Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome

Czynski, Adam J.; Davis, Jonathan M.; Dansereau, Lynne M.; Engelhardt, Barbara; Marro, Peter J.; Bogen, Debra L.; Hudak, Mark L.; Shenberger, Jeffrey S.; Wachman, Elisha M.; Oliveira, Érica L.; Lester, Barry M.

doi:10.1016/j.jpeds.2019.12.018

Cited by 37 publications

(23 citation statements)

References 21 publications

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“…In our analysis, there were no changes to the PK model published in our earlier work. Although long‐term neurodevelopmental outcomes have been explored in some clinical trials as secondary end points, 26 our investigation was confined to short‐term end points due to the difficulty of conducting such studies and expected large amount of variability in a small population. Future goals will be an updated PK model examining buprenorphine, norbuprenorphine, and glucuronidated buprenorphine measured in urine.…”

Section: Discussionmentioning

confidence: 99%

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Eudy-Byrne

Zane

Adeniyi-Jones

et al. 2021

Clinical Translational Sci

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Results from BBORN, a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of BPHORE, a new trial with buprenorphine in a similar population were to 1) optimize initial dose, up-titration to achieve symptom control and weaning steps of pharmacologic treatment and 2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when uptitration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose.Time to wean and time to cessation were dose-dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 ug/kg/day, 33% titration and 15% wean rate. Five subjects required adjuvant therapy. EC50 values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model-based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

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Section: Discussionmentioning

confidence: 99%

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Eudy-Byrne

Zane

Adeniyi-Jones

et al. 2021

Clinical Translational Sci

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“…This could be facilitated in a study by having a longer period of follow‐up that extends through the critical first 1000 days of development. Multiple domains of development could be assessed, at yearly intervals, with standardised tests such as the Bailey Scales of Infant and Toddler Development 13 …”

Section: Brief Discussion Of How To Do the Research Bettermentioning

confidence: 99%

“…Multiple domains of development could be assessed, at yearly intervals, with standardised tests such as the Bailey Scales of Infant and Toddler Development. 13 Furthermore, from a hospital resource point of view, it may have been useful to assess the duration of inpatient stay as a secondary outcome. It is possible that reduction in treatment days also translated to fewer days spent as an inpatient.…”

Section: Choose Primary and Secondary Outcomes That Are Clinically Mementioning

confidence: 99%

Does the addition of clonidine to opioid therapy improve outcomes in infants with Neonatal Abstinence Syndrome?

D'Abaco

2021

J Paediatrics Child Health

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To undertake a literature search and critical appraisal of best available evidence to answer the clinical question: Does the addition of clonidine (I) to standard treatment with an opioid (C) improve outcomes (O) in infants with Neonatal Abstinence Syndrome? A search of both comprehensive (MedLine and Embase) and pre-filtered databases (Dynamed, UpToDate and TRIP), utilising Boolean Operators to combine search terms appropriately. Three relevant studies were identified. One paper describing the outcomes of a randomised controlled trial by Agthe et al. (2009) most accurately answered the clinical question posed. This paper was critically appraised, and evidence applied to the clinical scenario. The use of clonidine as an adjunct to opioid in the management of infants with NAS reduces the total number of treatment days and dose of opioid required to control symptoms. However, there is a higher risk of rebound in symptoms post-cessation of opioid and clinicians need to account for this in their discharge planning. More large scale, multi-centre high-quality research is needed to clarify the role of clonidine in the treatment of NAS: as monotherapy versus adjunct, the optimal dose and longer-term impact on neurodevelopment.

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“…Methadone was associated with significantly shorter overall LOS, shorter LOS attributable to NAS, and shorter LOT compared to morphine in a larger multicenter randomized controlled trial ( N = 117) [ 27 ]. However, there were no differences in neurobehavioral outcomes when infants were followed to 18 months of age [ 28 ].…”

Section: Current Management Practicesmentioning

confidence: 99%

Neonatal opioid withdrawal syndrome: a review of the science and a look toward the use of buprenorphine for affected infants

et al. 2021

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Neonates born to mothers taking opioids during pregnancy are at risk for neonatal opioid withdrawal syndrome (NOWS), for which there is no recognized standard approach to care. Nonpharmacologic treatment is typically used as a first-line approach for management, and pharmacologic treatment is added when clinical signs are not responding to nonpharmacologic measures alone. Although morphine and methadone are the most commonly used pharmacotherapies for NOWS, buprenorphine has emerged as a treatment option based on its pharmacologic profile and results from initial single site clinical trials. The objective of this report is to provide an overview of NOWS including a summary of ongoing work in the field and to review the state of the science, knowledge gaps, and practical considerations specific to the use of buprenorphine for the treatment of NOWS as discussed by a panel of experts during a virtual workshop hosted by the National Institutes of Health.

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Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome

Cited by 37 publications

References 21 publications

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Does the addition of clonidine to opioid therapy improve outcomes in infants with Neonatal Abstinence Syndrome?

Neonatal opioid withdrawal syndrome: a review of the science and a look toward the use of buprenorphine for affected infants

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