PPA News

Posted by: Brandy Zeller on Aug 16, 2015

Authors: Densley Francois, PharmD, BCPS, Julie Neuman, PharmD, Priya Patel PharmD, BCPS, Elaine Simon, PharmD, Sylvia Stoffella, PharmD
Editors: Christopher McPherson, Pharm.D, Nicole Passerrello, Pharm.D, BCPS, Deb Pritchett, Pharm D, BCPS, Eloise Woodruff, PharmD

Neonatal abstinence syndrome (NAS) is a complication that can occur in a newborn after prenatal exposure to addictive illicit or prescription drugs. Common drugs of use or abuse include opioids, central nervous system stimulants or depressants, and hallucinogens.1 In contrast, iatrogenic withdrawal may occur in critically-ill infants that are treated with opioids and/or benzodiazepines in order to provide adequate sedation, analgesia or anxiolysis. Iatrogenic withdrawal can occur if medications are used for an extended period of time and abruptly discontinued.2 

Clinical Presentation

The clinical presentation, onset, and duration of NAS can vary with the maternal drug(s) of use/abuse and are variable both between infants and in the same infant over time.NAS signs and symptoms include central nervous system, metabolic, vasomotor, respiratory, and gastrointestinal disturbances (Table 1). Symptoms often overlap with other neonatal conditions, making the diagnosis of NAS more difficult.

TABLE 1 Clinical Features of Neonatal Abstinence Syndrome1




  • High-pitched cry
  • Increased wakefulness
  • Hyperactive Moro reflexes
  • Tremors
  • Hypertonia
  • Myoclonic jerks
  • Generalized convulsion
  • Excessive sucking
  • Poor feeding
  • Regurgitation or projectile vomiting
  • Loose or watery stools
  • Sweating
  • Fever
  • Frequent yawning
  • Mottling
  • Nasal stuffiness
  • Sneezing
  • Nasal flaring
  • Tachypnea


Much of our knowledge of NAS comes from term infant data, since the preterm infant population has not been a primary focus in NAS research. Although the reasons are unclear, preterm infants have a lower risk of drug withdrawal, a less severe course of NAS and are less likely to require treatment. Since preterm infants spend a shorter time in utero than term infants, drug exposure is reduced and increases in third trimester placental transfer are avoided.  Preterm infants also have lower fat deposits, immature hepatic metabolism and delayed CNS development that can contribute to the difference in NAS incidence and severity.4 The clinical evaluation of NAS severity in preterm infants is a challenge, as scoring tools were developed for term or late preterm infants.1

Assessment Tools

Assessment for signs of neonatal abstinence begins at birth for infants exposed in utero to addictive substances.  Several tools have been validated for quantifying NAS (Table 2). These tools guide the caregiver to evaluate a range of symptoms and result in a score indicating the severity of withdrawal. The scores can subsequently guide the initiation, adjustment, and weaning of pharmacotherapy for abstinence.

In 1975, both the Lipsitz (Neonatal Drug Withdrawal Scoring System)5 and Finnegan6 tools for assessing neonatal abstinence were described. The Neonatal Withdrawal Inventory (NWI) is a shorter tool which was validated in 1998.7 Modified versions of the Finnegan score are most commonly used today. Scoring is performed every 3-4 hours when the infant is in a resting state, preferably after feeding. The Withdrawal Assessment Tool (WAT)was developed to assess withdrawal in pediatric patients exposed to prolonged therapy with opiates and benzodiazepines.

TABLE 2 Neonatal Withdrawal Assessment Tools


Typical threshold score for treatment


> 4/20


≥ 8/44

Neonatal Withdrawal Inventory

≥ 8/19

Withdrawal Assessment Tool*

*for iatrogenic withdrawal

≥ 3/12

A standard scoring system is a necessary component of a NAS treatment protocol. Institutions should adopt a standard scoring system and ensure that caregivers are competent and consistent in assigning scores.  Inter-rater reliability should be re-evaluated at regular intervals.

Non-pharmacologic Treatment

Infants at risk of developing neonatal abstinence should be treated initially with supportive care measures.  These measures should be continued whether or not the infant requires pharmacotherapy.  One component, swaddling, reduces motor hyperactivity and prevents skin excoriation.  Gentle rocking can be useful to overcome irritability. Minimizing stimulation by maintaining a quiet darkened environment can promote sleep and improve behavioral state control. Provision of frequent small and calorie-dense feedings should minimize hunger and maximize nutrition in infants with poor coordination and at risk of vomiting. Breastfeeding is encouraged if not contraindicated. All of these interventions should be tailored to the infant’s symptoms and response.

Pharmacologic Treatment

Pharmacologic treatment of NAS is warranted when there are persistent scores of 8 or above on the Finnegan scale.1,9 However, institutional variability exists for the threshold to treat.  Each institution should develop guidelines for therapy with treatment goals to stabilize the clinical manifestations of withdrawal and restore normal newborn activities.10 Pharmacologic treatment is utilized to prevent complications such as seizures, fever, and weight loss or dehydration secondary to vomiting, diarrhea, or poor feeding.9

A variety of medications have been utilized for the treatment of NAS.  Opioids are the most widely used agents to treat intrauterine exposure to opioids.   The 2012 American Academy of Pediatrics guideline on neonatal drug withdrawal discusses several studies conducted between 1969 and 2004.  There are many study flaws described; however, the report states that 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."1  

The most common first-line medication used in the treatment of NAS is oral morphine.  The short half-life is advantageous in clinical practice allowing rapid titration to clinical response.11   Methadone is also a common opioid utilized in the treatment of NAS.  The longer half-life of methadone can be considered advantageous by allowing consistent serum concentrations; however, this presents challenges during dose titration.  There have been no significant differences in hospital stay and treatment duration amongst infants treated with morphine versus infants treated with methadone in clinical trials.9,10 Buprenorphine may have a role in pharmacologic treatment of NAS. It is still early in investigation, but initial reports show a trend toward decreased length of treatment and hospital stay when compared to treatment with oral morphine preparations.  However, buprenorphine may also be associated with increased need for adjunctive therapy.12,13  These studies have many limitations including small treatment groups, open label design, and many participant exclusions.  Additionally, there is not a commercially available dosage form for the neonatal population.  Thus, the studies describe compounding a solution with buprenorphine for injection in 100% ethanol USP and simple syrup.  The final solution contains 30% ethanol concentration.  The solution is given via the sublingual route, which may contribute to a high degree of intra-subject variability in serum concentrations of buprenorphine observed in the trial.12

Non-opioid therapy also has a role either as monotherapy or as adjunct to standard therapy.1,9,11 Common indications for adjunctive therapy include poorly controlled withdrawal symptoms despite optimizing first line therapy, inability to wean first line therapy, and relapse after initial treatment.11 Phenobarbital and clonidine are the preferred second line options, as other options such as chlorpromazine and diazepam may cause unwanted side effects (i.e. increased sedation, poor suck reflex, late onset seizures) and are formulated with potentially harmful additives (i.e. benzyl alcohol). 

Phenobarbital causes CNS depression and is the drug of choice for sedative-hypnotic withdrawal, in addition to its use as adjunctive therapy for opioid withdrawal. 10,11 Coyle et al. evaluated 20 infants exposed to opiates in utero treated with opioids and phenobarbital vs. opioids alone. Combination therapy resulted in a significantly decreased length of stay, lower cost and lower maximum daily dose of opioids. However, phenobarbital was continued for several months after opioid discontinuation.14 Limitations to phenobarbital’s utility include the absence of GI symptom relief, over-sedation, impaired suck reflex, rapid tolerance, potential drug interactions, and alcohol content in the commercially available formulation.9,10

Clonidine inhibits CNS sympathetic outflow and therefore ameliorates the autonomic over-activity that occurs during NAS (including GI symptoms).Currently, clinical trials cite the benefit of clonidine as both first line therapy and as adjunctive therapy for NAS.As first line therapy, several cases reviewed in two studies reported symptom resolution at clonidine doses up to 3-4mcg/kg/day with no toxic side effects.15,16  One retrospective study compared clonidine as a continuous infusion (0.5-3mcg/kg/hr) to morphine (with optional adjunct therapy of chloral hydrate and phenobarbital, respectively). The clonidine/chloral hydrate group exhibited shorter duration of therapy, reduced withdrawal symptoms and shorter length of stay with no differences in blood pressure.17  Another study compared clonidine at doses of 5mcg/kg/day (with option to titrate to 12mcg/kg/day) with morphine monotherapy. Results favored clonidine due to shorter median length of therapy and better neurobehavioral summary scores.18 As adjunctive therapy, Agthe et al. compared opioids with clonidine to opioids alone in 80 neonates exposed to opioids in utero. Length of stay significantly decreased and opioid dose was 60% lower in the combination group with no short-term adverse cardiovascular effects. However, rebound withdrawal occurred in seven infants in the combination group requiring re-initiation of opioid therapy.19 A recent study comparing clonidine and phenobarbital as adjunctive therapy concluded that the phenobarbital group had significantly fewer morphine

TABLE 3 Doses for Medications Used in the Management of NAS from Pooled Literature1,9,20


Dosage Formulation

NAS Oral Doses

Suggested Weaning



Intial: 0.03-0.1mg/kg every 3-4hours

Increment: 0.04mg/kg per dose to effect

Taper dose by 10-20% q2-3 days


1mg/mL oral solution

Initial: 0.05-0.1mg/kg every 6-24 hours

Increment: 0.05mg/kg per dose to effect

Taper dose by 10-20% per week



Initial: 5.3mcg/kg under the tongue every 8 hours

Taper dose by 10% per day


4mg/mL elixir

Loading dose: 16mg/kg

Maintenance dose: 1-4mg/kg every 12hours

Taper dose by 20%

every other day



Initial: 0.5-1mcg/kg every 4-6 hours

Taper dose by 0.25mcg/kg  every 6 hours

*Extemporaneous preparation treatment days; however, phenobarbital therapy was continued for several months, while clonidine was discontinued prior to discharge.20  Benefits for use of clonidine also include its potential shorter duration of therapy, low abuse potential and lower overdose risk. Future controlled trials are warranted to demonstrate the extent of these benefits in NAS management.

Of note, it is also prudent to consider the potential negative neurodevelopmental effects resulting from the use of opioids and phenobarbital in neonates. Chronic opioid use has been reported to impact brain growth and cause long term impairments in learning and motor abilities in neonatal patients.21 Currently, there is a lack of literature evaluating the neurodevelopmental effects after receiving long term phenobarbital therapy. One study in children reports that the early treatment of febrile seizures with phenobarbital may result in long- term adverse cognitive effects on developmental skills.22 In contrast, an animal study concluded that clonidine was neuroprotective against anesthetic induced neuroapoptosis. 23 Avoidance of negative cognitive effects could indicate another potential benefit of using clonidine as first line therapy.

There is a great degree of variability among nurseries in initial doses, titration of doses to stabilize the patient, and weaning to discontinuation. Table 3 provides some potential doses and formulations pooled from the current literature for both the first and second line options.

Management of Acquired Opioid and Benzodiazepine Dependency in Neonatal Patients with Iatrogenic Drug Withdrawal

Pharmacologic agents such as opioids and benzodiazepines are utilized to provide analgesia, sedation, and anxiolysis for critically ill patients, and may put patients at risk for iatrogenic drug withdrawal.  If these drugs are not discontinued within approximately 5-7 days, or are used in high cumulative doses, physical dependence may develop and withdrawal symptoms may occur with dose reduction or cessation of therapy.1,2 Critically ill, mechanically ventilated infants, complex surgical patients, or infants who are supported by extracorporeal membrane oxygenation (ECMO) therapy have the greatest risk for iatrogenic drug withdrawal.1,2 Management of iatrogenic drug withdrawal can occur by either slowly weaning opioid or benzodiazepine therapy or transitioning to an oral morphine/methadone and/or lorazepam wean in order to prevent withdrawal symptoms.

Optimal therapy for treatment of pediatric iatrogenic withdrawal is not established due to insufficient evidence; however, methadone is commonly used due to its excellent oral bioavailability (70%-100%) and long half-life (19-41 hours).1 A recent study found that the use of a pharmacist-managed, methadone-based opioid-weaning protocol standardizes patient care, and a methadone wean of 10% to 20% per day was well tolerated in both neonatal and pediatric patients.24 The American Academy of Pediatrics recommends that each neonatal intensive care unit (NICU) develop a protocol that provides evaluation and treatment for infants at risk of or showing signs of withdrawal.1 NICUs should select a withdrawal assessment tool, determine a threshold level of cumulative exposure to opioids and benzodiazepines above which drug dependency would likely occur,  and develop a standardized weaning protocol based on clinical evidence. Additionally, clinicians should recognize that protocols do not replace clinical judgment and consider specific characteristics of the patient when utilizing standardized protocols.

The 2012 American Academy of Pediatrics clinical report on neonatal drug withdrawal provides examples of several weaning protocols.1 Per Hudak and colleagues, the following procedure may be utilized when weaning patients from opioid or benzodiazepine therapy. If infants are below the threshold for prolonged exposure, a rapid taper of opioid or benzodiazepine therapy can be done within 24- to 48- hours.If infants are above the threshold or withdrawal symptoms are observed during the rapid taper, they may be converted to an equivalent opioid or benzodiazepine regimen. These therapies can then be gradually weaned by 10% to 20% of the initial dose every one to two days based upon clinical response and withdrawal assessment.1 Ultimately, there are no clear guidelines on how to wean concurrent benzodiazepine and opioid therapy; however, it seems reasonable to wean one medication at a time in order to clearly differentiate signs of withdrawal. Finally, the infant’s pain status should be assessed and adequately managed with behavioral interventions or medications prior to and during weaning.


Institutions should be prepared to treat infants with NAS and iatrogenic drug withdrawal. Adoption of a standardized scoring system and treatment algorithm are central to the optimum care of these patients. 


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