Neonatal pain management: still in search for the Holy Grail

Abstract

Inadequate pain management but also inappropriate use of analgesics in early infancy has negative effects on neurodevelopmental outcome. As a consequence, neonatal pain management is still in search for the Holy Grail. At best, effective pain management is based on prevention, assessment, and treatment followed by a re-assessment of the pain to determine if additional treatment is still necessary. Unfortunately, epidemiological observations suggest that neonates are undergoing painful procedures very frequently, unveiling the need for effective preventive, non-pharmacological strategies. In addition, assessment is still based on validated, multimodal, but subjective pain assessment tools. Finally, in neonatal intensive care units, there is a shift in clinical practices (e.g., shorter intubation and ventilation), and this necessitates the development and validation of new pharmacological treatment modalities. To illustrate this, a shift in the use of opioids to paracetamol has occurred and short-acting agents (remifentanil, propofol) are more commonly administered to neonates. In addition to these new modalities and as part of a more advanced approach of the developmental pharmacology of analgesics, pharmacogenetics also emerged as a tool for precision medicine in neonates. To assure further improvement of neonatal pain management the integration of pharmacogenetics with the usual covariates like weight, age and/or disease characteristics is needed.

Figure 1.. Individual clearance (L/kg/h) estimates in 30 (pre)term neonates following a single intravenous propacetamol (10 – 20 mg/kg paracetamol equivalent) administration show a modest increase with increasing weight (median clearance < 2 kg 0.123 to 0.16 L/kg/h in cases > 2 kg) (X-axis: weight, in g; Y-axis: paracetamol clearance, in L/kg/h) [28].

Figure 2.. The impact of age (preterm (< 37 weeks) or term) and the CYP2D6 activity score (either 1, 2, or 3) on the plasma log M/M1 value. A lower M/M1 value hereby reflects a higher CYP2D6 activity, depending on both age and genetic polymorphisms. Individual plasma log M/M1 values were extracted from an earlier published dataset on tramadol disposition in neonates. There were no cases with a CYP2D6 activity score of 3 in the preterm age cohort. (M = tramadol; M1 = O-desmethyltramadol) (X-axis: preterm (< 37 week) or term (≥ 37 week) cases, Y-axis: plasma log M/M1 value) [49].