The effects of opioids or opiates on the developing brain are not limited to newborn withdrawal symptomatology. An overlap between opiate effects and withdrawal is possible based on several preclinical and human studies. Opiates act through three separate and distinct classical opioid receptor subtypes: mu, delta, and kappa (μ, δ, and κ) (37). All three receptor subtypes have been molecularly cloned and pharmacologically well characterized. These receptors have different regional central nervous system distributions and use different second messenger systems for their cellular mechanisms of action. The μ and δ receptors both inhibit adenylyl cyclase and activate outward potassium currents. The action of κ-opiate receptors is at the presynaptic terminals, through inhibition of calcium channels. The different opiates or opioids are partially selective μ-receptor agonists; differences are in pharmacokinetics and not in pharmacodynamics. Depending upon the timing of gestational exposure, the dose, kinetics, and pharmacodynamics, gross malformations may or may not be observed in the neonate. Gross abnormalities in brain development have been reported in opiate-exposed infants, for example, hydrocephaly with prenatal heroin (3) and codeine exposures (38). We recently reported on neonatal stroke following prenatal codeine prescribed as antitussive during pregnancy (19). In human neonates, prenatal opiate exposure results in a 0.5 to 2 cm decrease in head circumference (7,39,40,41,42,43,44) proportional to the decrease in body size, that is, symmetric growth restriction associated with decrease in cell number and consistent with the findings of Naeye et al. (45) in heroin exposed fetuses at 30 weeks’ gestation. In animals, prenatal opioid or μ-receptor agonists’ exposure results in decreased cortical density of neurons and smaller dendritic arborization and branching, therefore, affecting programming of cortical structures (46,47,48,49). The μ-receptors in developing rat brain appear early during the formation of the cortical plate (50) and μ-agonists appear to modulate cell division in the ventricular zone of late embryonic mouse cortex (51). In particular, μ-receptor agonists decrease cell division in developing cortex (51) and decrease cerebellar granule cell proliferation (52). These findings suggest a role for μ-agonists or opioids (53) in regulating neurogenesis, perhaps down regulating this critical process. Prenatal exposure to μ-agonists has been found to increase adult levels of μ-receptors in the limbic regions in the rat (54,55) but not in isocortical or striatal regions (56). Local injection of μ-agonists into the hippocampal area CA3 can impair spatial learning in rats (57) suggesting that opioids continue to play a role in the adult, different from either their developmental role in utero or their well-known role in pain modulation. Early exposure to μ-agonists therefore might lead to decrease in neurogenesis in neocortex, limbic system, and/or cerebellum, leading to decreased volumes of these brain regions and corresponding behavioral effects in overall cognition (isocortex), emotion and social interactions (limbic system), and motor learning and performance (cerebellum). These findings may explain the reported prenatal and postnatal head growth deceleration in the human newborn (7,39,40,41,42,43,44,58,59,60,61). Such findings would lend support to the role of specific biologic mechanisms for decreased brain size in infants with prenatal opiate exposure, and the associated manifestations such as hypertonicity, hyperreflexia, irritability, tremors, shrill cry, and other behavioral alterations, which are also part of the constellation of manifestations in narcotic withdrawal or NAS. No significant abnormalities on clinical magnetic resonance imaging have been noted in the immediate newborn period (62) with exposure to the opiate, buprenorphine. Findings at later ages are suggestive of decreases in brain region volumes (63) with prenatal opiate exposure, suggesting a long-lasting effect of in utero drug exposure. Of concern are the experimental studies finding effects of a high gestational dose of buprenorphine on myelination of the developing brain (64) suggested by developmental delay in myelin basic protein expression and alterations in axon–glial interactions.

The central nervous and autonomic nervous systems manifestations (36) in neonates with prenatal opiate exposure comprise the neonatal narcotic withdrawal syndrome, also referred to as the “NAS.” During gestation complicated by prenatal opiate exposure, the fetus receives a supply of opiate for prolonged period through the placenta and the umbilical cord. At birth the disruption of opiate supply to the fetus through the placenta is a likely explanation of the occurrence of newborn abstinence symptomatology and hence the manifestations become evident when the newly born would have metabolized and excreted the opiate from his/her system within a few days after birth.

NAS is most common among infants born to mothers who used opiates during pregnancy. The reported incidence of NAS ranges from 21% to 93% among infants exposed to opiate in utero (14,35,36,65,66,67). A higher incidence is reported with in utero methadone exposure than that reported with heroin exposure (6,8). Whereas in some studies, the incidence of NAS following methadone exposure does not seem to differ significantly from the use of the newer drug, buprenorphine (13,67), other studies found a higher incidence of NAS and need for treatment in infants of mothers on methadone treatment than in infants of women treated with buprenorphine. Polydrug exposure is reported to be associated with greater severity of withdrawal manifestations (68); it also increases the odds for a neonate to develop signs of NAS; in a large cohort, a higher percentage of infants manifested the constellation of CNS/autonomic nervous system (ANS) signs consistent with withdrawal who had prenatal exposure to both opiate and cocaine than in those exposed only to either drug (35).

Monitoring of clinical manifestations is important not only as a basis for clinical diagnosis but also in the initiation, monitoring, and discontinuation of pharmacological treatment. The CNS manifestations in NAS include a high-pitched cry, irritability, disorganized sleep pattern, hypertonia, myoclonic jerks, seizures, exaggerated Moro reflex, frequent yawning, and sneezing (35,36,69). Other signs include autonomic nervous disturbances manifested as fever, temperature instability, mottling, increased sweating, nasal stuffiness, sneezing, nasal flaring, tachypnea, and loose or watery stools (36). Additional manifestations are the gastrointestinal signs of poor feeding, uncoordinated and constant sucking, and vomiting or regurgitation, which can result in dehydration and poor weight gain (36). Onset of manifestations is noted usually within the first 72 hours of birth (2) and in some infants as late as 2 to 4 weeks of postnatal age (70). The variability of onset depends on several factors including the type of maternal drug use during pregnancy, dosage of drug of use, timing of use prior to delivery, the type of anesthesia and/or analgesia used during labor and delivery, and metabolism, accumulation, and tissue binding of the drug in the fetus, which can affect neonatal drug excretion. Duration of withdrawal manifestations is variable but signs may last for longer duration (subacute) persisting for as long as 6 months (71). Depending upon severity, NAS may require pharmacological treatment.

The severity of NAS may differ as to the gestational age of the infant at birth, the type of drug of exposure, and whether there is polydrug exposure. Less severe signs may be noted with the exposed preterm infant, which could be attributed to shorter duration of in utero opiate exposure. Caution should be taken in evaluation of symptomatology because of overlap in manifestations related to disorders of prematurity and NAS. For example, respiratory difficulty, temperature instability, and cardiovascular signs are often noted in preterm infants with respiratory distress syndrome. In late preterm and term infants, more severe symptomatology is noted with methadone exposure (72). Conflicting findings are reported from multiple studies investigating the relationship between maternal methadone dose and the severity of withdrawal manifestations and the need for pharmacologic treatment (6,73,74,75,76,77). In prenatal cocaine exposure, the prevalence of CNS and ANS manifestations is lower than reported with prenatal opiate exposure. Because of the persistence of neurological tone abnormalities in infants with prenatal cocaine exposure, it is in question that the CNS/ANS manifestations are due to NAS and instead are likely to be manifestations of cocaine effects (78).

Evaluation and clinical monitoring of infants with NAS are carried out using neurobehavioral assessment procedures or clinical scoring scales or tools. A commonly used scale in the clinical setting for monitoring severity and number of signs of withdrawal is the Finnegan Scoring System (79). It consists of 21 items with some being weighted according to severity (Table 63.1). Another scale for scoring narcotic withdrawal was developed by Ostrea (80), which uses ranking but with no summation scale for severity of clinical signs of withdrawal. The Finnegan Scale was later modified in the Lipsitz’s tool (81) and the Neonatal Withdrawal Inventory by Zahorodny et al. (82). The Lipsitz scoring is abbreviated compared with Finnegan Scoring System and is shown in Table 63.2. Eleven items are scored, with two items (tremors and irritability) that are scored from normal (score = 0) to increasing severity with a score of 3 as worst. Five additional items are scored from 0 to 2; these are reflexes, stools, muscle tone, skin abrasions, and respiratory rate. Four items (repetitive sneezing, repetitive yawning, vomiting, and fever) are scored as not present (score = 0) or present (score = 1).

Other investigators have utilized the Neurobehavioral Assessment Scale by Brazelton (83), which has been modified to allow administration in preterm infants and those exposed to drugs in utero, through the National Institute of Child Health and Human Development Neonatal Intensive Care Unit (NICHD NICU) research network; the scale is known as the NICU Network Neurobehavioral Scale (NNNS) (84,85). In the Neurobehavioral Assessment Scale and NNNS, habituation, reflexes, tone, orientation, and state changes are assessed. The NNNS adds assessment of stress/abstinence signs and is sensitive for administration to infants of substance using mothers and those born at preterm gestation.

Some investigators utilize monitoring of physiological signals in NAS (86,87). Median activity score using a motion detector is higher in infants at pretreatment than in controls, those not requiring treatment and those stable with treatment (86). Those with NAS also demonstrate sleep deprivation, disorganization, and fragmentation; stabilization with treatment results in sleep and wakefulness similar to controls (88). Another physiological signal noted to be different in those infants exposed to opiates in utero from those nonexposed is the visual evoked potentials (89). Visual evoked potentials from those exposed are more likely to be immature or nondetectable and also smaller in amplitude than in controls. These aberrations in physiological signals may herald later problems in neurodevelopment (90).

Recent reviews of published treatment strategies and surveys of practices among clinical centers indicate variation in approach to management of NAS. Initial management of course begins with monitoring of the exposed infants and subsequent initiation of behavioral intervention techniques when necessary. If unresponsive to these supportive measures, administration of pharmacological agents is initiated. Although these behavioral intervention modalities have been tried in nursery settings, there is no uniformity on how and when such interventions are administered to newborns with prenatal opiate exposure. The simplest and most commonly employed behavioral interventions include infant swaddling and efforts to reduce exposure to excessive light and sound in the nursery. Specifically directed interventions such as prone positioning (91) and oscillating water beds have been shown to minimize symptoms of NAS evaluated using Finnegan Scoring System (92). From a recent report, neonates born to opiate using mothers did better with rooming-in compared with historical controls not rooming-in with their mothers; those in
rooming-in were less likely to need pharmacotherapeutic intervention and had shorter length of hospital stay (93). These previous studies have utilized a single behavioral intervention measure and outcomes were globally measured by severity of withdrawal symptoms without systematic detailed evaluation of clusters of measures of neurobehavior such self-regulation and stress reactivity and the impact of an intervention on caretaker–child interaction. Randomized studies are lacking on the effect of a comprehensive behavioral intervention in the management of NAS. In addition, as a part of a holistic approach to behavioral intervention, providing nutritional supportive will ensure growth, while promoting self-regulation to enhance maternal–child interaction. It makes further sense that behavioral intervention in the clinical setting should continue even if the infant would require pharmacological treatment, with an approach directed to the mother–infant dyad (94).