Neonatal Opioid Withdrawal Syndrome: 2 Years Later…Where Are We NOWS?

Neonatal opioid withdrawal syndrome (NOWS) is an increasingly prevalent condition with significant short- and long-term implications for infant and family health. The effects of opioid use and misuse can have profound consequences as these substances readily cross the placental-fetal blood barrier reaching the fetal circulation and the developing brain. Opioid use disorder (OUD) in pregnancy and subsequent neonatal opioid withdrawal syndrome have increased 131% and 82% respectively, between 2010 and 2017.¹ As a result, the neonatal community is facing a formidable challenge for which many questions remain unanswered. Traditionally, the Finnegan Neonatal Abstinence Scoring System (FNASS) was widely used.² The FNASS was developed in the 1970s to identify and determine the severity of NOWS by assessing the presence of 21 clinical signs of withdrawal. Each physiologic parameter is assigned a score based on severity and when a sustained threshold score is achieved, it indicates the need for pharmacologic therapy. However, the reliability and precision of this symptom-based assessment tool are limited by a high interobserver variability, need for strict training and the potential for staff fatigue due to the time it takes to complete. In 2017, Grossman et al³ introduced the eat, sleep, and console (ESC) method as a quality improvement project and demonstrated a significant reduction in length of stay, postnatal need for drug therapy and a decrease in hospital charges. The ESC method focuses on functional assessments of the infant and promotes non-pharmacologic treatments as first line therapy. The non-pharmacologic interventions include low stimulation environments, feeding on demand, breastfeeding, skin to skin contact, and parental rooming-in. When pharmacologic therapy is needed it can be utilized on an “as needed” basis rather than on a schedule. A few single center studies followed and in 2023, Young et al⁴ performed a large multicenter, stepped-wedge cluster randomized clinical trial at 26 hospitals in the United States (ESC-NOW study), the largest study to date, and it clearly reaffirmed the benefits of the application of ESC vs usual care for the management of NOWS. Again, the introduction of ESC in those centers translated into a decreased need for pharmacological intervention and a shorter length of hospital stay. However, there were concerns as to whether ESC managed patients who received pharmacological therapy had a higher opioid exposure.⁵ A post-hoc subgroup analysis of the ESC-NOW showed a decreased dose of opioid exposure, had a shorter length of treatment and total length of hospital stay when compared with the usual care group. Management with ESC was not associated with a higher peak dose of opioids, although pharmacologic therapy was initiated later. Additionally, a study comparing ESC vs FNASS showed lower costs to the health care system, solidifying the beneficial effects of this practice.⁶ ESC gained significant traction because of these findings, and it has now been widely adopted by many centers around the country.⁷ Implementation of ESC and allowing for rooming-in of parent-infant dyads at hospitals across the United States would support the shift towards a family centered approach. Evidence emerging from single center studies and meta-analysis evaluating inpatient unit vs rooming-in care models showed a 20% to 60% decrease in pharmacologic treatment and a decrease in total opioid treatment days favoring rooming-in practice. This practice is more conducive to the implementation of ESC and prevents unnecessary separation of the newborn from the family, potentially increasing breast feeding and bonding.⁸

Eat, sleep, console is not only a scoring tool; It is a restructuring of newborn care. Encouraging rooming in, parental involvement and environmental regulation can provide neurodevelopmental support and shift the focus away from strictly withdrawal management. Identifying and addressing barriers to ESC implementation is a key area of current research focus. Gallant et al⁹ utilized a scoping review to evaluate implementation strategies and identify several barriers to implementation. The most used strategies for implementing ESC included education of health care providers and parents and instilling a sense of empowerment in parents. An implementation framework was recommended to assist in successfully putting ESC into practice. Health care staff reported resource limitations including limited private rooms, high patient turnover, availability for training and language barriers as main constraints. Additionally, systemic oppression including racism, stigma and bias are barriers to care. Among parents, barriers include the needs of other children/jobs, limited hospital support (lack of access to private rooms, breastfeeding and childcare assistance), lack of parental education/feeling unprepared to care for withdrawing infant. A successful ESC practice model aims to address and mitigate potential barriers.⁹

Although pharmacologic therapy remains an essential tool for the care of many newborns with severe symptomatology of withdrawal, there exists a significant practice variability amongst centers in term of initial drug choice, dose escalation, introduction of adjunct drug therapy and weaning protocols. This variability highlights the urgent need for increased research to improve identification of patients at risk for the need of pharmacological intervention, and thus, improve therapeutic precision minimizing unnecessary treatments.¹⁰ Right drug, at the right time at the right dose for the right length of time. To address this issue, in a recent study by the Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Collaborative the authors identified prenatal and postnatal factors that may predict the need for pharmacological intervention. Lack of prenatal care and polypharmacy were associated with an increased need for pharmacological intervention, as well as male sex and maternal treatment with methadone. Buprenorphine prenatally administered to mothers and any breastmilk feedings lessened the use of pharmacotherapy.¹¹

The American Academy of Pediatrics currently recommends opioids for treatment of severe NOWS after trialing nonpharmacologic interventions. However, the specific pharmacologic agent and dosing regimens are not standardized among hospitals in the United States. Morphine, buprenorphine, and methadone are considered first line treatments, with clonidine and gabapentin primarily used as adjunct therapy.¹² In a large single center retrospective study, the use of sublingual buprenorphine was associated with a shorter length of stay compared to morphine and there was no difference in the need for adjunct medication.¹³ A recent randomized controlled trial compared morphine vs clonidine as monotherapy for NOWS infants and found that those patients receiving clonidine had a higher likelihood of requiring adjunct therapy compared to monotherapy with morphine.¹⁴ Clearly, further research efforts are necessary to fine tune pharmacological management with protocols that include initial dose, escalation parameters and taper schedule. The OPTimize NOW trial is designed to evaluate symptom-based dosing vs schedule taper and may provide new evidence to guide drug treatment.¹⁵

In the last few years, evidence is accumulating that suggests that opioid addiction has a genetic component, therefore, it is conceivable that NOWS may have a genetic predisposition too. The effects of genetic, epigenetic and pharmacogenetic mechanisms on severity of symptoms, need for pharmacological interventions and therapeutic response to drug therapy are rapidly being elucidated.

Genes associated with opioid addiction and withdrawal symptoms include the μ-opioid receptor (OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC). Single nucleotide polymorphism of COMT and OPRM1 have been associated with severity of symptoms and response to therapy.^16–18 Furthermore, the role of the placenta in NOWS severity is being actively evaluated. The expression and activity of placental drug metabolizing enzymes and placental transporters are key factors in determining fetal exposure to various substances and may play a significant role in fetal opioid exposure. Variations in these enzymes and cotransporters may also influence the newborn response to therapy in the postnatal period. In a recent study by Townsel et al,¹⁹ lower placental ABCB1 DNA methylation was associated with more severe NOWS. They suggest that unique placental methylation profiles near delivery may be indicative of fetal opioid exposure and NOWS severity risk.¹⁹ In the future, the application of pharmacogenetics and pharmacogenomics techniques and the discovery of how the patient’s genetic make-up affects symptom expression and therapeutic responses, may improve our diagnostic and therapeutic precision for the management of NOWS and, thus, provide a more individualized approach to drug therapy. Pharmacogenetic testing has become increasingly important in tailoring pharmacologic therapy in several areas of adult and pediatric medicine. Traditionally, testing requires obtaining a blood sample from the patient. However, in the last few years, testing in saliva samples has emerged as a very suitable alternative, especially for the pediatric patient where blood sampling can be difficult. Turn around time, usually measured in weeks, has been reduced to days and even hours with the introduction of newer techniques, for example, cartridge-based and portable polymerase chain reaction systems. It is conceivable that further advances of point-of-care molecular testing and the application of Artificial Intelligence will likely make rapid testing available at the bedside.²⁰ The implementation of these technologies will require a critical evaluation in terms of standardization, quality control, and certainly cost.

It is important to recognize that the effects of fetal opioid exposure during a critical period of brain development can have long lasting effects that may not be apparent until later in life. Long-term follow-up studies suggest increased risks for developmental, behavioral, and educational challenges.²¹ Consequently, close neurodevelopmental follow-up by Pediatricians or Developmental Specialists is necessary to monitor long-term effects of substance use, resulting from both prenatal exposures and postnatal pharmacological therapy for NOWS. Identification of developmental issues may prompt early referrals to speech, occupational and physical therapists. Furthermore, the thorough consideration of social determinants of health as their effect on outcomes are very significant. The development of post-discharge community-based support programs aimed at improving long-term outcomes is essential. Additionally, efforts should be made to improve social support for caregivers of infants affected by NOWS, as well as to provide education regarding the unique care needs of these families. As providers of neonatal care, we find ourselves at a turning point. We believe that in 2026 the management of NOWS must adopt a holistic and multidisciplinary approach, including family centered-functional care models and longitudinal family support to promote best outcomes. The neonatal community should strive for that to become the new standard of care.²² We hope that with the application of scientific principles of pharmacogenetics and pharmacogenomics, we will be able to improve our diagnostic and therapeutic precision for more individualized care. NOWS is a very complex public health problem that starts before and goes well beyond the newborn period. Health professionals, hospital leaders and community stakeholders must collaborate to establish a robust system of care for patients and families most affected by this health care crisis.

ABBREVIATIONS

ESC

Eat, Sleep, Console;

FNASS

Finnegan Neonatal Abstinence Scoring System;

NOWS

neonatal opioid withdrawal syndrome, OUD, opioid use disorder