Journal Year in Review

Medical Literature Review
Submitted by Charlotte Walter, MD, and Vidya Chidambaran, MD, MS

Pain in the neonatal period has long been an intriguing topic, with questions regarding neonatal pain modulation and the influence of painful procedures on the overall development of  newborn and premature babies. We reviewed three recent studies that address this interesting topic.

Hartley C, Moultrie F, Gursul D, Hoskin A, Adams E, Rogers R, Slater R.

Changing balance of spinal cord excitability and nociceptive brain activity in early human development

Cur Biol 2016 Aug; 26(15): 1998-2002.

In this study, investigators examined the relationship in infants between nociceptive brain activity (using EEG) and spinal reflex withdrawal activity (using EMG) in response to a clinically required noxious procedure (heel stick) in 40 patients aged 28–42 weeks’ gestation. Exclusion criteria were documented neurological malformations, genetic disorders, history of meningitis, culture positive sepsis or maternal substance abuse.  All infants were hemodynamically stable and had not required any analgesics or sedatives in the preceding seven days.  A heel lance was used as the pain stimulus.  EEG and EMG were recorded during the heel lance. They found that with increasing gestational age, there was an increase in the magnitude of the nociceptive specific brain activity and a decrease in the duration, magnitude and latency in the limb reflex response.  While this study was limited by a small sample size, a non-standardized pain stimulus in the heel lance, and no control for history of multiple sticks, hunger, or exposure to narcotics, it does show that in human neonates, that maturation of cortical networks contributes to the emergence of top-down inhibitory modulation of spinal nociceptive circuitry.

Lee JH, Espinera AR, Chen D, Choi K-E, Caslin AY, Won S, Pecoraro V, Xu G-Y, Wei L, Yu SP.

Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats

J Neuroinflammation. 2016; 13: 109.

In a study published in The Journal of Neuroinflammation,  investigators questioned whether repeated inflammatory pain experienced by preterm infants could lead to acute and delayed brain damage, that may be associated with social and behavioral abnormalities at the juvenile age. They studied this in male and female rat pups, that received subcutaneous injections of 5% formalin or saline solution, to each hind paw on postnatal day 3 (P3), P4 and P5.

One group received indomethacin IP along with formalin. They were either sacrificed 24 hours later to study immunohistochemistry in brain cells for acute inflammatory changes, or at postnatal day 21 for subacute and chronic consequences. TUNEL staining, reactive microglia cell count, axon measurement, blood and brain quantification of cytokines and western blot for gene expression of inflammatory and autism spectrum disorder (ASD) related genes were performed.  Sociobehavioral tests were also performed to assess behavioral changes, pain sensitivity, general sociability, and sensory memory function. Formalin group rats were found to have increased inflammatory cytokines in the blood and brain that persisted beyond local tissue damage; microglia increases in the cortex, and hippocampal cell death. Inflammatory pain in neonatal rat pup impaired axonal integrity/myelination and altered long term expression of ASD-related genes in the cortex of the juvenile brain. Rats in the formalin group also had behavioral deficits, and impaired social activity. 

Interestingly, in the group that received indomethacin along with the formalin injection, indomethacin effectively prevented all these alterations. The significant cellular, molecular and behavioral alterations in the inflammatory pain model of neonatal rats are consistent with pathophysiological, genetic and psychological changes in ASD, suggesting that repeated inflammatory pain suffered by premature neonates may be an important risk factor in the development of ASD-like syndromes. Short follow-up is a limitation of this study, which is addressed by the third study we present.

Carmo EC, Sanada LS, Machado NLB, Fazan VPS.

Does pain in the neonatal period influence motor and sensory fucntions in a similar way for males and females during post-natal development in rats?

Pain Medicine. 2016; 17: 1520-1529.

Investigators in this study addressed the long term effects of repeated painful stimuli in the neonatal period on the development of the sensory and motor systems and differences in responses by sex.  Thirty two male and 32 female Wistar rat pups were followed from birth to 180 days.  The Control group was subjected to tactile stimulation with a cotton swab of the right hind paw, while the pain group were submitted to painful insertion of a 30-gauge needle to the right hind paw, twice a day from birth to 15 days of life. Motor function was tested with grip strength, and sensory testing was performed for mechanical allodynia and hyperalgesia.  Grip strength ratio to body weight ratio was decreased in the pain group compared to the controls, in both sexes.  Mechanical allodynia and significant reduction in the pain threshold was seen with the pain group rats on the stimulated paw long after the stimulus ceased, demonstrating significant mechanical hyperalgesia.  This study had limitations in that no pain medications were on board (unlike clinical situations). Thus, this study demonstrates that pain in the neonatal period influences sensory and motor functions negatively during development of both male and female rats, even after the painful stimulus is ceased. 

These three studies offer new insights into the functional development of neural pathways that underlie development of human pain behavior and neonatal pain, and the long term negative neurodevelopmental effects of pain experienced in the neonatal period. Collectively, they suggest that in the absence of top down inhibitory pathways, painful stimuli are more detrimental to the developing neonatal nervous system. Therefore, special attention is needed for the analgesia and prevention of pain in neonates. Further studies are needed to understand how regional brain development modulates pain-related behavior in human infants, if these long-term consequences are indeed pertinent to humans, and if so, how they can be prevented.

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