Neonatal Abstinence Syndrome

Neonatal withdrawal syndrome, generically termed neonatal abstinence syndrome (NAS), is a complex disorder. It is defined as a constellation of behavioral and physiological signs and symptoms in newborns that are remarkably similar despite marked differences in the properties of the causative agent.[1] Two major types of NAS are recognized: NAS due to prenatal or maternal use of substances that result in withdrawal symptoms in the newborn and postnatal NAS secondary to discontinuation of medications such as fentanyl or morphine used for pain therapy in newborns admitted to the neonatal intensive care unit (NICU).[2] Chronic opioid exposure in the most common source of NAS.[1]

Postnatal NAS results when an abrupt discontinuation of opioid analgesia occurs, usually after prolonged drug exposure. Fentanyl is the most commonly used analgesic drug in the neonatal intensive care unit (NICU). It is a potent, rapid-acting, synthetic opioid with a relative lack of hemodynamic side effects. Clinical studies have found that continuous infusions of fentanyl and morphine produce a high rate of opioid withdrawal when administered to critically ill infants. Tolerance and physical dependence are thought to develop more rapidly with shorter acting drugs and after continuous infusions rather than with intermittent administration. Tolerance and withdrawal symptoms may occur after 5 or more days of continuous infusion of fentanyl. This occurs more often with fentanyl than morphine.[3, 4] This article focuses on prenatal or maternal use of licit or illicit drugs, although symptoms and therapy for postnatal NAS are similar.

Maternal substance abuse, the cause of prenatal NAS, is a leading preventable cause of mental, physical, and psychological problems in infants and children. Substance use by pregnant women has both medical and developmental consequences for the newborn, in addition to the legal, health, and economic consequences for the mother.

Drug abuse in pregnancy and neonatal psychomotor behavior consistent with withdrawal from opiate and polydrug withdrawal is currently a significant clinical and social problem. An estimated average of 5.4% of pregnant women aged 15-44 years used illicit drugs in 2012-2013, with the highest rate seen in those aged 15-17 years (14.6%), followed by women aged 18-25 years (8.6%), and those aged 26-44 years (3.2%).[5] From 2000-2009, the annual rate of NAS diagnosis among newborns in the United States increased almost 3-fold.[6]

Drugs frequently associated with neonatal problems are listed below.

Opiates and narcotics include the following:

• Codeine

• Fentanyl

• Heroin

• Methadone

• Meperidine (Demerol)

• Oxycodone

• Morphine

• Hydromorphone (Dilaudid)

• Butorphanol (Stadol)

• Pentazocine

• Propoxyphene (Darvon)

• Chlordiazepoxide

• Buprenorphine[7]

Other drugs include the following:

• Barbiturates

• Caffeine

• Cocaine

• Selective serotonin reuptake inhibitors (SSRIs)

• Antihistamines (Diphenhydramine, Hydroxyzine)

• Ethanol

• Marijuana

• Nicotine

• Phencyclidine

• Meprobamate

• Glutethimide

• Ethchlorvynol

• Diazepam and lorazepam

Most illicit drugs cause an addiction in the mother and dependence in the infant. Dependence or tolerance in the latter is due to passage of the drugs across the placental barrier; this occurs in varying degrees, depending on the pharmacokinetic properties of the individual drugs. Substances that act on the central nervous system (CNS) are usually highly lipophilic and have relatively low molecular weight. These characteristics facilitate crossing from maternal to fetal circulation, with rapid equilibration of free drug between mother and fetus. Once drugs cross the placenta, they tend to accumulate in the fetus because of the immaturity of the renal function and the enzymes used for metabolism. Disruption of the transplacental passage of drugs at birth results in the development of a withdrawal syndrome.

Neonatal abstinence syndrome (NAS) is often a multisystem disorder that frequently involves the CNS, gastrointestinal (GI) system, autonomic system, and respiratory system. Manifestations of NAS depend on various factors, including the drug used, its dose, frequency of use, and the infant's own metabolism and excretion of the active compound or compounds. In addition, prenatal NAS depends on the infant's last intrauterine drug exposure and the mother's drug metabolism and excretion. Withdrawal is generally a function of the drug's half-life; the longer the half-life, the later the onset of withdrawal. A longer half-life is also associated with a decreased likelihood of NAS in the infant.

It has been suggested that brain-derived neurotrophic factor (BDNF) may have a neuromodulatory role during withdrawal after in utero opiate exposure. A study of 67 infants with NAS (n = 34) and without NAS (n = 33) noted significantly elevated levels of plasma BDNF in infants with NAS during the first 48 hours of birth compared to those without NAS.[8]

The specific effects of illicit substances are complex and depend on the type of substance, the frequency and duration of use, the dose, the route of substance intake, and the timing of substance exposure with respect to gestational period.

Opiates produce the most dramatic effects on both the mother and fetus. Aside from the withdrawal symptoms, common findings in infants exposed to opiates include low birth weight, prematurity, and intrauterine growth retardation (IUGR). Because of its short half-life, heroin withdrawal may start as early as 24 hours after birth and usually peaks within 48-72 hours in 50-80% of infants born to mothers who are dependent on heroin. Some delayed withdrawal may occur as long as 6 days after birth. Sedative-hypnotics such as benzodiazepines and barbiturates have an even longer half-life, and withdrawal may not start until after the infant has been discharged from hospital (age 2 wk).

Methadone maintenance has been an acceptable form of therapy for opiate-dependent pregnant women since the late 1960s. This is currently the recommended treatment for opioid-dependent pregnant women; when properly used, methadone is considered relatively safe for the fetus. Methadone has been shown to decrease illicit behaviors, improve prenatal care and obstetric outcomes, and prevent acute maternal withdrawal that is associated with fetal death.[9] However, maternal methadone use is also associated with NAS, and its effects on the fetus are similar to the effects of heroin. Methadone's half-life is longer than 24 hours, and acute withdrawal may occur within the first 48 hours after birth and as long as 7-14 days later. The withdrawal may even be delayed for as long as 4 weeks after birth, with subacute signs developing as late as 6 months after birth. Neonates face an increased risk of fetal distress and demise, impaired fetal growth, and an increased risk of sudden infant death syndrome (SIDS). Thrombocytosis may occur in the second week of life and may continue until age 4 months.

The relationship between maternal methadone dosage and NAS is controversial, and the available data are conflicting. Several studies have shown that higher maternal doses are associated with an increase in the risk of preterm birth, the risk of symmetrically smaller infants, and longer hospital stays; the need for treatment for NAS indicates more significant withdrawal symptoms.[9, 10, 11] However, a more recent study showed that the incidence and duration of the NAS is not associated with maternal methadone dose.[12]

Buprenorphine is a semi-synthetic opioid approved for treating opioid addiction and dependence. A review suggested that buprenorphine and methadone have comparable maternal efficacy. Although methadone seems superior in terms of retaining patients in treatment, infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment of NAS, a significantly shorter period of NAS treatment, and a significantly shorter hospital stay than did infants with prenatal exposure to methadone.[13, 14]

The relationship between maternal buprenorphine dose and either NAS incidence or severity has been inconsistent. Secondary analysis study of data from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study failed to support any relationship between maternal buprenorphine dose at delivery and NAS severity, total amount of morphine needed to treat NAS, duration of treatment, or duration of hospital stay.[15] A more recent study indicated that polysubstance exposure was the most potent predictor of NAS severity in a group of buprenorphine-exposed neonates; there was a positive association between maternal buprenorphine dose and lower infant birth weight and length.[16] In another study, preliminary findings suggest that although marijuana exposure in the third trimester does not appear to complicate the pregnancy or the delivery process, such exposure may impact the severity of NAS, particularly the likelihood of needing pharmacologic therapy for NAS and the duration of hospital stay.[17]

Cocaine and amphetamines are stimulants with potent vasoconstrictor effects that stimulate the release and block the reuptake of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin.

Cocaine, a potent CNS stimulant, alters the major neurotransmitters and rapidly crosses the placenta. Neurobehavioral abnormalities frequently occur in neonates with intrauterine cocaine exposure, most frequently on day 2-3 postnatally. Because cocaine or its metabolites may be detected in neonatal urine up to 7 days after delivery,[18] observed abnormalities in exposed infants may reflect drug effect rather than withdrawal. Early studies suggested neonates exposed to cocaine exhibited a hyperactive Moro reflex, jitteriness, and excessive sucking. Studies do not support that neonates exposed to cocaine differ behaviorally from unexposed infants. The unresolved question is whether cocaine acts to limit head growth or disrupt brain development. A synergistic effect between cocaine and other CNS toxins is still possible.

Methylxanthine accumulates in the blood of breastfed infants whose mothers regularly consume caffeine substances. Nicotine is transferred through the placenta and may reach concentrations 15% higher than maternal levels. In utero exposure impairs neonatal habituation, orientation, autonomic regulation, and orientation to sound. Exposure also affects the infant's ability to be comforted and is associated with exaggerated startle reflex and tremor.

No evidence suggests neonatal withdrawal problems associated with maternal use of marijuana during pregnancy. Fetal exposure to marijuana has been associated with hypoglycemia, hypocalcemia, sepsis, hypoxic encephalopathy, intracranial hemorrhage, and jitteriness. Effects on the fetus depend on the dose, with evidence of intrauterine growth retardation (IUGR) noted in cases of heavier usage.

Neonates exposed to marijuana while in utero may also exhibit signs of nicotine toxicity, such as tachycardia, poor perfusion, irritability, and poor feeding. Growth inhibition is pronounced at birth and affects weight, length, and head circumference. Catch-up growth occurs within the first year in each growth category. Cognitive effects may persist to school age. However, withdrawal symptoms are generally not noted in infants in the newborn period. Extended follow-up does not show any effect in children aged 5-6 years.

Several studies have demonstrated that maternal cigarette smoking during pregnancy increases the risk of having a low birth weight infant.[19] Neonates born to mothers who smoke during pregnancy weigh an average of 150-250 g less at birth than neonates born to mothers who do not smoke during pregnancy. Research findings also suggest that infants of mothers who smoke during pregnancy may develop nicotine withdrawal in a pattern that is related to the magnitude of in utero exposure. Infants who have been exposed to tobacco have been found to be more excitable and hypertonic and demonstrate more stress and abstinence signs.

Neonates exposed to antidepressant medications during gestation are at increased risk of NAS. Selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine) are now the most frequently used drugs to treat depression both in the general population and in pregnant women, and they are also used to treat a wide spectrum of other mood and behavioral disorders. Infants exposed to SSRIs during the last trimester of pregnancy may exhibit neonatal adaptation syndrome. This is primarily manifested as CNS signs (eg, irritability, seizure), motor signs (eg, agitation, tremors, hypertonia), respiratory (eg, increased respiratory rate, nasal congestion), and GI signs (eg, emesis, diarrhea, feeding difficulty), fever, and hypoglycemia.[20] The onset of these signs ranges from several hours to several days after birth, and they are self-limiting, usually disappear by age 2 weeks. Symptoms are more commonly reported with fluoxetine and paroxetine exposure.

A prospective study showed no statistically significant differences between tricyclic antidepressants and SSRIs. It also revealed that women using antidepressants often use other medications as well during pregnancy, making the interpretation of antidepressant withdrawal symptoms difficult. A decrease in maternal SSRI and tricyclic antidepressant use during the third trimester may lower the neonatal risk of developing withdrawal syndrome; however, this needs to be balanced against the harmful effects of depression during pregnancy.

A case has been reported in which maternal tianeptine (atypical antidepressant) dependence during pregnancy appeared to induce a type of NAS that mimics opiate NAS.[21]

The current resurgence in heroin use is associated with the introduction of a cheap, smokeable form that is comparable to crack cocaine, only more potent. Cocaine's current popularity is related to increased availability and the presence of newer, cheaper forms.

Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal abstinence syndrome.

United States data

Neonatal drug withdrawal is a common problem in populations in which drugs taken for therapeutic, recreational, or addiction purposes are readily available to pregnant women. However, the incidence is difficult to determine because it is not uniformly tracked,[1] because of unreliable histories of maternal drug abuse, and because of limited health provider skills in eliciting drug histories and diagnosing nonopiate drug exposure in the newborn period. In addition, maternal use of more than one drug makes ascribing a given effect on the neonate to a specific drug difficult. One reported estimate was 3.39 per 1,000 hospital births (13,500 newborns).[1]

In the United States, substance use among pregnant and postpartum women is a public health issue. An estimated one third of childbearing women take prescription opioids.[22] A pooled analysis of data from the 2009-2013 National Survey on Drug Use and Health (NSDUH) revealed 0.9% of pregnant women met criteria for opioid analgesics, and 0.2% met the criteria for heroin.[1]

Between 2004 and 2013, neonatal abstinence syndrome (NAS) quadrupled and hospital length of stay increased from 13 days to 19 days, resulting in 7-fold increases neonatal intensive care unit stays for NAS.[22]

In 2011-2012, the NSDUH in the United States found that 5.9% of pregnant women aged 15-44 years reported using illicit drugs, compared with 10.7% of nonpregnant women in this age group.[23] The rate of illicit drug use among pregnant women aged 15-17 years was 18.3%, 9% among pregnant women aged 18-25 years, and 3.4% among pregnant women aged 26-44 years.[23]

In the 2013 report, among pregnant women aged 15-44 years, an estimated 8.5% reported current alcohol use, 2.7% reported binge drinking, and 0.3% reported heavy drinking. These rates were lower than the rates for nonpregnant women in the same age group (55.5, 24.7, and 5.2%, respectively).[23] In the same report, first trimester consumption was 17.9%, compared with significantly lower reporting during the second (4.2%) and third (3.7%) trimesters.

According to data from the Treatment Episode Data Set (TEDS), the proportion of female substance abuse treatment admissions aged 15 to 44 who were pregnant at treatment entry remained relatively stable between 2000 and 2010 (4.4 and 4.8 percent). However, there were shifts in the types of substances reported by these treatment admissions. The percentage of pregnant admissions reporting alcohol abuse (with or without drug abuse) decreased from 46.6 percent in 2000 to 34.8 percent in 2010, and the percentage reporting drug abuse but not alcohol abuse increased from 51.1 percent in 2000 to 63.8 percent in 2010.[24]

About 1 in 6 pregnant women aged 15-44 years had smoked cigarettes in the past month, based on combined data for 2011 and 2012. The rate of past-month cigarette use was lower among those who were pregnant (15.9%) than it was among those who were not pregnant (24.6%). This pattern was also evident among women aged 18-25 years (20.9 vs. 28.2 for pregnant and nonpregnant women, respectively) and among women aged 26-44 years (12.5 vs. 25.2, respectively). However, among those aged 15-17 years, the rate of cigarette smoking was higher for pregnant women than nonpregnant women (22.7% vs 13.4%).[23]

Data from the 2009 NSDUH report provide indirect evidence of dramatic increases in the prevalence of substance use following childbirth. Marijuana use was higher for recent mothers with children younger than 3 months in the household (3.8%) than for women in the third trimester of pregnancy (1.4%), suggesting resumption of use among mothers in the first 3 months after childbirth.[25]

Overall the incidence of drug-exposed newborns is reportedly 3-50%, depending on the specific patient population, with urban centers usually reporting higher rates. An estimated 10–11% of the 4.1 million live births (in 2005) involved prenatal exposure to alcohol or illegal drugs. When tobacco data are included more than one million children are affected by prenatal exposure. Among offspring exposed to opioids or heroin in utero, withdrawal signs develop in 55-94%.

Patrick et al reported that from 2000-2009, the rate of newborns diagnosed with NAS increased from 1.20 (95% CI, 1.04-1.37) to 3.39 (95% CI, 3.12-3.67) per 1000 hospital births per year. During the same period, total hospital charges for NAS are estimated to have increased from $190 million (95% CI, $160-$230 million) to $720 million (95% CI, $640-$800 million), adjusted for inflation. In 2009, the estimated number of newborns with NAS was 13,539 (95% CI, 12 441-14 635) or approximately 1 infant born per hour in the United States with signs of drug withdrawal.[6]

International data

No accurate data are available concerning worldwide incidence. Data from the UK Advisory Council on the Misuse of Drugs suggests 6,000 babies are born to mothers who abuse drugs each year (1% of all UK deliveries).[26, 27] In the past, heroin was the most commonly abused drug. Women are now more likely to use cocaine, methadone, or more than one illicit drug.

In Europe, each year as many as 30,000 pregnant women use opioids, and the number of pregnant women using drugs other than opioids may be equally as high.[28]

In Canada, 3 of every 1,000 babies born from 2009–2010 had NAS.[29]

In Australia, the incidence of NAS as a discharge diagnosis decreased from 5.07 per 1000 live births in 2002, to 3.18 in 2011.[30]

Race- and age-related demographics

Pregnant white women and Hispanic women had lower rates of illicit drug use (4.4% and 3%, respectively) than black women (8%).[31] Among women aged 15-44 years, the rate of cigarette use is higher among pregnant white women than among pregnant black or pregnant Hispanic women.[31]

Rates of substance use among pregnant women vary by age group, with past-month illicit drug and alcohol use highest among teenagers. The rate of illicit drug use among pregnant women aged 15-17 years was 16.2%, was 7.4% among pregnant women aged 18-25 years, and was 1.9% among pregnant women aged 26-44 years.[23]

Infants born to mothers who are chemically dependent face not only the experience of sudden withdrawal from poly intoxicants but also other medical and social challenges. Prognosis widely varies and depends on the family, socioeconomic variables, and whether either or both parents continue to use illicit drugs. A home environment with an addicted mother is a compromising variable.

Irner et al showed that children of mothers ceasing or decreasing their use of substances up to time of the birth delivered healthier babies than the mothers who continued to use substances. In addition, their results indicated that early intervention, including treatment of addiction during pregnancy, prenatal care, and psychosocial support, can help to prevent some developmental defects of newborn children of substance-using mothers.[32]

Long-term problems of children exposed to illicit drugs in utero include adverse neurodevelopmental outcomes. Lower intelligence quotient scores have been reported in children with in utero exposure to cocaine or methadone. Speech, perceptual, and cognitive disturbances have been reported in toddlers who were exposed to opiates. Difficulties with expressive language articulation have been reported in children of mothers who abused cocaine. Behavioral problems are also reported in children of mothers who have taken illicit substances in pregnancy. These include lower levels of learning and adapting to new situations; higher sensitivity to their environment resulting in irritability, agitation, aggression, poor social skills; and a lack of imitative play and late emergence of symbolic play.

In utero opioid exposure may have the potential to also affect gastrointestinal tract and the gut biome, which, in turn, may impair immunity and protection against pathogens, thereby affecting health over the long term.[33]

Prenatal exposure to marijuana has been associated with increased levels of depression during childhood.[34] Another study showed increased hyperactivity, impulsivity, inattention symptoms, and delinquency has been associated with prenatal marijuana use.[35]

The severity of withdrawal signs, including seizures, has not been proven to be associated with differences in long-term outcome after intrauterine drug exposure. Furthermore, treatment of drug withdrawal may not alter the long-term outcome.

Morbidity/mortality

Death is rarely associated with withdrawal alone but occurs as a consequence of prematurity, infection, and severe perinatal asphyxia.

Long-term mortality rate is likely to be extremely low, although the risk for SIDS is significantly higher among infants who are exposed to opiates. Infants exposed to methadone have a 3.7-fold higher risk of SIDS compared with controls. Infants exposed to cocaine have a 2.3-fold higher risk for SIDS compared with infants with no exposure. This increased risk is related to a complex interplay of factors; the compromised home environment associated with a mother who is drug addicted is an important variable.

Prenatal opioid exposures may cause birth defects, altered brain development and neonatal abstinence syndrome.[2, 22]

Complications

Narcotics may have a direct effect on the development of the respiratory center in the brain stem, but an adverse effect of opiates on long-term postnatal growth is not evident. In longitudinal studies, developmental sequelae have not been proven. Problems with habituation, visual and auditory responsiveness, and interactive patterns have been observed in the first months of life.

When assessing potential neonatal abstinence syndrome (NAS), the most reliable method of determining the extent of drug use in pregnancy is maternal history as part of routine antenatal assessment, with a structured interview providing a greater yield than an informal interview.

The amount of information obtained from the mother about prenatal drug exposure widely varies and may not be reliable. How the mother is questioned and the specificity of the questions are the most important factors. Maternal interviews have been reported to be the least sensitive method of identifying drug use in pregnancy when compared with maternal hair and meconium drug testing. Maternal self-report was found to underestimate in utero drug exposure by as much as 44% when compared with data from meconium analyses.[36]

Despite concerted efforts by health care professionals to promote prenatal care, the mother may not have received such care and the delivery hospitalization may be the only opportunity to elicit information on the nature and extent of the infant's in utero exposure to drugs and alcohol. The mother's concern for her infant's health may encourage valid responses; conversely, fear of legal reprisals or loss of custody of the infant may cause the mother to deny drug use.

The Committee on Substance Abuse of the American Academy of Pediatrics recommends obtaining a comprehensive medical and psychological history that includes specific information regarding maternal drug use as part of every newborn evaluation.[37]

The relationship between maternal cocaine use and placental abruption is well established. Therefore, a perinatal history of abruption should alert the medical caretaker that prenatal exposure to cocaine is a possibility.

A thorough physical examination of the neonate should include accurate assessment of weight, length, and head circumference and a standardized assessment of gestational age. Special attention should be paid to signs of intrauterine growth retardation (IUGR), microcephaly, prematurity, congenital infection, and major and minor congenital malformations.

Infants are suspected of having neonatal abstinence syndrome if they exhibit any of the signs listed below.

Central nervous system (CNS) dysfunction includes the following features:

• High-pitched cry

• Restlessness, with sleep duration less than 1-3 hours after feeding

• Hyperactive reflexes

• Jitteriness

• Tremors

• Hypertonia

• Myoclonic jerks

• Generalized convulsions

Metabolic, vasomotor, and respiratory disturbances include the following features:

• Sweating

• Fever

• Mottling

• Frequent yawning

• Sneezing (>3 times per interval)

• Nasal flaring

• Respiratory rate greater than 60 breaths per minute without retractions

• Apnea

Gastrointestinal (GI) dysfunction includes the following features:

• Excessive (frantic) sucking or rooting

• Poor feeding

• Hyperphagia, usually associated with poor weight gain

• Regurgitation or projectile vomiting

• Loose or watery stools

Alcohol-specific symptoms include the following:

• Withdrawal that presents within the first 24 hours of life is reported among infants with the dysmorphic features of fetal alcohol syndrome.

• Neonates also exhibit irritability, tremors, seizures, opisthotonus, and abdominal distention.

Lysergic acid (LSD) symptoms include the following:

• The effect of LSD on the fetus is clouded by the high incidence of polydrug abuse.

• Withdrawal symptoms manifest as hypertonia, tremors, poor feeding, and abnormal feeding patterns.

Other symptoms include the following:

• Nicotine may produce withdrawal symptoms in infants, including increased excitability and hypertonicity.

• Caffeine withdrawal includes feeding difficulties, vomiting, excessive crying, irritability, and poor sleep patterns. Onset of symptoms may occur as long as 5 days after birth and persist for weeks or months.

The timing of onset of the symptoms gives an indication of the maternal drug abuse. Withdrawal from high levels of maternal alcohol can occur within a day or 2 of birth. Heroin has a short half-life and withdrawal also occurs within 48–72 h of birth, whereas methadone withdrawal occurs at 7–14 days.

Preterm infants are at lower risk of drug withdrawal with less severe courses. Infants born at less than 35 weeks' gestation whose mothers received methadone maintenance had significantly lower total and CNS abstinence scores than did term infants of mothers receiving similar methadone dosages.[38] In a more recent study, lower gestational age correlated with a lower risk of neonatal withdrawal.[39] The apparent decreased severity of signs in preterm infants may relate to developmental immaturity of the CNS, differences in total drug exposure, or lower fat deposits of drug.[40]

Different scoring systems have been developed for assessing the severity of neonatal abstinence syndrome, such as those by Finnegan, Ostrea, Lipsitz, Rivers, and the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS).[41, 42, 43] These are based on opiate withdrawal and may not be entirely appropriate for the infant exposed to cocaine or other drugs.

The most widely used system is the Finnegan scoring system, in both its original (Finnegan Neonatal Abstinence Scoring System [FNASS]) and modified forms. An NAS scoring form is shown below.

Neonatal Abstinence Syndrome. Neonatal abstinence syndrome scoring form.

The Finnegan scale assesses 21 of the most common signs of neonatal drug withdrawal syndrome and is scored on the basis of pathological significance and severity of the adverse symptoms, which sometimes requires pharmacological treatment. Despite the number of items that can be scored, it is nevertheless a relatively easy and reliable system to use once staff have been adequately trained. However, the potential for bias and subjectivity may affect the scores, and the thresholds for treatment reported in the literature vary.[44] This scale can also be used to assess the resolution of signs and symptoms after initiating treatment.

To obtain a daily average score, measurements are performed every 4 hours until the patient is stable. If 3 consecutive scores are equal to or greater than 8, treatment for withdrawal is started. The decision to commence treatment can depend on factors other than this score alone, including the reported exposure, the age of the infant, consideration of comorbidities that might influence the score, whether an inpatient or outpatient strategy is used, and the experience of the clinician making treatment decisions.

The Eat, Sleep, Console (ESC) approach focuses on the comfort and care of infants diagnosed with NAS by maximizing nonpharmacologic methods, increasing family involvement in the treatment of their infant, and using morphine as needed. Shorter length of hospital stay and lower rates of medication usage have been reported in several studies.[45, 46, 47]

A recent study recorded the FNASS scores of 50 opioid-exposed infants every 2 to 6 hours but managed the infants using the ESC approach. The investigators showed that ESC is an effective method for treating infants with NAS with a significantly reduced need for pharmacologic treatment and may lead to substantial reductions in length of stay.[45]

The infant is best cared for in a unit with experienced personnel who can recognize problems, perform constant evaluations, and institute the necessary interventions.

Healthcare professionals, hospitals, and clinics have an obligation to assess newborns who exhibit signs and symptoms of drug exposure, whose mothers have been identified as probable substance users, or whose mothers have signs and symptoms of drug use.

Rapidly detecting fetal exposure to licit and illicit drugs is of considerable medical value. Such information can assist in making diagnosis of neonatal abstinence syndrome (NAS), as well as help clinicians focus the plan for treatment and follow-up for the neonates. Clear evidence suggests that recognizing the substance-exposed infant and implementing early intervention services for the child and mother are keys to minimizing the acute and long-term effects of prenatal substance exposure. Thus, even if the infant exhibits no clinically significant difficulties in the neonatal period, identification of the substance exposed infant can improve the long-term outcome.

Commonly accepted indications for toxicology analysis include no prenatal care, intrauterine growth retardation (IUGR), preterm delivery, abruptio placentae, or cardiovascular accidents in mother or child, especially in those cases in which no other reasons for poor outcome are noted.[52]

The studies discussed below may be necessary to diagnose neonatal abstinence syndrome (NAS).

Radioimmunoassay and enzyme immunoassay

These are the most commonly used drug screens. Both are semiquantitative and highly sensitive, but enzyme immunoassay takes less time to perform and is less expensive.

These tests inform the clinician about the presence or absence of substance abuse, rather than quantifying the drug level, as in toxicology screens. Perinatal drug testing aims to examine in utero drug exposure over the pregnancy. Each type of specimen has its own advantages and limitations.

Urine toxicology assays

Note the following:

• Urine was traditionally the specimen of choice for neonatal drug testing, although collection is difficult. The adhesive for the collection bag causes skin irritation and frequently fails to adhere. Another disadvantage is the short detection window; urine provides maternal drug use data only for a few days prior to delivery.

• Urine toxicology screening is useful for clinical and research purposes. Urinary excretion of metabolites may be detectable only for a few days (eg, benzoylecgonine) to a few weeks (eg, cannabinoids). One cannot expect to ascertain early pregnancy use or even relatively recent use if the metabolite concentration does not reach the detection threshold.

• Urine is relatively easy to obtain, requires minimal preparation (provided samples are not contaminated by meconium or feces), and can be analyzed using numerous laboratory techniques. Although urine samples generally contain a higher drug concentration than serum samples, the detection of compounds depends on obtaining an appropriate sample as close as possible to birth and also depends on the timing of maternal drug ingestion prior to delivery.

• These tests detect recent use of cocaine and its metabolites, amphetamines, marijuana, barbiturates, and opiates. Cocaine can be detected in urine 6-8 hours after use in the mother and as long as 48-72 hours after use in the newborn. Alcohol is detectable in neonatal urine for 6-16 hours after the last maternal ingestion.

• Detection of drugs depends on many variables, including individual drug metabolism, hydration status of the subject, route of administration, and frequency of ingestion.

• No drugs are known to cross react with the immunoassays for cocaine and marijuana. Several over-the-counter remedies and herbal preparations may contain ephedrine and phenylpropanolamine (recalled from US market), which can produce false-positive enzyme immunoassay test results for amphetamines. Therefore, confirmatory testing is required.

• Immunoassay for opiates does not distinguish between codeine, morphine, or their glucuronide conjugates.

Meconium analysis

Meconium analysis is currently considered the best method for detecting drug exposure in pregnancy. It provides a wider window of detection of gestational exposure, presumably as remote as the second trimester, when drugs begin to accumulate in meconium (by direct deposition from the biliary tree or when the fetus ingests amniotic fluid).

Meconium analysis is reliable for detecting opioid and cocaine exposure after the first trimester and can be used to detect a range of other illicit and prescribed medications.

However, meconium can be contaminated by infant urine, although only cocaine or opiate use within approximately 72 hours of birth is reflected. Thus, false-positive results occur if meconium is contaminated with urine, reflecting antepartum and perinatal exposure. Theoretically, lidocaine can cause a positive result, but a large amount is required.

When a meconium sample is stored at room temperature, it decreases cocaine and cannabinoid levels by 25% per day.

A study comparing umbilical cord tissue and meconium for the confirmation of in utero illicit drug exposure revealed different sensitivities of drug detection in both samples.[53] Meconium provided greater sensitivity over cord tissue, which led the study author to conclude that meconium is likely to remain the specimen of choice when sensitivity is of the greatest importance.[53]

Umbilical cord testing

An option for monitoring in utero drug exposure is the use of umbilical cord tissue testing.[54] A report suggested that detecting drug exposure from umbilical cord tissue has similar sensitivity and specificity to meconium samples and may have some advantages over the collection of meconium.[55] Testing umbilical cord tissue enables analysis to occur immediately after birth, in contrast to meconium testing that is delayed up to 3 days before specimen availability. Moreover, in some cases the meconium is passed in utero, making collection impossible. Umbilical cord tissue is easily and noninvasively collected and may reflect a long window of drug detection. Negative results are usually reported the same day the specimen is received. Presumptive positive results require several days to be reported.[56] Palmer et al showed that umbilical cord tissue toxicology testing yielded a similar detection rate compared to that from meconium testing.[57]

As a result of all these advantages, umbilical cord tissue testing is rapidly replacing meconium studies as the newborn toxicology gold standard because of its universal availability, shortened turnaround time, and improved chain of custody integrity.[56] Although cord tissue offers many advantages from an operational perspective, the yield of testing is lower than that of meconium drug testing, and it may be difficult to draw firm conclusions about timing or duration of exposure.[53]

Blood tests

Blood samples are of limited value, because the window of detection is narrow owing to the rapid effects of metabolism and the low concentrations of drugs present in blood.

Hair analysis

Neonatal hair testing can also identify prenatal drug exposure. Hair begins to form at approximately 6 months' gestation; a positive result indicates use during the last trimester. Hair testing is advantageous because the specimen can be collected at any point during the first 3 months of life, after which time infant hair replaces neonatal hair.[58]

This method is useful in detecting narcotics, marijuana, cocaine, and cocaine-alcohol metabolites, but the technique is expensive, is not widely available, and is limited by the procedures required to quantify the very small amounts of drug present. Obtaining an adequate sample may be difficult, and recent exposure might not be detected because hair growth is slow.

Analysis of 1.5 cm of maternal hair reveals the maternal drug use pattern during the previous 3 months. Drug metabolites can be detected in infant hair for 2-3 months after birth.

Cranial ultrasonography is not routinely recommended, but literature is suggestive of central nervous system abnormalities, including hemorrhagic ischemic lesions in some drug-exposed infants.[59]

Evidence is insufficient to support a mandate for cranial ultrasonography in all cocaine-exposed infants. van Huis et al studied 154 neonates exposed to cocaine in utero and found that none of the infants had severe abnormalities on cranial ultrasonography.[60] Also, the detected abnormalities were not correlated with the duration or maximum amount of cocaine use. Given these findings, the investigators recommended that routine cranial ultrasonography in infants exposed to cocaine in utero is not warranted.[60] However, special consideration should be given to specific neuroimaging of cocaine-exposed preterm infants, infants whose head circumference falls below the 10th percentile on standardized fetal growth curves, and infants with abnormal neurologic signs, neurobehavioral dysfunction, or seizure activity.[61]

Drug-exposed infants are at increased risk of acquiring infections transmitted from mothers whose lifestyles include unsafe sexual practices or intravenous drug abuse. Assessment of the mother who abuse drugs and their infants for hepatitis B and hepatitis C and sexually transmitted diseases including human immunodeficiency virus (HIV) should be incorporated into the prenatal care setting and delivery hospitalization.

The length of hospitalization in patients with neonatal abstinence syndrome (NAS) varies, depending on the drug, withdrawal symptoms, and social factors. In a 2016 report, gestational age at birth was not associated with pharmacologic requirements to manage NAS in late preterm and term infants.[62] When medication is needed, term infants may receive such therapy longer than their preterm or late-term counterparts.

Other issues that need to be addressed include breastfeeding and infectious disease prevention. If the mother abuses intravenous drugs, screen for human immunodeficiency virus (HIV), hepatitis B and hepatitis C, Chlamydia,syphilis, and gonorrhea.

Breastfeeding confers immunologic benefits to the neonate, and bonding benefits the mother. One study reported that only small amounts of methadone were detected in breast milk of women maintained on higher doses of methadone and recommended breast feeding for methadone-maintained women.[63] The benefits of breastfeeding often outweigh the effect of the small amount of methadone that enters the breast milk.

The previous recommendation of the American Academy of Pediatrics (AAP) was for mothers receiving maintenance doses of methadone more than 20 mg/24 h not to breastfeed.[64] However, the AAP now classifies methadone as compatible with breastfeeding.[65] The ACOG recommends that breastfeeding should be encouraged in patients without HIV who are not using additional drugs and who have no other contraindications.[66]

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used antidepressants in postpartum mothers. In general, SSRIs are well tolerated and effective for the mothers and probably are safe for their breastfeeding infants. Sertraline and paroxetine have minimal transfer into human milk and no adverse effects on infants. In contrast, fluoxetine produces significant plasma concentrations in some breastfed infants, especially if the exposure began in utero. Infant should be monitored closely for signs such as uneasy sleep, irritability, and poor feeding or sucking.[67, 68]

Enrollment in a drug rehabilitation program may be a prerequisite for breast feeding. Both marijuana and alcohol exposure through breast milk result in decreased motor development at age 1 year.

Breastfeeding is contraindicated if the mother is still using illicit drugs or has HIV infection.

The Substance Abuse and Mental Health Services Administration (SAMHSA) released Clinical Guidance for Treating Pregnant and Parenting Women with Opioid Use Disorder and Their Infants in 2018. This clinical guide provides comprehensive, national guidance for optimal management of pregnant and parenting women with opioid use disorder and their infants. The clinical guidance offers standard approaches to a range of real-world scenarios faced by healthcare professionals working with mothers and infants. For each scenario, the guidance offers clinical action steps and supporting evidence. The action steps reflect the best available treatment, including medication-assisted treatment for the mother and infant and appropriate types of social supports and follow-up services.[69]

The large number of infants who suffer from neonatal abstinence syndrome (NAS) and the associated long-term morbidity mandate that affected infants be accurately identified and their treatment and support should be optimized. Note the following:

• The assessment and management of NAS pose difficulties for staff and families and have been hampered by a lack of prospective studies and by few research studies that specifically assess the merits of one management approach over another.

• Infants at risk for NAS should be carefully monitored in the hospital for the development of signs consistent with withdrawal. The appropriate duration of hospital observation is variable and depends on a careful assessment of the maternal drug history. An infant born to a mother on a low-dose prescription opiate with a short half-life (eg, hydrocodone) may be safely discharged if there are no signs of withdrawal by age 3 days, whereas an infant born to a mother on an opiate with a prolonged half-life (eg, methadone) should be observed for a minimum of 5-7 days.[40] After discharge, outpatient follow-up should occur early and include reinforcement of the education of the caregiver about the risk of late withdrawal signs.

• Vomiting and diarrhea leading to dehydration and poor weight gain, in the absence of other diagnoses, are indications for treatment, even in the absence of a high drug-withdrawal score.

• In the delivery room, naloxone use is contraindicated in infants whose mothers are known to be dependent on opioids because of the risk of neonatal seizures from abrupt drug withdrawal. However, in the absence of a specific history of opioid abuse in a mother who has recently received narcotics, naloxone treatment remains a reasonable option in the delivery room management of a depressed infant if the infant continues to demonstrate respiratory depression after positive pressure ventilation has restored normal heart rate and color.

• The initial care of all infants who have been exposed to substances in utero and show signs and symptoms of withdrawal should be individualized, supportive, and nonpharmacologic (because pharmacologic therapy can prolong hospitalization and exposes the infant to additional agents that are often not necessary). The treatment for morphine administration has been reported to last 8-79 days.[70] This length of hospitalization interferes with maternal bonding, raises the potential for nosocomial infection, and is a major use of resources.[70]

• Studies suggest that infants who stay in the room with their mothers have a shorter length of stay, lower hospital costs, and reduced need of pharmacologic therapy, and they are more likely to be discharged home with their mothers. Rooming-in has also been associated with improved breast-feeding outcomes, and greater maternal involvement in the care of the newborn.[71, 72]

• Although rooming-in is a promising nonpharmacologic strategy, there are barriers to the implementation of this practice. Lack of funding, lack of personnel, and lack of appropriately designed hospital units may prevent many hospitals from providing rooming-in as a standard practice.[73]

• A recent study showed that acupuncture appears to be safe and effective for reducing withdrawal symptoms in infants, and suggested that it should be considered as an additional nonpharmacologic treatment option for NAS.[74]

• Pharmacotherapy for infants with more severe expression of neonatal abstinence syndrome is necessary to allow them to feed, sleep, gain weight, and interact with caregivers. Approximately 30-91% of infants who exhibit signs of NAS receive pharmacologic treatment. Although opioids are used to treat NAS, the best pharmacologic treatment has not been established. However, the limited available evidence from controlled trials of neonatal opioid withdrawal supports the use of oral morphine solution and methadone when pharmacologic treatment is indicated. Growing evidence suggests that oral clonidine is also effective either as a primary or adjunctive therapy, but further prospective trials are warranted.[40]

• There is evidence that, compared with oral methadone treatment, oral morphine sulfate therapy for NAS reduces the length of stay in the hospital and neonatal intensive care unit (NICU), treatment duration, maximum opioid requirements, and total cost.[75] However, two more recent studies showed that methadone had a shorter length of neonatal withdrawal treatment compared to that of morphine and shorter length of stay.[76, 77]

• Treatment with sublingual buprenorphine for NAS appears to be associated with a shorter duration of opioid therapy and hospitalization compared with oral methadone therapy.[78, 79, 80] Studies comparing buprenorphine to morphine have shown shorter duration of treatment and shorter hospital stay in infants treated with buprenorphine. Both groups had similar rates of side effects. However, these studies were single institution including small sample size.[81] More recent larger studies have demonstrated comparable findings.[80]

• There is significant variability in the severity of NAS due to in utero opioid exposure. Studies have shown that single nucleotide polymorphisms (SNPs) in opioid receptors and the prepronociceptin (PNOC) genes are associated with NAS severity.[82] Another study showed that among infants with NAS, variants in the μ-opioid receptor (OPRM1) and catechol-o-methyltransferase (COMT) genes were associated with a shorter length of hospital stay and less need for treatment.[83] However, the investigators suggested that further studies are needed in a larger sample.

Nonpharmacologic approaches include the following[1, 84] :

• Assess daily for signs of withdrawal, sleeping habits, feeding patterns, and weight gain.

• Room-in the infant.

• Minimize environmental stimuli by reducing light exposure, minimize excessive noise, avoid unnecessary handling, provide swaddling, and non-nutritive sucking with a pacifier.

• Breastfeed the infant.

• Provide frequent small feeds of hypercaloric formula and adequate nutrition to minimize weight loss.

Weaning

In a study of 547 late preterm and term neonates with narcotic abstinence syndrome who received inpatient pharmacologic treatment, including 417 who were managed with an established weaning protocol and 130 who were managed without an established weaning protocol, researchers found that use of a stringent weaning protocol reduced the duration of opioid exposure and the length of hospital stay.[85]

After adjustment for treatment site, infants who underwent protocol-based weans had a significantly shorter duration of opioid treatment (17.7 vs 32.1 days; P < 0.0001) and a significantly shorter hospital stay (22.7 vs 32.1 days; P = 0.004).[85] There was no difference among infants who received protocol-based weaning in duration of opioid treatment or length of hospital stay between those treated with morphine and those treated with methadone. The duration of administration of phenobarbital was significantly longer among patients treated with morphine compared with those treated with methadone (P ≤ 0.002).[85]

Transfer

Newborns with NAS are frequently cared for in NICUs. Studies suggest that care for NAS delivered in hospital settings outside of the NICU and outpatient management reduces length of stay and cost.[86, 87]

Interdisciplinary intervention for the mother and her offspring (and the father, when possible) should be available at all points of access to care. Professionals involved in this care should include obstetricians, neonatologists, pediatricians, nurses, nutritionists, mental health professionals, social workers, substance abuse counselors, and child development specialists, at a minimum.

Diet

The American Academy of Pediatrics (AAP), The American College of Obstetricians and Gynecologists (ACOG), and the Academy of Breastfeeding Medicine (ABM) support breastfeeding among opioid-dependent women if the women are enrolled in substance abuse treatment and no contraindications to breastfeeding are observed, such as ongoing drug use or HIV infection.[40, 66, 88]

Frequent small feedings are preferable and should provide 150-250 kcal/kg per 24 hours for proper growth of the infant undergoing significant withdrawal.

Neonates undergoing treatment of NAS have increased caloric requirements and may develop hyperphagia. Therefore, careful monitoring of fluid intake and weight gain are essential.

Activity

Swaddling, pacifiers, low lighting, oscillating cribs, and avoidance of abrupt changes in the infant's environment can be helpful.

Identification of substance abuse was the first step in attempting to break the cycle of reproductive morbidity or mortality. Ideally, substance use should be terminated by women and their male sexual partner before conception. Pregnant drug-using women should be counseled at the earliest opportunity to abstain completely from all injurious substances and to seek prenatal care. Adequate dietary intake and supplemental prenatal vitamins should be stressed.

Early drug screening during pregnancy reveals the need for counseling in pregnant women with a history of drug abuse.

Federal, state, and local agencies should reduce barriers to the use of family planning services and increase access to early prenatal care and other health services, including drug rehabilitation.

Health education specifically targeting consequences of drug abuse during and after pregnancy is beneficial to prevent this growing social problem.

The infant's discharge should occur after the following criteria are met:

• The infant is taking oral feeds and gaining weight satisfactorily.

• The infant is physiologically stable (has normal vital signs including blood pressure).

• The infant is showing neurobehavioral recovery (can reach full alert state, responds to social stimuli, and can be consoled with appropriate measures).

• All necessary assessments have been completed because adherence to follow-up schedules cannot be ensured.

Drug abuse during pregnancy is associated with medical, psychological, and economic problems that require extensive evaluation by qualified service providers. Mothers and fathers of drug-exposed infants need substance abuse treatment and a wide array of services to support them in their parenting role. Provision must be made for such services prior to an infant's discharge.

Provide follow-up care in the first few weeks to months of life to assess infant growth, behavioral characteristics, and motor ability.

Discharging otherwise healthy infants home once they are stable on treatment for neonatal abstinence syndrome can reduce hospital stay and associated costs. However, a safe discharge of the infant requires that support structures within the home and community are in place. In one study, compliance with the necessary clinic attendance was facilitated by establishment of a weekly follow-up clinic. This continuity of care was provided by staff with whom the families were familiar and which met all the families' needs for the infants, including vaccinations, subspecialist appointments, and prescriptions.

Medications used in patients with neonatal abstinence syndrome (NAS) should be considered when supportive measures fail to ameliorate the infant's withdrawal. This may be manifested early on as difficulty with feeding, extreme irritability, and poor sleeping. If a scoring system is used, pharmacological treatment is commonly started when the average of 3 scores is 8 or more on the Finnegan scale[41] or 4 or more on the Lipsitz scale.

The optimal treatment for neonatal abstinence syndrome has not been established. This is reflected in the considerable heterogeneity in the pharmacologic treatment of neonatal abstinence syndrome among different institutions. Many pharmacological agents have been used to treat neonatal abstinence syndrome. However, few randomized trials have compared the efficacy of the various pharmacological treatments. For opioid related neonatal abstinence syndrome, morphine and methadone are given as substitutes. Nonmorphine treatments (eg, phenobarbital, chlorpromazine, diazepam, clonidine) provide symptomatic relief.

Opioids are currently considered the first-line therapy. Second-line therapy has been phenobarbital. Phenobarbital has been effective for the treatment of opioid withdrawal seizures. Clonidine has been shown to be an effective and safe second-line medication for the treatment of NAS symptoms refractory to opioid therapy.[89]

Agthe et al studied 80 infants exposed in utero to methadone or heroin and subsequently had NAS to determine if oral clonidine, an alpha2-adrenergic receptor agonist, would reduce the duration of opioid detoxification.[90] Each infant received oral diluted tincture of opium (dosage according to standardized algorithm) and either oral clonidine (1 mcg/kg q4h) or placebo. Duration of opioid therapy was measured.

Results showed that the median length of therapy was 27% shorter in the clonidine group (11 d) versus placebo (15 d). Seven infants in the clonidine group required restarting opium after initial discontinuation, versus none in the placebo group, although total length of treatment was significantly less in the clonidine group. Higher opium doses were required by 40% of infants in the placebo group versus 20% in the clonidine group. Treatment failures occurred in 12.5% of the infants in the placebo group versus none in the clonidine group. The addition of clonidine to standard opioid therapy reduced the duration of pharmacotherapy for NAS.

A US survey reported that opioid medications are the most commonly used medications for the treatment of both opioid and polydrug withdrawal.[91] Diluted tincture of opium is recommended by the American Academy of Pediatrics for the treatment of neonatal abstinence syndrome due to opioid withdrawal.[64] Diluted tincture of opium is a 25-fold dilution of deodorized tincture of opium. Deodorized tincture of opium is equivalent to anhydrous morphine 10 mg/mL, whereas diluted tincture of opium is equivalent to anhydrous morphine 0.4 mg/mL. As a tincture, opium contains a high amount of alcohol. Diluted tincture of opium (Paregoric) contains 45% alcohol. The Institute for Safe Medication Practices considers this a high alert medication because of the confusion if abbreviated as DTO because the abbreviation could mean deodorized or diluted tincture of opium.

Many neonatal units use proprietary oral or intravenous morphine solutions, and methadone is also used. A study comparing duration of treatment of NAS between methadone and morphine showed that methadone was associated with a shorter length of treatment. However, due to the small sample size, the researchers recommended a larger multicenter randomized trial.[76]

A study showed chlorpromazine to be efficacious, with no adverse effects in neonates with neonatal abstinence syndrome and shorter treatment time when compared with morphine. A large multicenter trial was recommended by the author to confirm the safety and efficacy of chlorpromazine.[92]

Buprenorphine is the first prescription drug approved under the 2000 US Drug Addiction Treatment Act for office based treatment of addiction to narcotics.[93] Buprenorphine has numerous characteristics that make it an attractive agent in the treatment of neonatal abstinence syndrome. Buprenorphine has a ceiling effect for respiratory depression. It does not have the cardiovascular liability associated with methadone and has an established safety profile in adults. Finally, abuse liability is limited, which makes consideration of outpatient treatment for neonatal abstinence syndrome a possibility for carefully screened caregivers.

A pilot study showed that the treatment of NAS with sublingual buprenorphine is feasible, has an acceptable safety margin, and may represent a novel treatment.[94] A Cochran review found that among infants with NAS, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events.[81]

Currently, many infants are exposed to polydrug abuse. Unfortunately, evidence from randomized studies is insufficient to determine the best management for these patients. In 2 randomized trials, phenobarbital (rather than diazepam or paregoric) was best at controlling symptoms in infants exposed to polydrugs. The results of another study suggested that the combination of phenobarbital with diluted tincture of opium may be more effective than diluted tincture of opium alone because the combination was associated with a shorter hospital stay.[55]

Class Summary

These drugs have a long half-life and can be orally administered, allowing for the neonate to be discharged and treated as an outpatient.

Disadvantages include lack of effect on GI symptoms and ineffectiveness in treating seizures secondary to withdrawal. In addition, antiepileptics contain 14-25% alcohol, and larger doses are required to achieve the desired effect.

Phenobarbital (Luminal)

Interferes with transmission of impulses from thalamus to cortex of brain. Used as a sedative. Irritability and insomnia are controlled. Available in PO and IV preparations.

Class Summary

These agents are the mainstay of treatment for opiate withdrawal, either alone or in combination with other medications. These agents are CNS depressants with advantages that include oral administration, mild sedation that improves the effectiveness of sucking, and effectiveness in treating seizures secondary to opiate withdrawal.

Morphine sulfate (Roxanol, Astramorph PF)

PO solutions are available in concentrations of 2 mg/mL, 4 mg/mL, and alcohol-free 20 mg/mL. Administered to neonates as diluted PO solution containing 0.4 mg/mL.

Bioavailability is 20-40% when administered orally. Elimination half-life is approximately 9 h. Recommended that Neonatal Abstinence Scoring System be used to guide treatment management of NAS.

Methadone

Long-acting narcotic analgesic. PO bioavailability is 50%, with peak plasma levels obtained in 2-4 hours. Serum half-life ranges from 16-25 hours in neonates and is prolonged in patients with renal failure. Available as PO solutions in 1-mg/mL and 2-mg/mL concentrations containing 8% alcohol and 10-mg/mL alcohol-free solution.

Clonidine (Catapres, Catapres-TTS, Duraclon)

Alpha2-receptor agonists cause a decrease in sympathetic outflow (drop in vasomotor tone). These agents can be used as adjunct for infant with NAS (second- or third-line agent), and they are helpful for infants with acquired dependency, particularly if they are on a dexmedetomidine drip.