Pharmacotherapy For Neonatal Abstinence Syndrome Research Articles

Neonatal Abstinence Syndrome: A Review of Treatment in the Neonatal Intensive Care Unit.

Neonatal abstinence syndrome (NAS) is a collection of symptoms that neonates may experience following antenatal exposure to substances that induce withdrawal. Optimal management remains unknown, and there is variation in management and outcomes. To describe the management, length of hospitalization, and adverse events in near-term and full-term neonates with NAS for whom treatment (pharmacotherapy and/or supportive care) was initiated in the neonatal intensive care unit (NICU). A chart review was conducted of neonates admitted to the NICU of Surrey Memorial Hospital, Surrey, British Columbia, who received treatment for NAS between September 1, 2016, and September 1, 2021. A total of 48 neonates met the inclusion criteria. Opioids represented the most frequent type of antenatal exposure. Polysubstance exposures occurred in 45 (94%) of the neonates. Morphine was given to 29 (60%) of the neonates, and phenobarbital to 6 (13%); 5 of these neonates received both medications. The average duration of morphine treatment was 14 days, and the average length of hospitalization (all patients) was 16 days. All of the neonates experienced adverse events; in particular, 9 (30%) of the 30 who received pharmacotherapy were too sedated to feed, compared with 0% of the 18 with no pharmacotherapy. The common finding of polysubstance antenatal exposure, involving predominantly opioids, was associated with scheduled morphine pharmacotherapy for the majority of patients, prolonged hospitalization, and frequent adverse events. Pharmacotherapy for NAS was associated with levels of sedation that interfered with feeding in neonates.

Increased Severity of Neonatal Abstinence Syndrome Associated With Concomitant Antenatal Opioid and Benzodiazepine Exposure.

Polysubstance use is common among opioid-using women, yet its association with pharmacotherapy for neonatal abstinence syndrome (NAS) remains unclear. We hypothesized that benzodiazepine exposure would increase risk of an infant developing pharmacologically treated NAS. We conducted a retrospective cohort study of maternal-infant dyads enrolled in Tennessee Medicaid, using individual-level data linkage of vital records and administrative (ie, outpatient, inpatient, and prescription) data from 2009 to 2011. These data underwent chart review from 2013 to 2016 to obtain clinically relevant exposure data (eg, toxicology testing). The association of antenatal exposures with pharmacologically treated NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant factors and clustered by hospital. Among 112 029 maternal-infant dyads, we confirmed 822 cases of NAS, of which 598 (72.7%) were cases of pharmacologically treated NAS. Infants who developed pharmacologically treated NAS were more likely to have been exposed to antenatal benzodiazepines compared with infants with confirmed NAS not treated pharmacologically (40.9% vs 30.8%; P = .008). In adjusted analyses, benzodiazepine exposure was associated with greater risk of developing pharmacologically treated NAS (odds ratio: 1.51; 95% confidence interval: 1.04-2.21). Alternatively, exposure to tobacco, marijuana, cocaine, gabapentin, and selective serotonin reuptake inhibitors were not associated with increased risk of developing pharmacologically treated NAS. Among a population of infants with intrauterine polysubstance exposure, benzodiazepine exposure was an independent predictor of an infant developing pharmacologically treated NAS. Obtaining history of antenatal benzodiazepine exposure among opioid-exposed infants may allow for risk stratification and development of personalized care plans.

Novel biomarkers to assess in utero effects of maternal opioid use: First steps toward understanding short- and long-term neurodevelopmental sequelae.

Maternal opioid use disorder is common, resulting in significant neonatal morbidity and cost. Currently, it is not possible to predict which opioid-exposed newborns will require pharmacotherapy for neonatal abstinence syndrome. Further, little is known regarding the effects of maternal opioid use disorder on the developing human brain. We hypothesized that novel methodologies utilizing fetal central nervous system-derived extracellular vesicles isolated from maternal blood can address these gaps in knowledge. Plasma from opioid users and controls between 9 and 21 weeks was precipitated and extracellular vesicles were isolated. Mu opioid and cannabinoid receptor levels were quantified. Label-free proteomics studies and unbiased small RNA next generation sequencing was performed in paired fetal brain tissue. Maternal opioid use disorder increased mu opioid receptor protein levels in extracellular vesicles independent of opioid equivalent dose. Moreover, cannabinoid receptor levels in extracellular vesicles were upregulated with opioid exposure indicating cross talk with endocannabinoids. Maternal opioid use disorder was associated with significant changes in extracellular vesicle protein cargo and fetal brain micro RNA expression, especially in male fetuses. Many of the altered cargo molecules and micro RNAs identified are associated with adverse clinical neurodevelopmental outcomes. Our data suggest that assays relying on extracellular vesicles isolated from maternal blood extracellular vesicles may provide information regarding fetal response to opioids in the setting of maternal opioid use disorder. Prospective clinical studies are needed to evaluate the association between extracellular vesicle biomarkers, risk of neonatal abstinence syndrome and neurodevelopmental outcomes.

Finding the right treatment for neonatal abstinence syndrome: is this the right time?

Neonatal abstinence syndrome (NAS) is a constellation of withdrawal symptoms in infants born to mothers with chronic opioid use during pregnancy. A proportion of infants will need pharmacotherapy in addition to non-pharmacological interventions. In this article, we reviewed a clinical trial comparing the use of sublingual buprenorphine to oral morphine (the most widely used pharmacotherapy for NAS) in term infants. The primary end point was the duration of treatment, and secondary end points were the length of hospital stay, the proportion of infants who needed supplemental phenobarbital, and safety.

Variation in treatment of neonatal abstinence syndrome in US children's hospitals, 2004-2011.

Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome experienced by opioid-exposed infants. There is no standard treatment for NAS and surveys suggest wide variation in pharmacotherapy for NAS. Our objective was to determine whether different pharmacotherapies for NAS are associated with differences in outcomes and to determine whether pharmacotherapy and outcome vary by hospital. We used the Pediatric Health Information System Database from 2004 to 2011 to identify a cohort of infants with NAS requiring pharmacotherapy. Mixed effects hierarchical negative binomial models evaluated the association between pharmacotherapy and hospital with length of stay (LOS), length of treatment (LOT) and hospital charges, after adjusting for socioeconomic variables and comorbid clinical conditions. Our cohort included 1424 infants with NAS from 14 children's hospitals. Among hospitals in our sample, six used morphine, six used methadone and two used phenobarbital as primary initial treatment for NAS. In multivariate analysis, when compared with NAS patients initially treated with morphine, infants treated with methadone had shorter LOT (incidence rate ratio (IRR) = 0.55; P < 0.0001) and LOS (IRR = 0.60; P < 0.0001). Phenobarbital as a second-line agent was associated with increased LOT (IRR = 2.09; P<0.0001), LOS (IRR = 1.78; P < 0.0001) and higher hospital charges (IRR = 1.84; P < 0.0001). After controlling for case-mix, hospitals varied in LOT, LOS and hospital charges. We found variation in hospital in treatment for NAS among major US children's hospitals. In analyses controlling for possible confounders, methadone as initial treatment was associated with reduced LOT and hospital stay.

Methadone Maintenance and Breastfeeding in the Neonatal Period

In a sample of methadone-maintained breastfeeding women and a matched group of formula-feeding women, this study evaluated concentrations of methadone in breast milk among breastfeeding women and concentrations of methadone in maternal and infant plasma in both groups. Eight methadone-maintained (dose: 50-105 mg/day), lactating women provided blood and breast milk specimens on days 1, 2, 3, 4, 14, and 30 after delivery, at the times of trough and peak maternal methadone levels. Paired specimens of foremilk and hindmilk were obtained at each sampling time. Eight matched formula-feeding subjects provided blood samples on the same days. Infant blood samples for both groups were obtained on day 14. Urine toxicological screening between 36 weeks of gestation and 30 days after the birth confirmed that subjects were not using illicit substances in the perinatal period. Concentrations of methadone in breast milk were low (range: 21.0-462.0 ng/mL) and not related to maternal dose. There was a significant increase in methadone concentrations in breast milk over time for all 4 sampling times. Concentrations of methadone in maternal plasma were not different between groups and were unrelated to maternal dose. Concentrations of methadone in infant plasma were low (range: 2.2-8.1 ng/mL) in all samples. Infants in both groups underwent neurobehavioral assessments on days 3, 14, and 30; there were no significant effects of breastfeeding on neurobehavioral outcomes. Fewer infants in the breastfed group required pharmacotherapy for neonatal abstinence syndrome, but this was not a statistically significant finding. Results contribute to the recommendation of breastfeeding for methadone-maintained women.