Neonatal opioid withdrawal

Overview: What every practitioner needs to know

Are you sure your patient has opioid withdrawal? What are the typical findings for this disease?

Opiate withdrawal may appear in the child of a mother dependent on heroin, opioid-based prescription medications, methadone, or buprenorphine or in an infant treated with opioids for pain in the neonatal period.

Most opioid-exposed neonates exhibit altered neurobehavioral features in the neonatal period; the most recognized condition described is the neonatal abstinence syndrome (NAS), a constellation of dysregulated neurobehaviors displayed after intrauterine opioid exposure ceases at delivery. NAS expression can vary between infants and in the same infant over time. Severity is not clearly related to any known maternal or infant factor but is likely to be a conglomerate of individual biologic vulnerabilities combined with environmental circumstances such as exposure to other substances (e.g., nicotine), the physical environment, and caregiver responses. New research has found that infants with variants in the OPRM1 and COMT genes have shorter lengths of hospital stays and require less medication for NAS, suggesting that genetic and epigenetic factors may play a significant role in NAS expression. Thus, each neonate can have an individual repertoire of dysregulated neurobehaviors that can alter ability to feed, sleep, gain weight, and interact.

Opioid exposure can be comprised of exposure to licit opioids (i.e., methadone or buprenorphine maintenance for a maternal opioid use disorder), misuse of licit opioids (i.e., opioid containing pain relievers) or illicit opioids (i.e., heroin) or any combination thereof. The timing of the onset of NAS signs is likely to vary with the type of opioid exposure. Heroin exposed infants often have an early NAS presentation, with a later presentation more common among methadone or buprenorphine exposed infants.

Many opioid-exposed infants are exposed to other substances. Substances that can produce an independent “discontinuation” syndrome include alcohol, nicotine, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and benzodiazepines. Other substances, such as cocaine and marijuana, maternal psychiatric conditions, and/or medications during pregnancy can also produce altered neonatal neurobehavior. Any of the above can augment an infant's display of NAS. Features of each can overlap those of opioid abstinence, making a thorough maternal history and assessment important.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Assessment for maternal substance use should occur often in the prenatal period via an interview using a standardized tool such as the 4Ps Plus. Urine toxicology testing for the mother and/or infant at the time of delivery reflects only very recent use of most substances (except for chronic marijuana use and benzodiazepines). Meconium analysis can present difficulties to collection if meconium is lost in utero or its passage is delayed. Further, the utility of assessing maternal drug use in the second and third trimesters of pregnancy may be limited as it neither quantifies use nor reflect periods of drug abstinence closer to delivery. Testing of umbilical cord tissue or blood is easier to collect, but as for meconium, it neither quantifies use nor reflects drug abstinence. The utility of meconium and umbilical cord testing may be reserved for the infant who develops signs of NAS and whose mother denies substance use.

After confirmation of opioid exposure via maternal history, biologic matrices, or both, a thorough understanding of the infant's functioning is necessary for proper management as the need for pharmacotherapy is based on frequent and periodic assessment for the development of NAS. Maternal history should include drug use history and treatment, psychiatric co-morbidities, and licit (including opioid medications, nicotine, and alcohol) and illicit substances taken during pregnancy. The provider must approach the drug-dependent mother in a non-judgmental manner to facilitate communication. Punitive attitudes have no place in care.

Neonatal abstinence syndrome assessment

Best practices for assessment and treatment are currently undefined. The assessment and treatment strategy outlined below represents one method which uses a 19 item, weighted NAS scoring based on the Finnegan Scale and ia a symptom-based approach to treatment. Most practitioners use some variant of the Finnegan scale.

Assessment should begin at birth and continue for the duration of hospitalization, which should be a minimum of 4 days. Almost all opioid exposed infants will display some signs and symptoms of NAS, generally by 48-72 hours after delivery, but perhaps as late as several weeks. The infant should be evaluated every 3-4 hours and given a composite score reflecting behavior since the last assessment.

Signs and (and assigned score based on severity) include: excessive cry (2-3), time spent sleeping after feeding (1-3), hyperactive moro reflex (1-2), tremors: disturbed (1-2) and undisturbed (1-2), hypertonicity (1-2), excoriations (1-2), seizure (8), fever (>37.2; 1), frequent yawning (1), sweating (1), nasal stuffiness (1), sneezing (1), tachypnea (respiratory rate >60/min) (2), poor feeding (2), vomiting (2), loose stools (2), failure to thrive (weight >10% below birth weight) (2), excessive irritability (1-3).

Items are scored individually, but there can be some overlap, i.e., the infant with hypertonicity and tremors frequently presents with excoriations, but these are scored separately. Disturbed and undisturbed tremors are scored separately. Irritability may or may not occur with crying and are scored individually. Items are scored based on their severity.

At the end of every 3-4 hour assessment period, items are added to provide an overall score. If the score is less than a cut-off value, the infant continues to be scored in this fashion, receiving non-pharmacologic care, until discharge. An infant who reaches a cut-off score that defines the need for pharmacotherapeutic intervention is rescored in one hour after nursing care is provided, to ensure that the infant is not reacting to environmental stressors (i.e., being hungry, wet, tired, overstimulated etc.,). If the second score if above that cut-off value, medication therapy is to be instituted. The goal of providing pharmacotherapy is to permit the infant to sleep, feed and interact, not to sedate or “take the edge off." Oversedation may interfere with the infant's growth, development, and interactive capacities, and should be avoided.

Infant states are the stages of wakefulness between sleep and crying: State 1 is deep sleep, State 2 is light sleep, State 3 is drowsy, State 4 is quiet and alert, State 5 is fussy, and State 6 is irritable crying. It is important to consider an infant's state when scoring the infant for NAS. For example, infant tone should not be scored in a state 6 because it is likely to be elevated and not reflecting the true tone of that infant in an appropriate lower state.

It is important to consider an infant's state when scoring the infant for NAS. It is also important to consider both infant gestational and chronologic age in assessing NAS, as preterm infants express NAS differently than term infants, and older infants with NAS can have alterations in its presentation due to normal developmental processes, such as the ability to achieve a longer quiet alert state, sleeping for shorter periods of time, etc.

Infants older than 2 weeks of age may require adjustments to NAS scoring to reflect their developing capacities. An example of this is the omission of the sleeping scores, so that they do not "count against" an infant who is able to achieve and stay in a quiet alert state in between feedings.

The differential diagnosis for tremors or seizures includes metabolic disorders, such as acidosis, hypoglycemia, hyponatremia or hypocalcemia. Other causes for seizures, such as sepsis/meningitis, asphyxia, structural anomalies or intracranial hemorrhage should be considered. Irritability, fever, tachypnea, or color changes can indicate an infant with sepsis or infection. Fluctuations in tone are not uncommon, and infants can have tonal asymmetries as part of NAS that do not, in general, warrant imaging studies.

Myoclonic jerking, or rhythmic movements during sleep, occur not uncommonly in opioid-exposed infants, and should not be confused with seizure activity. Myoclonic jerking is the quick contraction(s) of muscle groups, generally of the extremities, occurring during infant sleep. The movements can be single or multiple, can be present in arms, legs and/or chin, and may be restricted to one side of the body. They do not stop when the extremity is held, and do not occur during awake states. Electroencephalograms in these infants are in general within normal limits and are not warranted.

The differential diagnosis for an infant with NAS should also consider the environment and handling that the infant is receiving. If there are environmental stressors, for example, medical procedures or insensitive handling that lead to the development of signs of NAS or augment an NAS display in any given infant, they should be removed and the infant re-evaluated.

NAS expression is variable, both between infants and in the same infant over time, in presentation, signs present and types of signs present, and in severity. The variability of the syndrome should be considered in any assessment of a substance-exposed infant.

It is important to note that occasionally infants present with a biphasic course of NAS, and require reassessment and infrequently rehospitalization after hospital discharge with or without the need for pharmacotherapy during the early neonatal period. Late onset NAS, or signs of NAS beginning at 2-4 weeks after birth, has been described, and may reflect poly drug exposures (particularly with benzodiazepines) in some infants. Mothers should be informed of this possibility, and infants should not leave the hospital without a pediatric care appointment to occur in the days after discharge. Contact with a knowledgeable primary care physician prior to discharge in case the infant experiences a rebound NAS prior to the institution of outpatient pediatric care is important due to the potentially serious consequences of untreated NAS.

Item definitions and assigned scores are as follows:

Excessive cry: Persistent infant crying is scored 1-3: Score = 1: With consoling (i.e., holding the infant's hands, talking, changing positions, pacifier use) the infant calms in 3-5 minutes; Score = 2: With consoling (holding, rocking, swaddling, pacifier use), the infant calms in 6-15 minutes. Score = 3: Reflects an infant who continues to cry after more than 15 minutes or one in whom no amount of consoling produces calm, (i.e., an inconsolable infant).

Sleeping:If the infant sleeps for 2-3 hours continuously, score 1. If the infant sleeps 1-2 hours continuously, score 2. If the infant sleeps less than 1 hour continuously, score 3. This item needs to be adjusted or omitted when scoring older infants who are able to maintain awake states for longer periods of time than infants in the immediate postnatal period. If the infant is able to maintain a quiet alert state in between feedings without displaying signs of discomfort, these periods should not be counted as lack of sleep. This item may also need to be adjusted for infants who are breastfed and may sleep for shorter periods of time due to decreased intervals between feedings. The individual development of the infant should be considered when making adjustments.

Moro reflex:A Moro reflex that is hyperactive, i.e., the arms stay elevated for 3-4 seconds and there is jitteriness of the hands, is scored 1. A markedly hyperactive Moro reflex, in which the arms stay elevated for more than 4 seconds, is scored 2.

Tremors:Jitteriness or rhythmical quivering occurring around a fixed point (i.e., joint). Myoclonic jerking as described above is not tremors. Mild tremors (lasting less than 3 seconds) are scored 1, while more moderate to severe tremors (lasting 3 or more seconds) are scored a 2. Disturbed tremors occur with stimuli such as movement, touch or sound. Undisturbed tremors occur without an apparent stimulus.

Tone: Infant tone, or muscle resistance to movement, can be assessed via extremity recoil or head lag. The infant scores 1 for some resistance to extension or flexion of extremities, and the extremity returns quickly to its original position; 2 for difficult but possible straightening or bending the arms with head lag on pull to sit; 3 for not possible straightening/bending of arms with no head lag on pull to sit. This item should be scored in states 3, 4, or 5, and not during sleep or irritable crying.

Excoriation: The result of rubbing a skin surface against fabric or diaper due to increased tone, increased rooting or tremors. Excoriations generally occur on extremities at elbows and dorsi of hands, knees, chin or buttocks. Buttock excoriations must be distinguished from diaper dermatitis, particularly in older infants, and are the wearing of the top layer of skin in parallel patches at the point where the buttocks touch the diaper (and not, in general, in the perianal area). Using preventative diaper rash formulations may allay the development of excoriated buttocks in hypertonic or tremulous infants. Paper bibs or napkins used during feeding or cleaning the baby's face may contribute to chin excoriation and should be avoided.

Seizures: Seizures related to opioid withdrawal occur in infants with other significant signs and symptoms of NAS. When they occur they are scored 8 and treated with phenobarbital; though infants with NAS-related seizures do not generally warrant ongoing outpatient phenobarbital therapy. The true incidence, pathophysiology, and significance of NAS-related seizure activity are not known. They may represent a manifestation of poly-drug (likely barbiturate) or alcohol-related drug effects. They must be distinguished from tremors, exaggerated myoclonus, myoclonic jerking, and intracranial pathology. An EEG and brain imaging studies are usually warranted in the event of neonatal seizures.

Mottling: A feature of autonomic dysregulation, skin discoloration with a marbled or lace-like appearance of pink and pale or white areas, typically seen on chest, trunk and extremities. Mottling should not be assessed in a chilled infant. Scored 1.

Fever:A feature of autonomic dysregulation, fever is defined as an infant axillary temp of 37.3 degrees C or more, and scored 1. Infants presenting with fever may present a challenge to the practitioner if they are also hypertonic or have difficulties with arousal and need to be consistently swaddled. Fever must be distinguished from overheating due to excessive blankets or tight swaddling. May require further medical evaluation.

Yawning: If the infant yawns 4 or more times in 3-4 hours in the absence of stimuli, score 1.

Sweating: If the infant’s forehead or upper lip is damp score 1. Must not be scored in an overheated or over swaddled infant, who is likely to be sweating on the back of the neck.

Nasal stuffiness: Any persistent nasal noises occurring with respirations, with or without a runny nose, are scored 1. Must be scored in infants whose nares have been cleared of any birth debris. Must not be scored in infants who have been overzealously suctioned at birth resulting in swollen, excoriated, or bloody nasal tissue. The practitioner should first try to clear the nose with saline drops and gentle suction prior to applying a score for this item.

Sneezing: If the infant sneezes 4 or more times in 3-4 hours, score 1. May occur serially or individually.

Tachypnea: If the infant at rest has respirations greater than 60 per minute, score 2. Respirations should be counted for a full minute. The presence of retractions or use of intercostals muscles with breathing, or nasal flaring or grunting should warrant further medical evaluation. This item should be scored in a quiet state (1-4) and not when the infant is fussy or crying (5 ,6).

Poor feeding: May be due to uncoordinated suck/swallow mechanism and frequently occurs in very hypertonic infants. It is recognized by the presence of gulping with frequent pauses for breathing, burping or spitting up, placement of tongue above or to the side of the nipple, inability to form a tight seal around the nipple and/or formula loss at the sides of the mouth. Often infants with poor feeding make clicking noises when sucking. Feeds in these infants often take 20 minutes or more. Poor feeding is scored 2. Every effort should be made to avoid gavage feeding in infants with NAS when possible, as the presence of the NG tube often potentiates other symptoms of NAS. Intervention for feeding problems by occupational therapy or lactation consultation may be necessary.

Vomiting: Defined as the effortless return of gastric contents from the infant’s mouth or nose, is scored 2 when the infant frequently vomits the whole feeding or two or more times during a single feeding not associated with burping, or regurgitates large amounts with burping. Do not score occasional small regurgitations with burping. Gentle handling with feeding/burping should be provided particularly to sensitive infants who gag easily, as insensitive handling may contribute to vomiting which can then be scored unnecessarily. This item should be distinguished from the infant with retained secretions after birth.

Loose stools: Are scored 2 if the infant has a stool that is half liquid and half solid, or a liquid stool. Using preventative diaper rash formulations may allay the development of excoriated buttocks.

Failure to Thrive: Defined as the infant weight on any given day that is greater than or equal to 10% below birth weight, this item is scored 2 for as many days as this definition holds true. Infants who fail to thrive often have associated feeding and/or tonal symptoms of NAS in conjunction. If a feeding problem exists, appropriate interventions (i.e., consultation with occupational therapy, lactation consultant) should be instituted.

Excessive irritability: This item is distinct from, but may occur in tandem with crying, and is defined as fussy or irritable posturing or grimacing with any stimuli. These infants are often very sensitive to sound and light and become fussy with light touch or handling despite attempts to console them. This item may represent the infant’s difficulty with modulation of arousal or tendency to easy overstimulation.

These infants generally require much observation to determine the source of the noxious stimuli, which may not be readily apparent (i.e., arm or leg bands, textures of blankets or clothing, pulse oximeter wires or noises, and/or other stimuli that do not affect other infants with or without significant NAS) and time spent in modifying their environments to assist them with regulation. This item is scored 1 to 3 depending on degree of irritable or hyper-aroused behavior(s) evident (3 generally representing infants who are not consolable with maximal intervention).

Beginning at hour three, each of the above items are scored and totalled. If the score is >8, the infant has nursing cares (feeding, diaper changing, soothing, modification of environment, and/or interactive patterns) and is rescored again in one hour. If the second score is >8, the infant requires pharmacotherapy which is instituted based on the higher of the two scores.

If you are able to confirm that the patient has neonatal opioid withdrawal, what treatment should be initiated?

Non-pharmacologic interventions

All opioid-exposed infants should receive non-pharmacologic interventions beginning at birth for as long as needed, regardless of the need for medication and/or prolonged hospitalization. Although not a substitute for pharmacotherapy, properly applied non-pharmacologic care can reduce or mitigate the need for medication. These interventions should be performed together with the mother or other caregivers to allow for appreciation of the infant’s strengths, weaknesses, capabilities, and cueing abilities.

The mother may have feelings of guilt and anxiety or a co-morbid psychiatric problem that can impair her ability to interact with or understand her infant. This may produce unrealistic or distorted perceptions of the infant’s behaviors and create maladaptive developmental trajectories in the infant. Awareness of her feelings and ability to deal with them in a positive way should be explored with the mother. This supportive care should continue in outpatient settings, such as the pediatric clinic, at every opportunity that the dyad presents for care, and the mother should be encouraged to perform the techniques that address her infant’s specific needs at home.

Principles of non-pharmacologic interventions

Non-pharmacologic interventions should incorporate the following principles:

1. Individualized therapy and care for the infant, based on behavioral observations, with the goal of promoting organization, physiologic stability and competence in the infant’s self-calming and interactive capabilities. Each infant should be observed carefully and over time to recognize:

a) the infant-specific signs of physiologic and behavioral regulation and dysregulation,

b) the particular sensory input that provides the source of morbidity for the infant (visual, auditory, tactile, or movement) and interventions that alleviate the discomfort,

c) support for the infant’s efforts to become stable and organized.

2. Modification of the environment to support state control, autonomic, sensory, motor and interactive development.

3. Encourage parental involvement, working to develop an ongoing individualized care plan to support the infant’s specific patterns of neurobehavior and simultaneously addressing parental perceptions of the infant and his/her development.

Pharmacologic interventions

Early identification and treatment of NAS will decrease infant morbidity; it is never acceptable to delay therapy for NAS to further observe the infant, nor is it acceptable to treat an infant with medication to prevent his display of NAS, as only a subset of opioid-exposed infants requires pharmacotherapy.

Infants receiving medication should be monitored and frequently evaluated for alterations in therapy and to avoid oversedation. Many medications have been used for first and second line NAS treatment. No best medication has been identified; however, many feel that opioid preparations such as morphine should be used as treatment for opioid withdrawal. Methadone is also employed. Phenobarbital is generally not used as a primary medication for opioid withdrawal, but it may play a role in the treatment of polydrug exposure. Buprenorphine and clonidine are experimental agents for first line NAS pharmacotherapy. When the infant’s NAS display is uncontrolled on maximal doses of first line medication, a second drug is added. Second line medications include clonidine or phenobarbital.

Some medication protocols call for a mg/kg dose of medication (weight-based protocols), others for a dose based on the severity of the infant’s NAS display (symptom-based protocols). In either event, medication should be delivered to the infant at intervals no longer than every 4 hours (if a short-acting medication, i.e., morphine, is used) to avoid a rebound withdrawal and increase in NAS scores even if it means waking the infant to administer medication.

Medication is given to the infant until the infant achieves a plateau of NAS scores below the defined cut-off value. The infant is kept at this dose for 48 hours, and then the medication is gradually withdrawn. It is important to note that some infants can have a biphasic NAS course or require increases in medication dose once weaning has begun. Infants are weaned until the medication is withdrawn and then observed for 24 hours prior to hospital discharge.

Pediatric follow-up should occur in the days after discharge and frequently thereafter to assess maternal competence and comfort in her ability to care for the infant and to establish and maintain contact with an outpatient provider in the event of rebound NAS symptoms after discharge and to assist with the presence of residual dysregulated behaviors that are often present after hospital discharge. It is important to note that subacute NAS symptoms, such as tonal alterations, may persist for weeks or months after hospital discharge.

Inpatient treatment for NAS is generally advised, though many centers do wean medication on an outpatient basis. This calls for caregiver interpretation of infant signs and symptoms which may be altered by other agendas or inaccurate parental perceptions. Additionally, the presence of even small amounts of opioids in the home may place the caregiver at risk for relapse or harm by others.

It is important to mention that care of the mother should occur in tandem with care of the infant with NAS, and pediatric care staff may be most poised to observe and assist the mother, particularly for infants that require prolonged hospitalization. Maternal care may include referral to drug treatment that optimally is gender-specific and accepts the infant; referrals for psychiatric care when warranted; and parenting assistance and assurance of confidential and non-judgemental care. Avoidance of the use of terms such as "addicted newborn", "methadone baby", or "NAS baby", which are pejorative terms, should occur at all times. Rooming in care and inclusion of the mother in NAS scoring are optimal, but may not apply to all mothers.

It is important to note that optimal practice for this group has not been defined due to the lack of definitive research.

In summary, the opioid exposed infant more often than not presents a major challenge for the provider. A thorough understanding of the parent and the infant combined with early assessment and treatment as well as the assurance of ongoing care of the dyad is critical to avoid or allay possible maladaptive developmental trajectories.

Pharmacotherapy for neonatal abstinence syndrome

This algorithm uses oral morphine solution as a first line and clonidine as a second line medication, and is a symptom-based (doses of medication delivered based on the severity of the infant’s NAS display as defined by NAS score) as opposed to weight-based (medication delivered on a mg/kg basis without regard for NAS scores) strategy. Oral morphine solution is administered at a maximum of every 4 hours to avoid rebound increases of NAS scores. It is important to note that optimal medication strategies for infants affected by NAS have not been determined. Medication administration for the pharmacological treatment of NAS may need to be individualized. For example, some infants require medication for NAS to be able to achieve a quiet state to feed, while others may become drowsy and unable to feed. Infants who achieve high states of arousal may require medication prior to interactions with caregivers.

Oral morphine solution (OMS; 0.04 mg/0.1 ml) is initially dosed as follows:

Infant NAS ScoreDose OMS (0.04 mg/0.1 ml) every 3-4 hours with feeds

0-8 0 mg

9-12 0.04 mg

13-16 0.08 mg

17-20 0.12 mg

21-24 0.16 mg

> 25 0.20 mg

The infant is reassessed every 3-4 hours and the morphine dose increased as necessary based on the infant’s NAS scores if they are >8. If the infant scores 0-8 after medication is initiated, maintain the current dose. If the infant’s NAS score is:

9-12 then Increase dose by 0.02 mg q 3-4 hours

13-16 Increase dose by 0.04 mg

17-20 Increase dose by 0.06 mg

21-24 Increase dose by 0.08 mg

Once the initial objective of a plateau of NAS scores <9 has been achieved, the infant is maintained on the same dose of OMS for 48 hours prior to beginning the weaning process.

Weaning of OMS: OMS is weaned by 0.02 mg every day for scores of 0-8. Occasionally, infants will have elevated NAS scores during the weaning process and require a re-escalation of medication dosing. Defer the wean for a single score of 9-12.

Re-escalation of OMS dosing: If the infant scores 9-12 at the next scoring time, repeat the scoring after nursing cares and within one hour. If the score remains > 8, increase OMS as follows:

If the infant’s score is:

9-12 then Increase dose by 0.01 mg

13-16 Increase dose by 0.02 mg

17-20 Increase dose by 0.03 mg

21-24 Increase dose by 0.04 mg

>24 Increase dose by 0.05 mg

Restart the weaning process when NAS scores are <9 for 48 hours, and de-escalate treatment as above.

Second medication (clonidine) use: If the infant at any point is receiving 0.20 mg OMS every 3 hours and continues to have NAS scores >8, a second medication is warranted. One medication used frequently as a second line medication is clonidine, 0.75 mcg/kg by mouth every 3 hours. If the infant continues to have NAS scores >8, increase to 1.0 mcg/kg every 3 hours. If the infant continues to have NAS scores >8, increase OMS as above. Infants on clonidine should be in a monitored bed. Vital signs and blood pressure should be monitored every 2 hours for a period of 12 hours at the beginning of clonidine treatment and again once clonidine is discontinued.

Weaning of infants on OMS and clonidine: Wean off morphine first. For infants on morphine doses greater than 0.20 mg of morphine per dose, wean 0.04 mg morphine every 24 hours for NAS scores <9 until the 0.20 mg per dose threshold is reached, then wean 0.02 mg morphine every 24 hours for NAS scores < 9, as above.

After morphine is discontinued, decrease clonidine by 0.5 mcg/kg/dose every 24 hours, keeping the infant’s NAS scores <9. When clonidine has been discontinued, careful observation for rebound hypertension for 48 hours before hospital discharge is warranted.

If the infant has 2 consecutive NAS scores one hour apart >8 while weaning from clonidine, defer wean for scores 9-12 and resume de-escalation protocol after 24 hours if infant scores are <9. If infant has 2 consecutive scores of 13-16 while weaning clonidine, increase dose to previous dose (i.e., by 0.5 mcg/dose greater than current dose). Maintain this dose for 24 hours before restarting the de-escalation protocol. If the infant has 2 consecutive NAS scores >8 once off clonidine, begin morphine per protocol for new onset NAS. If the infant has failed a clonidine wean, i.e., has required re-escalation dosing during a clonidine wean, decrease the clonidine dose by 0.25 mcg/kg/dose after 24 hours. Continue to decrease clonidine by 0.25 mcg/kg/dose until the infant is off of clonidine.

Once off all medication, observe the infant for 24 hours prior to hospital discharge. If the infant has failed weaning at least once or receives clonidine for NAS treatment, observe for 48 hours prior to discharge.

What are the possible outcomes of neonatal opioid withdrawal?

Many factors can affect the opioid-exposed infant, either the effects of the opioid exposure itself or other factors associated with opioid exposure.

Fetal brain development and the development of neurotransmitter and neuromodulator systems can be directly and variably affected by substance exposure, depending on types and amount of substances of exposure, timing during gestation and a host of maternal and fetal risk and protective factors that modulate the effects on the infant.

Indirect mechanisms of harm include effects on fetal and infant development related to the effects of the drugs on the maternal-fetal-placental physiology (i.e., placental vasoconstriction, hypoxia, reduced transplacental transport of nutrients), risk factors associated with maternal addiction (such as use of several psychoactive substances, psychiatric co-morbidities, violence exposure, lack of medical care, poverty, poor nutrition and stress) and the caregiver’s capabilities in providing a competent postnatal environment for the infant. Further, there are likely roles of genetic and epigenetic alterations that affect the neurobehaviors of the infant and the development of the child that have yet to be defined conclusively.

Despite the largely indefinable possibilities of harm mechanisms for the opioid-exposed child, the importance of early recognition and treatment for the dyad is clear. Appropriate and timely care of both the infant and the caregiver in the neonatal period may provide an avenue to prevent maladaptive developmental trajectories of development in the infant and improve both the short and long term consequences of maternal drug use on the child.

What is the evidence?

References/suggested reading

Jansson, LM, Velez, M, Harrow, C. "The opioid exposed newborn: assessment and pharmacologic management". Journal of Opioid Management. vol. 5. 2009. pp. 47-58.

Osborn, DA, Cole, MJ, Jeffrey, HE. "Opiate Treatment for Opiate Withdrawal in Newborn Infants (Review)". John Wiley & Sons. 2005.

Velez, M, Jansson, LM. "Non-pharmacologic care of the opioid dependent mother and her newborn". Journal of Addiction Medicine. vol. 2. 2008. pp. 113-120.

Wachman, EM, Hayes, MJ, Brown, MS. "Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome". JAMA. vol. 309. 2013. pp. 1821-1827.

Kocherlakota, P. "Neonatal Abstinence Syndrome". Pediatrics. vol. 134. 2014. pp. e547-561.

Kraft, WK, Stover, MW, Davis, JM. "Neonatal abstinence syndrome: pharmacologic strategies for the mother and infant". Semin Perinatol. 2016;Jan 18.

Kaltenbach, K, Jones, HE. "Neonatal abstinence syndrome: Presentation and treatment considerations". J Addict Med. 2016.

Ongoing controversies regarding etiology, diagnosis, treatment

Optimal scoring and treatment algorithms have not been defined. Protocols and medication choices displayed here are suggested.

While most opioid or polysubstance exposed infants are hospitalized for a period of 4-7 days after birth, optimal evaluation periods for the development of NAS signs have not been determined.

Biological screening that is universal may be beneficial in some areas where treatment for pregnant and parenting women is accessible, but can lead to punitive reactions against mothers (never fathers) that are not warranted and will serve to drive women with substance use disorders away from needed treatments during pregnancy.

The identification of a dyad as opioid-exposed can lead to the attribution of every infant adaptation to extra-uterine life as a sign of NAS and medication that may not be warranted.

Many hospitals treat infants with NAS in NICUs, which can be difficult for sensitive infants who are sensitive to their environment, causing an unnecessary elevation in NAS signs. Rooming in has been found to be associated with reduced lengths of hospitalizations in infants with NAS, but may not be appropriate for every dyad.

While inpatient management of NAS is advocated here, many hospitals use outpatient NAS management strategies, which are not standardized and may lead to unnecessary exposures to medications over long periods of time for the infant.

Breastfeeding infants with NAS can be challenging, and often requires intervention from a knowledgeable lactation consultant.

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