Stability Study of Compounded Ethanol-Free Buprenorphine Oral Syringes for the Treatment of Neonatal Opioid Withdrawal Syndrome.

Maternal-fetal biodisposition of buprenorphine and its metabolites in opioid dependent pregnant individuals

Interaction between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome

OBJECTIVE Sublingual (SL) buprenorphine is a cornerstone of care in the treatment of adult opioid use disorder. Recent studies have demonstrated its advantages in the management of neonatal opioid withdrawal syndrome (NOWS). Commercially available SL tablets and transdermal patches are not amenable to neonatal use, and published compounding formulas of SL solutions contained undesirable excipients, including ethanol, sugars, and preservatives. The objective of this research is to explore the stability of a novel SL buprenorphine formulation free of alcohol, sugars, and preservatives. METHODS A 0.075 mg/mL buprenorphine solution was prepared by diluting the commercial injectable solution with normal saline and packaged into polyethylene terephthalate amber prescription bottles and polypropylene amber oral syringes and stored in refrigeration. Quality assessments were conducted by visual, pH, and high-performance liquid chromatography (HPLC) analysis immediately after preparation, and at 7 and 14 days of storage. RESULTS There were neither visual nor pH changes detected through 14 days. HPLC analysis indicated that all samples retained >99% initial buprenorphine concentration. Drug concentration increased slightly in the oral syringe after day 7, probably due to moisture loss. No degradation peaks were observed in chromatograms. CONCLUSIONS This novel buprenorphine is free of alcohol, sugar, and preservatives, and it may offer a significant safety advantage for NOWS patients. Additional clinical studies are recommended to verify the bioavailability and efficacy of this formulation.

OBJECTIVES/GOALS: Buprenorphine (BUP) is used for opioid use disorder during pregnancy but causes neonatal opioid withdrawal syndrome (NOWS). The goal of this study was to determine the contribution of the active metabolite, norbuprenorphine (NorBUP), to the development of NOWS when the parent drug, BUP, is administered during pregnancy. METHODS/STUDY POPULATION: Subcutaneously implanted osmotic minipumps delivered BUP (0, 0.01, 0.1 or 1 mg/kg/day) ± NorBUP (1 mg/kg/day) to pregnant Long-Evans rats from gestation day 9 until after delivery. NOWS was measured between 3 and 12 hours after delivery. Withdrawal was precipitated by an intraperitoneal injection of a mu opioid receptor antagonist naltrexone (NTX; 0, 1 or 10 mg/kg), and movement duration (MD; a validated proxy for NOWS) was measured using Noldus Ethovision. Concentrations of BUP, NorBUP, and their glucuronide conjugates in the brains of neonatal littermates not undergoing withdrawal testing were determined using LC/MS/MS. Two-way ANOVA and multiple linear regression analyses tested for interactions between BUP and NorBUP on MD and related brain concentrations to MD, respectively. RESULTS/ANTICIPATED RESULTS: There was no interaction effect between BUP and NorBUP on MD for either sex or at any dose of naltrexone. In females, but not males, BUP (1 mg/kg/day) significantly increased NorBUP-induced MD by 58% following an injection with 1 mg/kg NTX. A multiple linear regression model that included BUP and NorBUP brain concentrations as predictors of MD was significant and well-fitting [FEMALES: F (2, 40) = 23.97, P < .0001, adj R2 = 0.52; MALES: F (2, 40) = 5.84, P = .0059, adj R2 = 0.19]. There was a differential contribution of NorBUP brain concentrations to MD based on sex. The partial regression coefficient for NorBUP was 51.34 (p < .0001) for females and 19.21 (p = 0.093) for males. The partial regression coefficient for BUP was similar for females and males (FEMALES:βBUP = 10.62, p = .0017; MALES:βBUP = 11.38, p = .009). DISCUSSION/SIGNIFICANCE: We show for the first time a differential contribution of NorBUP to BUP-associated NOWS in each sex, suggesting sex differences in NorBUP susceptibility and implicating that treatment strategies reducing prenatal NorBUP exposure may be more effective for females than males.

Delivery dose of methadone, but not buprenorphine, is associated with the risk and severity of neonatal opiate withdrawal syndrome

Neonatal opioid withdrawal syndrome (NOWS) remains a national crisis, affecting 6 to 8 per 1000 live births in the United States.1 Nonpharmacologic treatment is considered the first-line of medical management for infants with NOWS, with pharmacotherapy being secondary.2 Approximately 50% of infants with NOWS receive pharmacologic treatment with associated prolonged hospitalizations.3,4 There is currently no universally accepted pharmacologic treatment approach for NOWS; however, the American Academy of Pediatrics recommends utilizing an opioid medication, such as morphine or methadone, as first-line pharmacotherapy.2 There are very few studies that have examined nonopioid agents as first-line pharmacotherapy for NOWS. Clonidine is a nonopioid α−2-adrenergic agonist which inhibits noradrenaline release and decreases opioid withdrawal symptoms. Prior small clinical trials and cohort studies have demonstrated preliminary effectiveness for NOWS, either as a primary or adjunctive agent; however, no large trials had previously been conducted.5–7In this issue of Pediatrics, Bada et al conducted a large single-center randomized control trial of morphine versus clonidine as a first-line pharmacotherapy for NOWS.8 The study randomized 120 infants ≥ 35 weeks gestational age with NOWS and found no significant differences in length of treatment between morphine and clonidine (15 vs 17 days, P = .48); however, more clonidine-treated infants (45% versus 10%) received adjunctive pharmacotherapy.8 Infants were examined with the NICU Network Neurobehavioral Scale at the completion of treatment, with no differences identified between groups.We commend Bada et al for the conduct of this rigorous randomized trial, which is the largest to date to include clonidine as a primary pharmacologic agent. Large-scale clinical trials for NOWS have been limited, with only a handful conducted over the past decade.2,9 This trial also addressed some of the limitations of prior studies, with rigorous evaluation of prenatal coexposures to nonprescribed substances and psychiatric medications in their analyses. There are potential benefits of utilizing clonidine as a primary agent for NOWS, including the lack of respiratory depression risk, the decrease in neuronal apoptosis, and suppression of inflammatory cytokines.10 This could lead to beneficial effects on the developing neonatal brain. However, the effects of short courses of opioids for the treatment of NOWS on long-term outcomes are not well established. Though some differences in infant neurobehavior have been identified after postnatal opioid exposure for the treatment of NOWS, these have not translated into significant differences in later neurodevelopmental outcomes.11,12 A prior study by Bada et al identified no differences in neurodevelopmental outcomes at 12-months of age when comparing clonidine and morphine treated infants.7Though the study did find similar treatment durations for primary pharmacologic agents, the high adjunctive treatment rate with phenobarbital in the clonidine group warrants discussion. Phenobarbital has been demonstrated to be beneficial as an adjunctive agent for NOWS, particularly for polypharmacy exposure and easing of neurologic manifestations, and has the advantage of an outpatient weaning option.13,14 However, of concern is the potential for adverse neurodevelopmental outcomes with prolonged phenobarbital exposure; a recent NOWS randomized trial found that phenobarbital-exposed infants had lower developmental scores and more behavioral problems at 18 to 24 months.15–17One key question this study raises is how these results will translate into current clinical practice in which hospitals have increasingly adapted nonpharmacologic care bundles in nonintensive care settings, the Eat, Sleep, Console (ESC) approach, and symptom-triggered opioid dosing.2 The recent multicentered ESC NOW clinical trial demonstrated significantly shorter lengths of treatment (11.8 vs 18.1 day) with the ESC approach in comparison with scoring with the Finnegan scale.18 Many hospitals are also transitioning to symptom-triggered opioid dosing, with associated shorter lengths of treatment and hospitalization.19,20 Recent NOWS clinical trials have also focused on comparisons of morphine to either methadone and buprenorphine, finding shorter hospitalizations with the longer-acting opioids.21,22 No studies, to our knowledge, have focused on comparing clonidine as a first-line pharmacologic agent with methadone or buprenorphine.In conclusion, this is a robust new clinical trial in the field of NOWS demonstrating efficacy of clonidine as a primary pharmacologic agent with comparative hospitalization outcomes to morphine, with the exception of higher secondary agent use. Future studies should incorporate multicentered designs, examine longer-term neurodevelopmental outcomes, emphasize the importance of standardized nonpharmacologic care bundles as primary medical management, compare clonidine to methadone and buprenorphine, and incorporate symptom-triggered dosing and the ESC care approach for broadest generalizability into clinical practice.

Buprenorphine (BUP) is widely used in the treatment of neonatal opioid withdrawal syndrome (NOWS). However, the most compounded formulation contains 30% ethanol, despite regulatory and clinical concerns regarding ethanol exposure in pediatric patients. Thus, this research aimed to develop an ethanol-free sublingual (SL) gel formulation of BUP that would be safe, stable, and suitable for NOWS. Multiple polymers were screened as gelling agents, with hydroxypropyl methylcellulose (HPMC) emerging as the ideal base polymer for the formulation due to its optimal pH, rheological characteristics, and stability. The formulated gels were stored at room temperature and refrigerated conditions for 30 days and evaluated for stability using pH, rheology, and liquid chromatography-mass spectrometry. BUP content was between 90-110% of the labeled amount of the dosage form (75 µg/mL) at all time-points, and the pH remained close to physiological values. Release studies demonstrated a drug release of 23-24% for SL gels without surfactants stored at room temperature and refrigerated conditions, respectively. Incorporation of non-ionic surfactants (Tween 20 and Tween 80) significantly increased drug release to 33% and 40%, respectively, reflecting enhanced solubilization and improved mucosal penetration. The ethanol-free formulation demonstrated physicochemical stability and favorable release characteristics suitable for neonatal administration. These findings represent a meaningful advance in the development of safer pediatric formulations for NOWS.

Neonatal opioid withdrawal syndrome (NOWS) is associated with long and costly birth hospitalization and increased readmission risk. Our objective was to examine readmissions in the first year of life for infants diagnosed with NOWS compared with infants without NOWS, adjusting for sociodemographic and clinical factors, and to describe use during readmissions in this population. Using data from the Pediatric Health Information System, we identified singleton term infants with NOWS and without NOWS or other major condition (by diagnosis codes and All Patient Refined Diagnosis Related Groups coding, respectively) discharged from 2016 to 2019. We predicted time to first readmission within the first year of life using Cox regression analysis. Predictors included NOWS diagnosis, sociodemographic factors, birth NICU use, and birth weight. We included 155 885 birth discharges from 17 hospitals (n = 1467 NOWS) with 10 087 readmissions. Unadjusted 1-year readmission rates were 9.9% among NOWS infants versus 6.2% among those without NOWS. The adjusted hazard ratio for readmission within the first year was 1.76 (95% confidence interval: 1.40-2.22) for infants with NOWS versus those without. Readmissions for infants with NOWS were longer and costlier and more likely to require intensive care and mechanical ventilation. Readmissions among infants without NOWS were most commonly for jaundice and respiratory and other infections, whereas respiratory infections were the leading cause of readmissions among NOWS infants. Infants with a NOWS diagnosis were more likely to be readmitted within the first year of life. In future work, researchers should explore potential interventions to prevent readmissions and provide resources to families affected by opioid dependence.

In a number of countries, the prevalence of neonatal opioid withdrawal syndrome (NOWS) is increasing. While NOWS is ultimately the result of opioid exposure in utero, a wide range of risk factors have been associated with the prevalence of NOWS, extending beyond just drug exposure. This article reviews the available literature on factors associated with the incidence of NOWS in opioid-exposed neonates. A range of risk factors have been associated with NOWS, including features of neonatal drug exposure, maternal and neonatal characteristics, aspects of labor and delivery, and genetics. Increased length of gestation and higher birth weight were consistently associated with an increased risk of NOWS, while breast feeding and 'rooming-in' were associated with a reduced risk of NOWS. Additionally, several genetic factors have also been associated with NOWS severity. There is conflicting evidence on the association between NOWS and other risk factors including opioid dose, neonate sex, and the use of some medications during pregnancy. This may be in part attributable to differences in how NOWS is diagnosed and the variety of methodologies across studies. While a large number of risk factors associated with NOWS are non-modifiable, encouraging pregnant women to reduce other drug use (including smoking), breast feed their child, and the judicious use of medications during pregnancy may help reduce the prevalence of NOWS. The presence or absence of NOWS in an opioid-exposed neonate is associated with a wide range of factors. Some of these modifiable risk factors may be potential targets for the primary prevention of NOWS.

Post-discharge healthcare utilization in infants with neonatal opioid withdrawal syndrome

Analyze maternal and infant characteristics by Neonatal Opioid Withdrawal Syndrome (NOWS) status and examine the association between mothers with Hepatitis C Virus (HCV) and infants diagnosed with NOWS. Hospital discharge diagnoses of low-income women in Tennessee were used to identify NOWS cases (n = 1,369) in 2013 and 2014 and randomly selected controls (n = 1,369) were matched on county of residence and birth year. Maternal and infant characteristics were obtained by linking these data to birth certificate data. Of Tennessee's 683 cases of NOWS in 2013 and 686 in 2014, most (69%) occurred in Eastern Tennessee. Mothers of infants with NOWS were more likely to be older, unmarried, and white than mothers of infants without NOWS. Mothers of infants with NOWS also faced greater health risk: more smoking, HCV, herpes simplex diagnosis, and no or less frequent prenatal care (p < .0001). Infants with NOWS were more likely to present with infection, be admitted into the NICU, have lower birth weight, be enrolled in TennCare, but less likely to be breastfed than infants without NOWS (p < .0001). After adjusting for demographic factors and smoking, compared to mothers of infants without NOWS, mothers of infants with NOWS had an alarmingly increased odds of HCV [OR = 12.97 (95% CI 7.42, 22.66)]. This study emphasizes the complexity of challenges facing families impacted by NOWS, the importance of multifaceted prevention, and the need to conduct HCV testing in NOWS infants.

Placental DNA methylation profiles in opioid-exposed pregnancies and associations with the neonatal opioid withdrawal syndrome

Although cases of neonatal opioid withdrawal syndrome (NOWS) increased 5-fold in recent years, no study has examined national hospital readmission rates for these infants. To examine hospital readmissions for infants with and without NOWS. This retrospective cohort study analyzed serial cross-sectional samples of US hospital discharge records from the Nationwide Readmissions Database for calendar years 2016 to 2020. Infants with NOWS were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes. The data analysis was performed between January 5, 2023, and May 6, 2024. Neonatal opioid withdrawal syndrome. Survey-weighted logistic regression was used to examine 90-day all-cause and cause-specific hospital readmissions. Multivariable models adjusted for sex, low birth weight, gestational age, multiple gestation, type of insurance, and year of birth. Of the 13 855 246 newborns identified in this weighted analysis, 89 018 (0.6%) were diagnosed with NOWS, of whom 53.8% were male and 81.1% born full-term (>36 weeks gestation). The 90-day all-cause readmission rate was 4.2% for infants with NOWS compared with 3.0% for those without NOWS (P < .001). After risk adjustment, the odds of all-cause readmission were higher among infants with NOWS (adjusted odds ratio [AOR], 1.18; 95% CI, 1.08-1.29). Infants with NOWS had significantly higher odds of readmissions for seizures (AOR, 1.58; 95% CI, 1.01-2.46), failure to thrive (AOR, 1.99; 95% CI, 1.36-2.93), traumatic brain injury (AOR, 2.95; 95% CI, 1.76-4.93), and skull fractures (AOR 3.72; 95% CI, 2.33-5.93). Infants with NOWS had higher odds of receiving a diagnosis of confirmed maltreatment (AOR, 4.26; 95% CI, 2.19-8.27), including for neglect (AOR, 14.18; 95% CI, 5.55-36.22) and physical abuse (AOR, 2.42; 95% CI, 0.93-6.29); however, the latter finding was not statistically significant. In this nationally representative cohort study, infants with NOWS were at increased risk of readmission for any cause as well as for trauma and confirmed maltreatment. These findings may in part reflect the dual stressors that mothers with opioid use disorder face in caring for a newborn with NOWS in the context of a substance use disorder and underscore the need for family-based, in-home services that focus concurrently on substance use treatment and parenting support.

The opioid crisis in the United States affects everyone—including pregnant women. As opioid use disorder (OUD) increased in the general population, it also increased for pregnant women. In November, the American Academy of Pediatrics (AAP) published a clinical report with recommendations for neonatal opioid withdrawal syndrome (NOWS). For mothers with OUD, optimal care includes either methadone or buprenorphine replacement therapy, according to the report. Despite clear data on the safety and efficacy of these drugs, however, barriers limit access to OUD therapies. The guideline authors, led by Stephen Patrick, MD, from Vanderbilt University Medical Center, cite social, economic, and environmental factors as primary barriers, as well as systemic racism and mental health issues in patients. NOWS requires chronic exposure to opioids throughout the pregnancy, not exposure around the time of delivery. Factors such as opioid type and maternal and fetal pharmacokinetics affect the presentation of NOWS. Concurrent use of benzodiazepine, gabapentin, or nicotine can impact the onset, severity, and/or duration. Methadone and buprenorphine used to treat OUD do not have this same relationship, the guideline authors said. Symptoms of NOWS include irritability, loose/watery stools, vomiting, sweating, fever, increased respiratory rate, frequent yawning and sneezing, nasal stuffiness, nasal flaring, and even seizures. These withdrawal symptoms may begin within 24 hours of birth for opioids excreted/metabolized quickly (heroin) or up to 3 days for longer acting opioids (methadone). To further complicate presentation, sometimes these symptoms do not show up until day 7, when many infants have been discharged from the hospital, the authors noted. This is why screening for OUD is important for the duration of a patient's pregnancy. Diagnosing NOWS is challenging because there is no single agreed-upon scoring system for diagnosis. Multiple scoring tools are available. A newer tool, called the Eat, Sleep, Console (ESC), is easy to use and can help guide treatment decisions. Infants are evaluated on their ability to eat 1 ounce or more (or breastfeed well), sleep undisturbed for 1 hour or longer, and be consoled. If any of these three items are not met, the medical team should discuss environment changes, as well as nonpharmacologic and pharmacologic approaches to NOWS management. The guideline authors recommend that health systems decide which scoring tool to use and focus heavily on standardizing the scoring process at their institution. This standardization is valuable because evaluation in some scoring tools is subjective. AAP does not endorse any specific scoring tool, as studies do not show any to be clearly superior to another. Managing an infant after chronic opioid exposure should occur for at least 72 hours, according to the guideline. In addition, nonpharmacologic management—such as a dimly lit environment for an overactive infant or swaddling for an infant with hypertonia—are helpful, stated the authors. For infants with severe NOWS, pharmacotherapy is warranted. Opioids are first-line agents for opioid withdrawal, and the most common first-line agent is morphine. Methadone or buprenorphine are also appropriate to consider. Common secondary agents for NOWS include phenobarbital and clonidine. However, phenobarbital has been shown to be associated with neurotoxicity and adverse developmental outcomes and should be avoided. Secondary agents may be useful if the primary agent does not adequately treat the infant's withdrawal symptoms. Agents with a high alcohol content (some formulations of buprenorphine), tincture of opium, or tincture of opioid should not be used for NOWS, the authors stated. Following discharge from the hospital, mothers are at risk for losing access to medications to treat OUD, and this risk could translate to overdose death. The authors stressed that it is important to make sure mothers have additional support and that OUD treatment is not interrupted. According to the guideline, an infant with NOWS should be seen by a pediatrician within 48 hours of discharge and followed up 1 week later. Multiple studies have evaluated duration of outpatient drug therapy for infants with NOWS, but the lack of follow-up data makes evaluating outcomes difficult. For this reason, the guideline authors do not recommend outpatient opioid tapers for infants with NOWS unless a structured and comprehensive follow-up schedule has been established.

Could genetic variations explain variability in neonatal opiate withdrawal syndrome?