Clinical pharmacology of analgosedatives in neonates: ways to improve their safe and effective use

Abstract

Objectives To propose approaches tailored to the specific needs of neonates, such as structured product development programs, with the ultimate goal to improve the safe and effective use of analgo-sedatives in these fragile patients. Key findings The feasibility and relevance of a structured product development program in neonates (optimal study design based on preliminary data; model development; internal, external and prospective evaluation; an individualized dosing regimen; long term safety; pharmacogenetics) is illustrated for the use of morphine. Based on changes in clinical practices, similar development plans are in progress for short acting analgo-sedatives such as propofol, but are in need of tailored pharmacodynamic tools to assess and quantify effects. Furthermore, for drugs like paracetamol where there is already sufficient clinical pharmacology knowledge, attention needs to be given to long-term safety aspects. Finally, new covariates such as pharmacogenetics might further improve neonatal pain management, but clearly need to be integrated with other well established covariates like age or weight. Summary Product development programs for analgo-sedatives in neonates are needed. These programs should be tailored to their specific needs (short acting sedation, pain relief), should include long term safety, and should incorporate the exploration of newer covariates like pharmacogenetics.

Large differences in neonatal drug use between NICUs are common practice: time for consensus?

“…Nervous system drugs also showed large variability, which may be a reflection of the variation in drugs mentioned in pain treatment protocols of these four NICUs. This may be explained by the worldwide discussion on the neurodevelopmental safety of nervous system drugs such as opioids, paracetamol and benzodiazepines in the preterm brain . A comparable discussion accounts for the choice of premedication for intubation .…”

Cerebral autoregulation and activity after propofol for endotracheal intubation in preterm neonates

“…32,33 Suppression of cortical activity after surfactant treatment with or without premedication and intubation is described, ranging from 10 to 30 min after surfactant, and up to 24 h if premedication with morphine was used. [34][35][36] In the current study, it is impossible to disentangle the impact of intubation or surfactant from propofol on brain activity.…”

Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants

“…The large inter‐individual variability regarding PK variables needs to be further investigated to elucidate which individual factors are important. Individualised treatment with fentanyl requires further pharmacogenetic knowledge about important genetic variants influencing metabolism and efficacy of the drug . Further studies with higher bolus doses should be conducted for procedures considered to be too painful for a non‐pharmacological approach.…”