Hydroxypropyl Methylcellulose as a Mucoadhesive Polymer in Ethanol-Free Buprenorphine Gel for Neonatal Sublingual Delivery.

Pediatrics group issues guideline on neonatal opioid withdrawal syndrome

The assessment of opioid withdrawal in the neonate, or neonatal opioid withdrawal syndrome (NOWS), is problematic because current assessment methods are based on subjective observer ratings. Crying is a distinctive component of NOWS assessment tools and can be measured objectively using acoustic analysis. To evaluate the feasibility of using newborn cry acoustics (acoustics referring to the physical properties of sound) as an objective biobehavioral marker of NOWS. This prospective controlled cohort study assessed whether acoustic analysis of neonate cries could predict which infants would receive pharmacological treatment for NOWS. A total of 177 full-term neonates exposed and not exposed to opioids were recruited from Women & Infants Hospital of Rhode Island between August 8, 2016, and March 18, 2020. Cry recordings were processed for 118 neonates, and 65 neonates were included in the final analyses. Neonates exposed to opioids were monitored for signs of NOWS using the Finnegan Neonatal Abstinence Scoring Tool administered every 3 hours as part of a 5-day observation period during which audio was recorded continuously to capture crying. Crying of healthy neonates was recorded before hospital discharge during routine handling (eg, diaper changes). The primary exposure was prenatal opioid exposure as determined by maternal receipt of medication-assisted treatment with methadone or buprenorphine. Neonates were stratified by prenatal opioid exposure and receipt of pharmacological treatment for NOWS before discharge from the hospital. In total, 775 hours of audio were collected and trimmed into 2.5 hours of usable cries, then acoustically analyzed (using 2 separate acoustic analyzers). Cross-validated supervised machine learning methods (combining the Boruta algorithm and a random forest classifier) were used to identify relevant acoustic parameters and predict pharmacological treatment for NOWS. Final analyses included 65 neonates (mean [SD] gestational age at birth, 36.6 [1.1] weeks; 36 [55.4%] female; 50 [76.9%] White) with usable cry recordings. Of those, 19 neonates received pharmacological treatment for NOWS, 7 neonates were exposed to opioids but did not receive pharmacological treatment for NOWS, and 39 healthy neonates were not exposed to opioids. The mean of the predictions of random forest classifiers predicted receipt of pharmacological treatment for NOWS with high diagnostic accuracy (area under the curve, 0.90 [95% CI, 0.83-0.98]; accuracy, 0.85 [95% CI, 0.74-0.92]; sensitivity, 0.89 [95% CI, 0.67-0.99]; specificity, 0.83 [95% CI, 0.69-0.92]). In this study, newborn acoustic cry analysis had potential as an objective measure of opioid withdrawal. These findings suggest that acoustic cry analysis using machine learning could improve the assessment, diagnosis, and management of NOWS and facilitate standardized care for these infants.

Methadone and morphine are commonly administered medications for neonatal opioid withdrawal syndrome (NOWS). Infants are increasingly treated with as-needed or "pro re nata" (PRN) medication. The optimal pharmacologic agent for PRN treatment of NOWS has not been examined. This study's objective is to compare NOWS hospital outcomes between infants treated with PRN methadone versus morphine. We performed a retrospective cohort study of infants pharmacologically treated for NOWS across 4 Massachusetts hospitals between January 2018 and February 2021. Infants born ≥36 weeks gestation with prenatal opioid exposure treated with PRN methadone or morphine were included. Mixed effects logistic and linear regression models were employed to evaluate differences in transition rates to scheduled dosing, length of stay, and number of PRN doses administered depending on PRN treatment agent. There were 86 infants in the methadone group and 52 in the morphine group. There were no significant differences in NOWS hospital outcomes between groups in adjusted models: transition to scheduled dosing (methadone 31.6% vs morphine 28.6%, adjusted odds ratio 1.21, 95% confidence interval [CI] 0.87-1.19), mean length of stay (methadone 15.5 vs morphine 14.3 days, adjusted risk ratio 1.06, 95% CI 0.80-1.41), and the mean number of PRN doses (methadone 2.3 vs morphine 3.4, adjusted risk ratio 0.65, 95% CI 0.41-1.02). There was an association with nonpharmacologic care practices and improved NOWS hospital outcomes. There were no significant differences in NOWS hospitalization outcomes based on pharmacologic agent type; nonpharmacologic care practices were most strongly associated with improved NOWS hospitalization outcomes.

361: Neonatal head circumference in opioid-exposed neonates with and without Neonatal Opioid Withdrawal Syndrome (NOWS)

The aim of this study was to investigate the association between race and severe neonatal opioid withdrawal syndrome (NOWS) in infants exposed to intrauterine opioids. This is a prospective observational study on intrauterine opioid-exposed term infants. Exposure to opioids was based on maternal disclosure, urine, or umbilical cord drug screening. Severe NOWS was defined based on modified Finnegan scoring and the need for pharmacological intervention. One hundred and fifty mother-infant pairs, 60 Black and 90 White with history of opioid exposure during pregnancy, were included. More White than Black infants developed NOWS that required pharmacological treatment, 70 vs. 40%: RR = 1.75 (1.25-2.45). In adjusted analysis, there was no significant association between race and the development of severe NOWS in mothers who attended opioid maintenance treatment program (OMTP). However, in mothers who did not attend OMTP, White race remained a significant factor associated with the development of severe NAS, RR = 1.69 (1.06, 2.69). Severe NOWS that required pharmacological intervention was significantly higher in White than in Black infants born to mothers who did not attend OMTP. Larger studies are needed to evaluate the association between social as well as genetic factors and the development of NOWS. There is a significant association between race and development of severe NOWS.

Polysubstance use, particularly combining opioids with stimulants such as cocaine, is rising among individuals with substance use disorders. This practice aims to balance cocaine's stimulant effects with opioids' sedative effect, potentially decreasing adverse outcomes. We hypothesized that concurrent exposure to cocaine and opioids would reduce the risk of neonatal opioid withdrawal syndrome (NOWS) compared to opioid use alone. This analysis draws from an ongoing prospective study of maternal substance use (SUD) at Regional One Health's perinatal center in Memphis, TN, and included mothers and their infants born between 2018 and 2022. Maternal SUD was identified via screening questionnaires, urine toxicology, or umbilical cord tissue analysis. Participants were grouped into using (a) opioids with cocaine (OwC) and (b) opioids without cocaine (OwoC). Univariate and regression analyses were conducted to assess the risk of NOWS. A total of 353 infants were born to 342 mothers, with 31% (110/353) of the infants born to women who used cocaine along with opioids. While maternal demographics were similar, the OwC group had significantly lower rates of prenatal care, chronic pain history, and MOUD enrollment (p = 0.03). Infants in the OwC group had significantly higher rates of NOWS (p < 0.01), longer hospital stays (p < 0.01), and 6.5 times greater odds of developing NOWS (p < 0.001). NOWS was associated with an average 15-day increase in the length of stay for term infants (95% CI: 11.2, 18.8; p < 0.001). Contrary to our hypothesis, our study highlights the significant impact of maternal cocaine use on the increased likelihood of NOWS and extended hospital stays for affected infants.

Many infants with neonatal opioid withdrawal syndrome (NOWS) from prenatal exposure to opioids require transfer to a pediatric inpatient unit for medication weaning. The purpose of this study is to assess the difference in the duration of medication weaning between infants transferred by day of life (DOL) 14 versus later (DOL 15 and after) to a tertiary care setting for pharmacological and nonpharmacological management of NOWS. This single-site retrospective cohort study uses medical chart data from infants with NOWS transferred to specialized care between May 2016 and June 2021 (n = 87). The primary outcome is length of medication weaning, calculated as the number of days between transfer from the NICU to a tertiary care setting and the cessation of pharmacotherapy. The majority of the infants in this sample are transferred from acute to tertiary care after DOL 15 (62% versus 38% by DOL 14). The predicted number of days to wean is 14.2 among those infants transferred by DOL 14, whereas the duration of weaning is 6.6 days longer among the later transfer group (20.8 days), adjusting for key covariates. The duration of weaning is also prolonged among infants with greater NOWS symptom severity and with prenatal exposure to psychotropic medications. Delayed treatment prolongs NOWS symptoms and increases the burden on the health care system. Earlier referral from NICUs to pediatric inpatient units with environmental supports could reduce prolonged medication exposure and length of hospitalization for infants diagnosed with NOWS.

Background The opioid epidemic in the United States continues to threaten public health. As a result of this crisis, neonatal opioid withdrawal syndrome (NOWS) has risen exponentially and requires a multitude of non-pharmacologic treatments to ensure healthy neonatal outcomes. Methods: This feasibility study implemented an acupressure protocol as informed by the Near-Term Infant (NTI) conceptual framework for the treatment of NOWS. Aims of this study were to assess provider training, effective integration of acupressure within the standard of care, and acceptance of this treatment by mothers and healthcare providers. Results: With maternal consent, a total of 12 participants were enrolled and underwent auricular acupressure. Nurse Practitioners were credentialed (75%) and effectively administered neonatal acupressure (100%) in accordance with the study protocol. Mothers were very satisfied with acupressure for the treatment of NOWS (Client Satisfaction Questionaire-8 mean scores 3.8–4.0 of a possible 4.0), and the majority of healthcare providers were supportive (66%, mean scores 3.6 to 4.0 out of possible 5). Conclusions: Auricular acupressure was successfully implemented within the standard of care for NOWS. Future studies should incorporate outlined suggestions and include qualitative measures of acceptance as well as randomized controlled trials to evaluate efficacy.

To reduce transfers to the neonatal intensive care unit (NICU) for neonates with opioid withdrawal while also reducing length of stay and pharmacologic intervention, and maintaining standards of safety. This was a single-center quality-improvement (QI) initiative in a free-standing maternity hospital comparing outcomes for neonatal opioid withdrawal syndrome (NOWS) before and after a series of QI bundles in infants >36 weeks' gestation age (GA). We compared outcomes to our preintervention period (January, 2013 to December, 2013; n = 42) with outcomes postintervention cycle 1 (October, 2016 to September, 2017; n = 126), and postintervention cycle 2 (November, 2017 to October, 2018; n = 160). Cycle 1 included organizing a multidisciplinary task force who focused on emphasis on nonpharmacologic and dyad-centered care, and also standardized pharmacologic management. Cycle 2 reflects the transition to a functional assessment tool and as-needed morphine administration on the postpartum floor. Transfer to the NICU for management of NOWS dropped from 71.4% before the quality improvement project down to 5.6% (P < 0.001), with the remainder managed on the mother-baby unit. Length of stay decreased from 17.8 days to 7.2 days, and opioid replacement dropped from 60% down to 16% (P < 0.001 for both). There were no adverse events from morphine administration for any of the infants in this series. Our study demonstrates how care can be safely provided to most infants with neonatal opioid withdrawal on a postpartum unit without needing transfer to another unit or a higher level of care facility.

A transition from a pharmacological-based model of care, such as Finnegan scoring, to a behavioral-based model, such as the Eat-Sleep-Console, for newborns experiencing neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS) has resulted in shorter lengths of stay and a decreased need for pharmacological management. However, many newborns continue to be exposed to opioids. Use of opioids for NAS/NOWS prolongs the length of stay and often the separation of mothers and their newborns as well. Additionally, opioids may have detrimental neurodevelopmental consequences for newborns. Researchers are seeking safe and effective pharmacological adjuncts to behavioral-based NAS/NOWS management. Could ondansetron be an answer? This column provides a brief review of a meta-analysis supporting the benefits of a behavioral approach to NOWS, a discussion about why ondansetron may be useful in NOWS, an overview of a pharmacokinetic study of ondansetron in mother-infant dyads, and a review of a recently published clinical trial of ondansetron for NOWS.

Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS, and a therapeutic mechanism was proposed based on preferential delivery of 6BN to fetal brain with relative exclusion from maternal brain. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ∼0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies in rodents and non-human primates. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This high potency appears to run counter to our pharmacokinetic studies showing slow 6BN transit of both the placenta and maternal blood brain barrier in guinea pigs, and calls into question the preferential delivery mechanism. Rather, it suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence at all developmental stages, even in adults, as compared to its well-established low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.

RationaleOpioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments.ObjectivesWe sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.MethodsWe employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal.ResultsOn P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice.ConclusionsWe identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome

In uteroopioid exposure is associated with lower weight and a neonatal opioid withdrawal syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparingin uteroonly opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Here, we sought to understand the impact of continued postnatal opioid exposure on long term behavioral consequences. We implemented a rodent perinatal opioid exposure model of oxycodone (Oxy) exposure that included Oxy exposure until birth (short Oxy) and continued postnatal opioid exposure (long Oxy) spanning gestation through birth and lactation. Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following short or long Oxy exposure. Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored.

CHAPTER 55 - Treating Neonatal Abstinence Syndrome in the Newborn