In the United States, the opioid epidemic has increased substantially over the past few years. In 2012, the national estimated total hospital fees for neonatal abstinence syndrome (NAS) were $1.5 billion (Patrick, Davis, Lehmann, & Cooper, 2015). The evaluation and diagnosis of NAS are predominantly based on the Finnegan score developed in the 1970s, but it is subject to bias and has strong interrater variability. The scoring system was largely developed for term or late preterm neonates, making it more difficult to evaluate preterm neonates who are likely to have lower risk and severity of withdrawal symptoms (Finnegan, Kron, Connaughton, & Emich, 1975).

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At this time, the U.S. Food and Drug Administration has not yet approved any medications specifically for NAS. The goals of therapy are to ensure proper feeding and development, increase the bond between the mother and the infant, and decrease duration of therapy and hospitalization (Kraft & van den Anker, 2012). Initiation of treatment is based on a Finnegan score of two consecutive scores of >=12 or three consecutive scores of >=8 (Kocherlakota, 2014); however, some institutions initiate therapy at a single score of >=10 (Agthe et al., 2009). Scoring begins within 24 hours of birth (Kocherlakota, 2014).

Morphine and methadone, full mu receptor agonists, are the most common opioid treatments (Ng et al., 2015). Because morphine has a short half-life, doses are usually given at approximately 4-hour intervals (Kocherlakota, 2014). Methadone has a longer half-life than morphine, which provides less variability between peak and trough levels and allows for longer dosing intervals (Kraft & van den Anker, 2012). Compared with methadone, the recent support for buprenorphine, a partial mu receptor agonist, in NAS is due to a lower likelihood of respiratory depression (Kraft & van den Anker, 2012) and no occurrence of "torsades de pointes," an abnormal heart rhythm. In addition, buprenorphine has a long half-life and duration of action (Ng et al., 2015) compared with morphine. Research shows that the average duration of treatment is significantly shorter with buprenorphine (23 days) in comparison with morphine (38 days; Kraft et al., 2011).

Adjuvant treatment for NAS includes the addition of phenobarbital or clonidine to opioid treatment (Kocherlakota, 2014). A study has suggested that combination treatment (i.e., opioid + adjuvant therapy) is superior to single treatment with an opioid (Agthe et al., 2009). Phenobarbital is commonly used for multiple-substance abuse and is the drug of choice for non-opioid-exposed neonates (Kocherlakota, 2014). It is likely to decrease severity of symptoms and duration of hospitalization (Coyle, Ferguson, Lagasse, Oh, & Lester, 2002). Long-term outcomes in adults have shown neurodevelopment and behavioral compromises with prolonged exposure to phenobarbital, which is a concern for the developing brain in infants (Meador, Baker, Cohen, Gaily, & Westerveld, 2007). Clonidine, an alpha₂ receptor agonist, is reported to stabilize infants in combination with diluted tincture of opium faster than diluted tincture of opium alone (Agthe et al., 2009). A second study compared a combination therapy regimen of an opioid with phenobarbital or clonidine. This study reported that the total duration of treatment was shorter with clonidine because infants were weaned off the medication before being discharged home. Phenobarbital had a shorter duration of hospitalization because infants were discharged home with phenobarbital but continued therapy for up to 8 months. Clonidine can cause severe hypotension or rebound hypertension, but this is unlikely when the dose is titrated downward (Surran et al., 2013). In 2016, gabapentin was published in a case series describing its use as an adjuvant therapy among neonates who experienced unique withdrawal symptoms with NAS. The effects of gabapentin on neonates require more research, but it is recommended that clinicians become aware of atypical withdrawal symptoms due to subsequent polysubstances such as methadone plus gabapentin (Loudin et al., 2017).

In conclusion, developing improved pharmacotherapy protocols aims to provide symptom control without compromising safety to decrease duration of treatment and hospitalization (Kraft & van den Anker, 2012). It is recommended that healthcare providers recognize the potential for polysubstance use in pregnant mothers. New treatment strategies, such as combination versus single therapy, may offer improved, evidence-based benefits to pharmacologic treatment of NAS.

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