title: Morphine treatment for neonatal abstinence syndrome: huge dosing variability underscores the need for a better clinical study design.
abstract: BACKGROUND
  At present, morphine is the most commonly used first-line therapy to treat Neonatal Abstinence Syndrome (NAS). Unfortunately, there is still lack of evidence and consensus to guide pharmacologic therapy for NAS. In this review, we provide an overview on dosing regimens of morphine currently reported to treat NAS, with the aim to stimulate discussion on the need for a standardized dosing through better study design.
  
  
  METHODS
  A search strategy was performed in PubMed to identify studies that provide a dosing regimen used, or advised by a review or guideline for morphine to treat NAS. In addition, dosing regimens from labels and formularies were collected.
  
  
  RESULTS
  On 138 articles identified, 33 were retained after reading the full-text. In addition, 10 articles were included based on reference check. Extensive variability was observed for dosing advice, threshold in the initiating phase, dosing advice and maximum dose in the escalating phase. The same applies for dosing advice and detail during weaning, dosing interval and stabilization phase.
  
  
  CONCLUSIONS
  This review shows a large variability in dosing regimens of morphine used to treat NAS. This is likely a reflection of the heterogeneous populations included in NAS studies, the lack of standardization in assessment tools and study outcomes. We suggest that the development and validation of a core outcome set, subsequently applied in pragmatic point-of-care clinical trials or specific subgroups (e.g. iatrogenic postnatal NAS) are useful approaches to improve the current setting.
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia, Rotterdam, the Netherlands - p.mian@erasmusmc.nl.
authors.forename: Paola
authors.initials: P
authors.lastname: Mian
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia, Rotterdam, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia, Rotterdam, the Netherlands.
authors.forename: Enno D
authors.initials: ED
authors.lastname: Wildschut
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia, Rotterdam, the Netherlands.|Department of Development and Regeneration, KU Leuven, Leuven, Belgium.|Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: van den Anker
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia, Rotterdam, the Netherlands.|Division of Paediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D002986:Clinical Trials as Topic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007231:Infant, Newborn; D009020:Morphine / Q000008:administration & dosage*; D009357:Neonatal Abstinence Syndrome / Q000188:drug therapy*; D012107:Research Design
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine