Biomarkers for assessing pain and pain relief in the neonatal intensive care unit.

Newborns admitted to the neonatal intensive care unit (NICU) regularly undergo painful procedures and may face various painful conditions such as postoperative pain. Optimal management of pain in these vulnerable preterm and term born neonates is crucial to ensure their comfort and prevent negative consequences of neonatal pain. This entails accurate and timely identification of pain, non-pharmacological pain treatment and if needed administration of analgesic therapy, evaluation of treatment effectiveness, and monitoring of adverse effects. Despite the widely recognized importance of pain management, pain assessment in neonates has thus far proven to be a challenge. As self-report, the gold standard for pain assessment, is not possible in neonates, other methods are needed. Several observational pain scales have been developed, but these often rely on snapshot and largely subjective observations and may fail to capture pain in certain conditions. Incorporation of biomarkers alongside observational pain scores holds promise in enhancing pain assessment and, by extension, optimizing pain treatment and neonatal outcomes. This review explores the possibilities of integrating biomarkers in pain assessment in the NICU.

Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats.

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a "second hit" in adulthood. As the nociceptive system and the hypothalamic-pituitary-adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a "second hit" and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8 weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.

Early-life exposure to selective serotonin reuptake inhibitors: Long-term effects on pain and affective comorbidities.

A growing body of evidence indicates that early-life exposure to selective serotonin reuptake inhibitor has long-term consequences on the offspring's pain in addition to affective disorders like anxiety disorder and major depression. Serotonin, besides its role in regulating pain and emotions, promotes neuronal network formation. The prefrontal cortex and the amygdala are two key brain regions involved in the modulation of pain and its affective comorbidities. Thus, the aim of this review is to understand how early-life selective serotonin reuptake inhibitor exposure alters the developing prefrontal cortex and amygdala and thereby underlies the long-term changes in pain and its affective comorbidities in later life. While there is still limited data on the effects of early-life selective serotonin reuptake inhibitor exposure on pain, there is a substantial body of evidence on its affective comorbidities. From this perspective paper, four conclusions emerged. First, early-life selective serotonin reuptake inhibitor exposure results in long-term nociceptive effects, which needs to be consistently studied to clarify. Second, it results in enhanced depressive-like behaviour and diminished exploratory behaviour in adult rodents. Third, early-life selective serotonin reuptake inhibitor exposure alters serotonergic levels, transcription factors expression, and brain-derived neurotrophic factor levels, resulting in hyperconnectivity within the amygdala and the prefrontal cortex. Finally, it affects antinociceptive inputs of the prefrontal cortex and the amygdala in the spinal cord. We conclude that early-life selective serotonin reuptake inhibitor exposure affects the maturation of prefrontal cortex and amygdala circuits and thereby enhances their antinociceptive inputs in the spinal cord.