Long-term Effects of Early Exposure to Stress, Pain, Opioids and Anaesthetics on Pain Sensitivity and Neurocognition

Abstract

Background Experimental studies have shown that neonatal exposure to stress, pain, opioids and anaesthetics may cause histologic and morphologic changes in the central nervous system with associated functional and behavioural changes in the long term. An important question is whether this holds true for humans also - and in particular for sick neonates who often are exposed to pain and receive anaesthetics and sedatives. Methods In this narrative review, we evaluate the effects of neonatal exposure to stress, pain, opioids and anaesthetics in infancy and childhood in animals and in preterm born and term born humans on pain sensitivity, brain morphology, cognition and behaviour later in life. Results In animals, neonatal exposure to stress, pain, opioids and early exposure to anaesthetics are associated with neurodegeneration and cognitive problems later in life. Human studies mainly focus on pain sensitivity, cognition and behaviour and find contradictory outcomes. Dramatic long-term effects found in animal studies could not be confirmed in human. Conclusion While studies in animals suggest neurotoxic effects of early exposure to stress, pain, opioids and anaesthetics, these effects seem clinically less relevant in humans. A possible reason is that the latter often receive opioids in the presence of pain and opioids and anaesthetics in balanced therapeutic dosages and with adequate monitoring of physiological parameters, in contrast to animal studies.

Analgesics and Sedatives in Critically Ill Newborns and Infants: The Impact on Long‐Term Neurodevelopment

“…Although animal studies have fairly consistently demonstrated brain development to be negatively affected by various classes of drugs, such as anesthetics, benzodiazepines, and to some extent opioids, associations in survivors of neonatal critical illness seem less obvious . This may be due to differences between animal and human studies, resulting in more contradicting conclusions in humans (for a review on this matter, please refer to van den Bosch et al …”

“…This mechanism may be underlying the negative effects of midazolam found on the hippocampus in preterm infants and may subsequently lead to memory deficits later in life in these children. (Please also refer to a recent review on other proposed mechanisms underlying the effects of analgosedatives and anesthetics on the brain by van den Bosch et al …”

“…Ranger et al showed that pain‐related stress predicted cortical thickness at 7 years in preterm‐born children, independent of morphine exposure. Also, a higher number of painful (skin‐breaking) procedures in preterm‐born children was found to be associated with reduced white and subcortical gray matter . In addition to pain, studying the association between analgosedatives and neurodevelopmental outcome is likely to be affected by differences in dosages.…”

“…Alterations are in part drug and dose dependent, and there is an age‐related window of vulnerability for apoptosis or dendritic changes . Moreover, the balance between pain and exposure to analgosedatives may also play an important role . Specifically, the limbic system undergoes rapid development in the third trimester and neonatal period .…”

“…As the majority of infants admitted to neonatal or pediatric intensive care units now survive to discharge, this is of major concern. Although there may be long‐term effects of anesthetic agents on the brain as well, this has been extensively described and reviewed in the past few years due to a recent Food and Drug Administration warning about its use in children younger than 3 years, and is therefore beyond the scope of the current review …”