Pharmacologic and Adjunctive Therapies for NAS

Giavanna Hosack, Madison Kessler, Mary Kuhns, and Melissa Mershimer

Youngstown State University

NURS 3749: Nursing Research

Dr. Danielle Class

April 9, 2023
 Pharmacologic and Adjunctive Therapies for NAS

Neonatal Abstinence Syndrome (NAS) describes the withdrawal symptoms seen in

infants whose mothers suffer from chronic opioid use. According to the CDC, every 19 minutes

a baby in the United States is diagnosed with NAS. The condition is associated with numerous

health complications and poor outcomes generally leading to longer hospital stay, high rates of

Neonatal Intensive Care Unit (NICU) admissions and higher health care costs. Cost of stay and

length of stay in NAS patients are on average respectively $8,000 and 11 days compared to

$1,100 and 2 days in all other neonates (CDC, 2022).

Treatment for NAS in the past has consisted of evaluation of the need for

pharmacotherapy using Finnegan Neonatal Abstinence Syndrome Score (FNASS).

Pharmacotherapy for NAS if deemed necessary includes medically assisted weaning from the

opioid and may include adjunctive therapies such as the use of barbiturates for seizures. Various

nonpharmacologic treatments have been evaluated for their effect on length of stay (LOS), length

of treatment (LOT), and the eventual need for pharmacotherapy.

Search Strategy

The PICO question for this paper is: In neonates whose mothers suffer from opioid

addiction, what is the effect of medication assisted treatment as opposed to nonpharmacologic

treatment on NAS? The literature in this review was found through multiple CINAHL searches.

The searches yielded less than 300 results combined after filtering by peer reviewed academic

journals and publication date from 2018-2022. Search terms included NAS or NOWS,

buprenorphine or methadone, opioid, Finnegan, or non pharmacologic or rooming-in. Articles

that are not pertinent to this review were not used, which narrowed the search even further. The

search strategy also consisted of a citation search to find related articles and studies. Abstracts
and conclusions were reviewed to determine if articles met inclusion criteria. Some of the

literature included are out of the original search date and were included due to relevance and

remarkable findings.

Literature Review

Opioids are commonly used to treat withdrawal manifestations in NAS patients. This is

because opioids decrease central nervous system and autonomic nervous system irritability

(Kraft et al., 2017). CNS and ANS irritability is manifested with increased muscle tone,

vomiting, tremors, tachypnea, and excessive perspiration, all of which are common symptoms in

NAS patients. Oral morphine is a schedule II narcotic used to treat 80% of NAS victims.

Methadone is another schedule II narcotic similar to morphine in that it is also used to limit

withdrawal symptoms. Sublingual buprenorphine is a schedule III narcotic commonly used to

treat withdrawal symptoms in adults but has been more recently identified to treat withdrawal

symptoms in neonates (Kraft et al, 2017). The lower the schedule category of the medication, the

more addictive and dangerous it can be. Many clinical trials have been organized to determine

the safest, most effective medication due to the potential these narcotics have for adverse effects.

While each medication is effective in treating NAS, the success of each individual narcotic is

determined by LOT, LOS, adverse effects, and required use of adjunctive treatments (Cook et al,

2019; Kraft et al., 2017; Kraft et al., 2008).

As a result of various clinical trials, buprenorphine has been selected as most optimal in

decreasing LOS and LOT by providing therapeutic effects to withdrawal symptoms (Cook et al,

2019; Kraft et al., 2017; Kraft et al., 2008). Furthermore, it was less likely to cause respiratory

depression than morphine and has a longer half-life, so the time between scheduled doses was

longer than morphine. Morphine was effective in treating withdrawal symptoms such as diarrhea
and agitation, although hospital stay was prolonged (Cook et al., 2019). Morphine has been

found to increase LOS in all clinical trials compared with methadone and buprenorphine

(Czynski et al., 2020; Cook et al, 2019; Kraft et al., 2017; Kraft et al., 2008).

The clinical trial Buprenorphine for the Treatment of Neonatal Abstinence Syndrome,

organized by The New England Journal of Medicine (2017), compared treatment of neonates

with buprenorphine and morphine (Kraft et al., 2017). Appropriate dosing was individualized

based on weight and disease severity. If the maximum dosage based on weight did not control

symptoms to stabilize the neonate’s condition, an adjunctive agent such as phenobarbital was

initiated with half of the narcotic’s maximum dose. Buprenorphine was intended to treat a

sample size of 30 neonates while morphine was intended to treat a sample size of 28 neonates.

The median LOT averaged 15 days and LOS averaged 21 days in neonates receiving

buprenorphine. This is a significant finding compared to morphine, in which the median LOT

was 28 days and average LOS was 33 days (Kraft et al, 2017).

Another point evaluated in comparing buprenorphine and morphine included the potency

of the medications. Morphine has a shorter half-life than buprenorphine, so it required frequent

dosing every 4 hours to maintain consistent levels of the medication. Buprenorphine has a longer

half-life so the dosing was once daily. As far as effectiveness in reducing symptoms, morphine

reduced agitation, tremors and crying. However, neonates treated with buprenorphine

experienced less overstimulation and excitability due to the decrease in physical opioid

dependence (Kraft et al, 2017). Despite success in relieving symptoms of withdrawal in neonates

with both choices of medications, more research should be done to examine why LOT and LOS

were longer with morphine compared to buprenorphine treatment.

 Across the country there is little standardization of treatment protocol for NAS patients.

For example, some studies used adjunctive agents like phenobarbital to control seizures in all

patients regardless of maximum dose of narcotic. In a randomized trial conducted by JAMA

Pediatrics (2018), a sample size of 117 NAS patients were treated to compare the safety and

efficacy of methadone and morphine. Outcomes were measured by LOS and LOT. FNASS was

utilized to yield a Finnegan Score (FS) which determined the severity of the neonate’s

withdrawal. The FS is calculated from the infant's crying, sleep patterns, muscle tones, and many

other symptoms to determine how severe the withdrawal was. Infants who received treatment

were assessed using FNASS every 4 hours. Morphine was given every 8 hours, methadone was

given every 4 hours, while a placebo was given every 8 hours. The hospital’s treatment protocol

was initiated if the FS remained above 8 or higher on 2 occasions or 12 or higher on 1 occasion.

This protocol included a dose of phenobarbital (20 mg/kg) given as an adjunctive agent to

control severe withdrawal symptoms (Davis, 2018).

Aside from alluding to the variation in treatment protocol, it is important to discuss the

results of the trial. There was minimal resulting evidence that methadone was significantly safer

than morphine. Thirteen adverse events occurred across both treatment groups which included

symptoms of respiratory depression and GI upset. Specific to the methadone group, 1 infant had

severe adverse effects including apnea, hypothermia, and lethargy resulting in readmission to the

NICU (Davis, 2018). Despite the adverse effects, the neonates continued in the study after

treatment dosing was decreased. The morphine treatment group had a mean LOS and LOT of

21.1 days and 16.6 days respectively while the methadone group had a mean LOS of 18.9 days

and LOT of 14.7 days. In the discussion of results, methadone was stated to be slightly more

desirable in the treatment of NAS when comparing short-term effects (Davis, 2018).
 Another controlled pilot-study similarly compared the effects of morphine and

methadone on LOS and LOT. The study organized by BMC Pediatrics (2022) concluded that

there is no significant difference between methadone and morphine in average LOS or LOT. The

sample size in this study was even smaller with 87 neonates included. However, it is worth

discussing because it adds to prior research and is more recent. While LOS and LOT were

slightly decreased for the neonates given methadone, BMC Pediatrics concluded that this could

be due to multiple factors mainly including small sample size. Another contributing factor is that

neonates in the morphine group had more frequent dosing and an increase in nutritional demand

which contributed to a longer LOS. Since methadone is a long acting drug and was given less

frequently than morphine in this study, infants could also receive non-pharmacological treatment

in adjunct (Sutton et al., 2022). This may be the key to maximizing pharmacotherapies if given

more research and may eventually be standardized across the country.

Overall, more research should be done to determine the long-term effects of

pharmacotherapies. However, while there are many pharmacotherapies used in the treatment of

NAS patients, there are also many non-pharmacological therapies that can be implemented.

Programs like rooming-in care and adjunctive therapies like stochastic vibrotactile stimulation

may help to alleviate withdrawal symptoms and decrease LOS and LOT (Zuzarte et al., 2017).

This is an important topic to include in the research given the potential for adverse effects and

discrepancies with current pharmacotherapies. Some neonates may present with more severe

symptoms of withdrawal and may need multiple medications with a strict regimen. These

patients will likely be separated from the mother for treatment in the NICU.

Non-pharmacological therapies can be implemented to hopefully prevent the need for NICU

admission and encourage mother-infant bonding. This was the case in the study by BMC
Pediatrics, in which rooming-in was implemented for patients who were treated with methadone

(Sutton et al., 2022).

Rooming-in is when the mother and baby are admitted into a private room in the pediatric

unit. The mother receives postpartum care while the neonate is monitored closely in the same

room to promote bonding early on. If the mother is discharged before the baby, she can stay in

the private room until her baby is discharged. It is significant to promote mother-infant bonding

early on post-partum to prevent depression in the mother and worsening complications for the

baby, so rooming-in care could be an effective intervention for NAS patients (Newman et al.,

2015).

In the study, Rooming-in Care for Infants of Opioid-dependent Mothers, 21 mother-infant

dyads were included in a rooming-in program (Newman et al., 2015). The infants were scored on

the severity of withdrawal using FNASS. Three of the infants required admission to the NICU

for pharmacologic therapy. The 3 infants received oral morphine to help with withdrawal

symptoms. The 18 other participants were monitored closely in their private rooms (Newman et

al., 2015).

The results of this program showed a significant decrease in the requirement for

pharmacotherapy and a significant decrease in LOS. The need for pharmacotherapy decreased

from 83.3% receiving usual care in the NICU to 14.3% for those in the rooming-in program.

Meanwhile, LOS significantly decreased from 24.8 days to 7.9 days (Newman et al., 2015).

Given the significance of these results, the question becomes: is the standardization of this

program feasible? After examining the results of this study, Kingston General Hospital in

Ontario transitioned from immediate admission into the NICU to rooming-in (Newman et al.,

2015). The exception they made was to admit the infant to the NICU only if required for
pharmacotherapy or to promote safety (Newman et al., 2015). While it may be possible to

implement the program in some hospitals, it requires far more research and development before

it can be used in every hospital that treats these patients.

Another non-pharmacologic treatment that has been evaluated as an adjunctive therapy is

stochastic vibrotactile stimulation (SVS). In the study, Vibrotactile Stimulation: A

non-pharmacological Intervention for Opioid-exposed Newborns, 22 NAS patients were

evaluated during SVS treatment (Zuzarte et al., 2017). This intervention could potentially help to

decrease the infant’s movement, improve breathing patterns, and lower heart rate. Treatment

involved a special mattress equipped with a SVS device which provided stimulation in on and

off intervals. The study was completed between the hours of 8 A.M. and 6 P.M. to prevent

further interruptions in sleep patterns overnight. Stimulation was delivered randomly for each

infant but was planned around feeding schedules to prevent complications and skewed results.

Prior to the study, the infants were scored using FNASS and were subsequently treated with

morphine due to the severity of withdrawal. Respiratory pattern, heart rate, pulse oximetry, and

temperature were monitored to identify abnormalities and evaluate treatment. Movement of the

infant was also monitored before and during treatment to determine if the stimulation was

beneficial (Zuzarte et al., 2017).

The results showed no remarkable difference in Finnegan scores. However, infant valid

non-movement was reduced by 35% with stimulation (Zuzarte et al., 2017). Eupneic breaths and

beats were increased with SVS while tachypnic breaths and tachycardic beats in turn were

significantly decreased, but average temperature and oxygen saturation levels did not change.

Interestingly, there was a notable difference in results between the sex of the infant. Females

generally showed less movement and had lower heart rates than males as a result of treatment.
 The reason SVS could have a significant effect on autonomic function is because it

stimulates pressure receptors causing an improvement in some of the severe symptoms of

withdrawal (Zuzarte et al., 2017). More research should be done to determine the effects of

longer stimulation and whether it could be beneficial for the infant long-term. Ultimately, the

severity of withdrawal determines whether pharmacotherapy is necessary, so there are many

other factors of NAS treatment to be researched. Non-pharmacologic therapies have proven their

potential to be beneficial for those suffering with NAS. However, this is especially the case when

used in adjunct with medications like morphine, methadone, and buprenorphine.

Discussion

The proper treatment of NAS is a complex, multifactorial issue that still requires more

research. What the majority can agree on is that each case should be treated on an individual

basis. The research proves this statement to be true but opens room for another issue; there is a

wide range of inconsistency in protocol for treatment of NAS patients. For example, some resort

to a dose of oral morphine after birth while others start with nonpharmacologic therapy.

Pharmacotherapy will likely be required in many cases, so nonpharmacologic treatment is not

always effective alone. When pharmacotherapy is deemed necessary, sublingual buprenorphine

has been most advantageous compared to methadone and morphine. Other adjunctive

medications may be used to treat severe symptoms before resorting to oral morphine, which

requires frequent dosing, longer hospital stay and treatment, and a higher likelihood of

oversedation.

While there is confidence in the results of this research, there are still some general

limitations to be aware of. One important factor is sample size. A small number of eligible

participants were included especially in studies that examined nonpharmacologic therapies. The
reason for this is most commonly due to the need for pharmacotherapy because of the severity of

withdrawal which decreases the subjects treated solely with nonpharmacologic therapy. Another

limitation of the research is a lack of studies comparing the effects of all treatments in a

controlled setting to distinguish the actual effects of each therapy. Strengths of this research

include that there were multiple studies which supported prior findings, all studies were

peer-reviewed, and there was successful implementation of rooming-in at Kingston General

Hospital to support the study’s findings. More research should be done given the limitations and

minimal research on certain adjunctive treatments.

In the field of nursing with special consideration to areas that have been hit hard by the

opioid epidemic, it is unfortunately common to see patients suffering from opioid addiction.

Those who work in obstetrics or neonatology have likely cared for NAS patients and may have

even witnessed the effects of an underdeveloped and outdated treatment protocol. Besides the

patients and their mothers, these healthcare professionals have experienced first-hand the

devastation and heartbreak caused by the opioid epidemic. It is up to these nurses and other

healthcare professionals to contribute to the research of this topic. Research of NAS treatments is

one of the most influential actions that nurses can take to advocate for patients who are victims

of opioid addiction.
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