode of delivery, and last maternal methadone dose are
significant risk factors for the development of NAS requiring
treatment [13].
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In the United States, heroin and methadone are the most

common opioids that infants are exposed to prenatally. In the
general population, heroin is the most commonly abused
opioid. Because withdrawal of opioids from the mother is
associated with significant fetal distress and demise, medical
detoxification is rarely attempted and pregnant women need
to be maintained on an opioid. For addicted pregnant women,
methadone is the drug of choice because it is easier to
administer and manage than other opioids. (See "Substance
use in pregnancy", section on 'Methadone treatment'.)


withdraw from opioids present with a well-recognized
constellation of symptoms known as the neonatal abstinence
syndrome (NAS) [14]. These findings include:

Central nervous system Tremors, irritability, increased

wakefulness, high-pitched crying [15], hypertonicity and
hyperactive reflexes, seizures, yawning, sneezing, and
skin excoriation due to excessive rubbing. In addition,
they are more likely to have benign neonatal sleep
myoclonus compared to infants without NAS [16]. In the
absence of other neurological findings, this condition
requires no further evaluation or treatment.

Gastrointestinal Poor feeding, uncoordinated and

constant sucking, vomiting or regurgitation, loose or
watery stools, dehydration

Autonomic/metabolic signs Increased sweating, nasal

stuffiness, fever, temperature instability, tachypnea, and
mottling of the skin

Withdrawal from heroin is usually apparent within 48 hours

after birth and with methadone 48 to 72 hours after birth.
However, withdrawal may be delayed as late as four weeks
with both drugs [14].

In addition, infants born to mothers who are substance

abusers are at risk for preterm birth and intrauterine growth
restriction [17]. (See "Smoking and pregnancy" and "Alcohol
intake and pregnancy" and "Substance use in pregnancy" and
"Infants of mothers with substance abuse".)

Evaluation of in utero opioid exposure to premature infants

<35 weeks gestation is more complicated because these
infants appear to have decreased severity of withdrawal
symptoms compared to term infants [3]. Possible explanations
of the decrease in symptomatology in preterm compared to
term infants may be due to developmental immaturity of the
preterm central nervous system (eg, dendritic ramifications,
specific opiate receptors, or neurotransmitter function), or
reduced total drug exposure during the intrauterine period.

DIAGNOSIS The diagnosis of prenatal opioid exposure is

based upon a positive opioid identification in either a maternal
or neonatal specimen. If there is a negative or no maternal
screening, neonatal screening of meconium or urine samples
is indicated in infants with maternal or infant characteristics

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known to be associated with drug use in pregnancy [14]. (See

"Substance use in pregnancy".)

Infants who have clinical findings that are suggestive of NAS

should be screened. In the United States, the consent process
for neonatal screening and the legal implications of a positive
result vary among the states [18]. The clinician needs to be
aware of the local laws that affect the screening of an infant
who may be at risk for prenatal opioid exposure.

Meconium drug testing is more sensitive than neonatal urine

testing in identifying fetal exposure to opioid drug use [2].
Urine screening of the newborn has a low sensitivity (high
false-negative rate) because only infants with recent exposure
will have a positive test. The ability to detect in utero drug
exposure was reported to be similar in umbilical cord tissue
compared to meconium samples [19]. The use of umbilical
cord tissue as a screening specimen is appealing as some
infants have passed meconium in utero making collection
impossible and in other cases it may take several days for the
passage of meconium, thereby delaying the diagnosis.
However, further studies are needed to confirm these results
before the universal use of umbilical cord specimens can be

Screening for substance abuse during pregnancy is presented

separately. (See "Alcohol intake and pregnancy" and
"Substance use in pregnancy".)

DIFFERENTIAL DIAGNOSIS Other common neonatal

problems may have similar features to the neonatal
abstinence syndrome (NAS). This includes colic, infections
(such as sepsis), and metabolic abnormalities (such as
hypocalcemia, hypoglycemia, and hypothermia). Clinical signs
should not be attributed solely to withdrawal without
appropriate assessment and diagnostic tests (such as
screening of opioid exposure, complete blood count, blood
cultures, and electrolytes) to differentiate these diseases from


Scoring systems Several abstinence scoring methods (eg,

Lipsitz tool, neonatal abstinence scoring system, and the
neonatal withdrawal inventory) have been developed based
upon the clinical manifestations of NAS [20-22] (figure 1).
These tools measure the severity of neonatal withdrawal and
can be used to guide management. In each clinical setting
that cares for infants with NAS, an abstinence scoring system
should be adopted as it provides a semi-objective and
19.3 standardized assessment of the patient's withdrawal
symptoms. Scoring systems are used to initiate, adjust, and
wean pharmacologic therapy.

The neonatal abstinence Finnegan scoring system is the most

widely used of these methods and assesses 31 specific clinical
items and is the one used in our clinical practice [21] (figure
1). Pharmacologic therapy is generally started with three or
more scores above eight. Each institution decides upon the
number of consecutive scores below a threshold value for
initiation of weaning.
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TOPIC OUTLINE Supportive care The initial treatment of NAS should be

supportive, because pharmacologic therapy may not be
needed and will prolong hospitalization. Supportive care
EPIDEMIOLOGY includes [14]:
Decrease sensory stimulation (eg, quiet room and
swaddling the infant)
MANAGEMENT Administer small frequent feedings
Scoring systems
Administer increased calorically dense formula (24
Supportive care cal/oz) or fortified breast milk (for mothers on
- Breastfeeding methadone) to supply additional calories. Estimated
- Skin care caloric intake for adequate growth ranges from 150 to
Pharmacologic therapy 250 cal/kg per day because of the infant's increased
- Indications metabolic needs [14].
- Opioid therapy
- Adjunct therapy Breastfeeding Breastfeeding by mothers who continue
- Naloxone to abuse heroin is not recommended because heroin is
LONG-TERM OUTCOME excreted into breast milk resulting in adverse effects on the
infants [23]. Breastfeeding by mothers who continue to use
methadone appears to be safe [23]. In one study of infants of
mothers who continue to use methadone, methadone
concentration was low in breast milk (range 21 to 462 ng/mL)
REFERENCES and was not related to the maternal dose of methadone [24].
However, methadone concentration increased over time from
1 to 30 days after delivery. In plasma samples of infants at 14
FIGURES days of age, methadone concentration was also low ranging
NAS assessment score sheet from 2.2 to 8.1 ng/mL and was not different in infants who
were breastfed compared to those who were formula-fed. In
addition, there was no difference in neurodevelopmental
Alcohol intake and pregnancy assessments between infants who were breastfed compared
Infants of mothers with substance to those who received formula at 3, 14, and 30 days of age.
Overview of diaper dermatitis in Monitor weight and readjust dietary intake to ensure
infants and children appropriate growth. Poor weight gain in the face of
Smoking and pregnancy adequate caloric intake may reflect the need to
introduce pharmacologic intervention as well as increase
Substance use in pregnancy
the pharmacologic doses being utilized.

Monitor temperature stability, sleeping patterns, and

gastrointestinal symptoms (eg, diarrhea and vomiting).
The presence and persistence of these findings may
indicate the need for pharmacologic therapy.

Skin care The best approach to prevent skin excoriation

due to excessive rubbing is to swaddle the infant, thereby
reducing trauma to the skin.

In those patients with skin excoriation, routine skin care

includes keeping the area clean, dry, and open to the air.
Topical barrier creams used to treat diaper dermatitis may
also be applied to affected areas to protect the skin and

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prevent further damage. (See "Overview of diaper dermatitis

in infants and children", section on 'Topical barriers'.)

Pharmacologic therapy Pharmacologic intervention is

aimed at the short-term improvement of clinical
symptomatology. Long-term benefits from treatment, in the
symptomatic infant, remain unproven.

Indications Infants with confirmed prenatal drug

exposure who are asymptomatic or respond to supportive care
do not require pharmacologic treatment.

Indications for drug therapy include [14]:

Poor feeding with failure to gain weight, especially when
adequate calories are being ingested
Inability to sleep
Fever unrelated to another source
Significant diarrhea and/or vomiting resulting in weight
loss or hypovolemia

If an abstinence scoring method is utilized, pharmacologic

treatment is initiated when the assessment of the infant's
symptoms exceeds a predetermined score (figure 1).

Opioid therapy If pharmacologic treatment is

necessary, opioid therapy is recommended. In a meta-analysis
of randomized or quasi-randomized controlled studies, opioid
therapy (morphine, paregoric, or methadone) was compared
to supportive care alone or sedative treatment
(phenobarbital or diazepam) [25,26]. Results were as follows:

In one study, opioid therapy compared to supportive

care alone reduced the time to regain birthweight and
duration of supportive care. Opioid therapy increased
the duration of hospital stay. Infants included in this
study had three consecutive scores on the Neonatal
Abstinence Scoring System that exceeded the
predetermined score indicated for treatment.

In an analysis of four studies, there was no difference in

treatment failure rate in infants treated with opioid
compared to those who received phenobarbital [27-29].
In three of the four studies, inclusion criteria were based
upon the infant exceeding a predetermined score on a
NAS scoring system indicating requirement for
treatment [25-27,30]. In a subset analysis of one of the
studies, opioid compared to phenobarbital therapy
reduced treatment failure in infants with only prenatal
opioid exposure [30]. In one of the these studies, opioid
therapy resulted in a shorter duration of therapy (8
versus 12 days) [27]. There was no difference in the
duration of treatment or hospital stay in two of the other
studies [25,26,30].

One study reported a small reduction in the incidence of

seizures with opioid therapy compared to
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phenobarbital [28].

One study reported a significant reduction in treatment

days and nursery admissions in infants who received
morphine [26].

In an analysis of two studies, there was a reduction in

treatment failure in patients who received opioid therapy
compared to diazepam (RR 0.36, 95% CI 0.18 to 0.69).

A second meta-analysis compared sedative therapy

(phenobarbital, chlorpromazine, and diazepam) to one
another or to supportive therapy alone [31,32]. Results are as

Phenobarbital compared to supportive care alone does

not reduce treatment failure or the time required to
regain birth weight but reduced the duration of
supportive care.

In two studies, phenobarbital compared to

diazepam reduced treatment failure.

There were insufficient data on the use of

chlorpromazine or clonidine to be able to recommend
either drug in the treatment of infants with NAS.

These results suggest that opioid therapy is better at reducing

the symptoms of withdrawal compared to
phenobarbital therapy or supportive care alone in infants with
significant withdrawal symptoms. However, caution should be
exercised, as these studies were limited because many of the
infants were exposed to more than one drug of abuse and the
long-term effects of opioid therapy are unknown. Despite
these concerns, we suggest that opioid therapy be used in
infants who, despite supportive care, continue to have
significant withdrawal symptoms. If a sedative agent is
required then phenobarbital is the preferred medication.
Chlorpromazine or clonidine should only be used in the
context of a clinical trial because there are insufficient data
demonstrating that they are effective in the treatment of NAS

There are several different forms of opioid therapy, which

include the following [14]:

Tincture of opium is also referred to as deodorized

opium tincture and DTO. The preparation that is used to
treat NAS is a 25-fold dilution and contains the same
concentration of morphine equivalent (0.4 mg/mL) as

Paregoric contains anhydrous morphine (0.4 mg/mL)

and is also referred to as camphorated tincture of
opium. The use of this therapy has decreased because
of its additional ingredients. These include
antispasmodics (noscapine and paverine), ethanol (high
concentration of 45 percent), and the additive benzoic
acid (which may compete with bilirubin binding sites).

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As a result, paregoric is no longer recommended to treat

neonatal opioid withdrawal.

Morphine, both parental and oral preparations are

available for use in infants with NAS.


A survey of academic neonatology centers in the United States

reported a wide variation in the treatment of infants with NAS
pharmacologic treatment [34]. The majority of these sites
initially used an opioid, most commonly tincture of opium or
morphine sulfate solution [34].

If the infant has been exposed to multiple drugs in utero

including opioids, opioid therapy should be used if the infant
has symptoms of withdrawal [14]. (See "Infants of mothers
with substance abuse", section on 'Polydrug use'.)

Adjunct therapy The use of adjunct therapy has been

suggested in infants with severe NAS or in those who have
been exposed to multiple drugs.

Phenobarbital Phenobarbital has been added to opioid

therapy in infants with severe NAS and in infants
exposed to multiple drugs. In one study, the combined
used of opioid and phenobarbital therapy compared to
opioid therapy alone reduced the length of hospital stay
and duration of symptoms [35]. (See "Infants of
mothers with substance abuse", section on 'Polydrug

Clonidine Clonidine is used in older children and

adults for opioid withdrawal. In a clinical trial of 80
neonates with intrauterine exposure to methadone or
heroin, the addition of oral clonidine (1 g/kg every four
hours) versus placebo to standard opioid therapy
decreased the duration of pharmacologic therapy (11
versus 15 days) [36]. Higher doses of opioid therapy
were needed in the placebo group. There were no
significant short-term complications (eg, hypertension,
hypotension, bradycardia, or oxygen desaturations) in
either group. There were three deaths in the clonidine
group (myocarditis, sudden infant death syndrome, and
homicide). Although, the authors state the deaths were
not attributable to combined therapy with clonidine,
further trials are needed to demonstrate the efficacy and
safety of this therapeutic regimen.

Naloxone Naloxone may precipitate rapid withdrawal

symptoms [33], and therefore should be used with caution in
the infant exposed prenatally to opioids. In the delivery room,
the use of a small dose of naloxone has been suggested for
apneic infants who have been exposed to opioids in utero [7].

However, in most infants whose mothers received opioids

during labor, naloxone is not required. This was illustrated in a
prospective study that determined the frequency of naloxone
administration after the introduction of resuscitation
guidelines for neonatal naloxone administration in the delivery

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room [37]. Of the 1000 total births, 434 mothers (43 percent)
received an opioid during labor but only 1 infant received
naloxone after delivery. Thirty-six infants of mothers who
received opioids developed respiratory symptoms. In one
case, respiratory symptoms may have been due to maternal
opioid administration. This infant did not receive naloxone. In
the remaining 35 cases, opioid exposure was ruled out as a
cause of neonatal respiratory distress.

If naloxone is used, the clinician needs to be aware of the

potential risk of rapid withdrawal and be prepared to treat the
infant if they become symptomatic [14].

In our practice, we begin with opioid therapy in patients with

symptoms that exceed a predetermined level on an
abstinence scoring system despite supportive care. The choice
of opioid therapy is physician dependent. The dose of opioid
therapy is determined by the response of the patient. If the
patient remains symptomatic, an increase in drug dose is
indicated. Once the patient responds to therapy and a
decrease in withdrawal symptoms and weight gain is
established, medication can be weaned. Understanding that
there are increased metabolic demands of the patient who is
withdrawing becomes an important parameter to follow while
making decisions in weaning the opioid. The rate of wean is
dependent on the patient's clinical status. Use of abstinence
syndrome scoring method facilitates this process (figure 1).

LONG-TERM OUTCOME It has been difficult to ascertain

the long-term effects of prenatal opioid exposure on the
developmental outcome of affected children because of
confounding variables. These include prenatal factors, such as
other drug exposures, prematurity, and low birth weight, and
postnatal factors, such as care provider's socioeconomic and
educational level.

There have been reports of developmental and behavioral

problems in both prenatal methadone and heroin exposed
children. However, these studies have had small numbers of
patients and confounding risk factors making it difficult to
determine the primary contribution of prenatal drug exposure
to abnormal outcome [38,39].

In contrast, other studies have reported normal outcome as

evaluated by the Bayley scales of infant development at six
months and one year of age [40,41]. Another report of in
utero opioid exposed infants compared to patients without in
utero exposure, which controlled for socioeconomic status and
birth weight, reported that the amount of prenatal care and
the postnatal home factors were more predictive of the
infant's developmental performance at two years of age than
prenatal drug exposure [42].

Further large studies controlled for confounding medical and

socioeconomic factors are required to determine whether in
utero opioid exposure has an independent adverse effect on


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A newborn infant born to a mother addicted to opioids is

at risk for drug withdrawal. These infants present with a
constellation of withdrawal symptoms known as the
neonatal abstinence syndrome (NAS). (See
'Epidemiology' above and 'Clinical
manifestations' above.)

Heroin and methadone are the most common opioids

that infants are exposed to in utero. Withdrawal from
heroin is usually apparent within 48 hours after birth
and with methadone from 48 to 72 hours after birth.
However, withdrawal may be delayed as late as four
weeks with either drug.

The diagnosis of in utero opioid exposure is based upon

a positive identification of an opioid in either a maternal
or neonatal specimen. Neonatal screening of meconium
or urine samples is indicated if maternal or infant
characteristics known to be associated with drug use in
pregnancy are present and/or if the infant exhibits
symptoms suggestive of NAS. The clinician needs to be
aware of the local laws that impact on the screening of
prenatal opioid exposure in an at risk infant. (See
'Diagnosis' above.)

Other common neonatal problems including colic, sepsis,

and hypoglycemia, have similar features to the neonatal
abstinence syndrome (NAS). Careful clinical assessment
and diagnostic tests (eg, neonatal screen for NAS,
complete blood count and blood cultures for sepsis, or
serum blood glucose level for hypoglycemia) help
differentiate NAS from these disorders. (See 'Differential
diagnosis' above.)

It is unclear whether there are any long-term adverse

effects on neurodevelopmental outcome in children who
were exposed to prenatal opioids. (See 'Long-term
outcome' above.)

Treatment Management of infants with NAS includes:

Evaluation of the severity of NAS and response to

treatment. We suggest the use of an abstinence scoring
method to measure the severity of neonatal withdrawal
and guide management (figure 1), (Grade 2C). (See
'Scoring systems' above.)

Supportive care Initial treatment of NAS is

supportive, because pharmacologic therapy may not be
needed and will prolong hospitalization. Supportive care
includes decreasing sensory stimulation, providing
adequate nutrition for the infant's increased metabolic
needs, and assessing the need for pharmacologic
therapy (eg, monitoring temperature stability, sleeping
patterns, and gastrointestinal function). (See
'Supportive care' above.)

Pharmacologic therapy Pharmacologic therapy is

indicated for infants who have seizures, weight loss or
failure to gain adequate weight, inability to sleep, or
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fever. If an abstinence scoring method is utilized (figure

1), pharmacologic therapy is initiated when the infant
exceeds a predetermined symptomatic score. (See
'Indications' above.)

If pharmacologic treatment is necessary, we recommend that

the initial drug of choice be an opioid (Grade 2B). There are
no controlled studies comparing the different forms of opioid
therapy including tincture of opium, paregoric, morphine, and
methadone. The choice of opioid agent is physician
dependent. (See 'Opioid therapy' above.)

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