Visceral Pain in Preterm Infants with Necrotizing Enterocolitis: Underlying Mechanisms and Implications for Treatment

Abstract

Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC-visceral pain-could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well.

Fig. 1

Simplified diagram of the transduction and transmission of noxious stimuli in patients with NEC. Chemical agents released during ischemia, inflammation, and necrosis can activate ion channels on the nociceptor terminal, thereby exciting or sensitizing the nociceptor (primary nociceptive afferent) [24]. The primary afferents can be grouped into vagal afferents and spinal afferents. Vagal afferents terminate in the nucleus of the solitary tract, from where secondary neurons convey the information to various brain(stem) structures. Spinal afferents travel via the dorsal column pathway and the anterolateral tract [86]. The dorsal column pathway contains branches from primary afferents as well as secondary neurons in the dorsal horn (postsynaptic dorsal column neurons; not included in this figure)

Fig. 2

Simplified diagram of the descending modulation of visceral pain. The PAG receives input from various structures, including the amygdala, hypothalamus, nucleus of the solitary tract (NTS), and nociceptive pathways. For clarity, input from nociceptive afferents has been omitted from this figure. The PAG exerts its descending influences on nociceptive processing mainly via projections to the RVM, which in turn sends output to the dorsal horn. Additional sources of descending control (not shown in this figure) include the pontine noradrenergic cells groups, dorsal reticular nucleus, and ventrolateral medulla. For clarity, direct projections from the cortex, hypothalamus, and NTS to the dorsal horn and from the NTS to the hypothalamus have been omitted [125]

Fig. 3

Simplified diagram showing central processing of noxious visceral stimuli. This is largely similar to somatic pain, although there are some differences in the level of activation in the different brain regions. Afferents traveling via the dorsal column pathway project to secondary afferents in the nucleus gracilis, which project to the thalamus posterior. Secondary afferents in the spinothalamic tract either project directly to the medial or posterior thalamus or terminate onto tertiary neurons in the dorsal reticular nucleus that project to the medial thalamus [298]. Thalamocortical fibers from the posterior cortex project to the primary (SI) and secondary somatosensory cortex (SII). Thalamocortical fibers from the medial cortex project to the insula and cingulate cortex (anterior cingulate cortex [ACC]; midcingulate cortex [MCC]). Projections from the nucleus of the solitary tract, which receives vagal input, have been omitted from this figure

Fig. 4

Targets for analgesic and sedative therapy in infants with NEC. Only agents discussed in this review have been included in this figure. Non-steroidal anti-inflammatory drugs (NSAIDs), also antagonizing the COX system, are relatively contraindicated as analgesics because of adverse effects in preterm infants