Current Evidence for Biological Biomarkers and Mechanisms Underlying Acute to Chronic Pain Transition across the Pediatric Age Spectrum

Abstract

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted.

Keywords: EEG; QST; biomarkers; central sensitization; chronic pain; chronification of pain; developmental; genetics and epigenetics of pain; mechanisms; molecular markers; neuroimaging of pain; neurophysiological markers; pediatric pain; peripheral sensitization.

Figure 1

Peripheral and central mechanisms associated with chronification of pain with relevance to the pediatric population (based on animal studies). The main adult mechanisms are mentioned in bold black color denoted by letters, with pediatric-specific features that contribute to pain chronification overlaid in blue-colored text. Figure depicts (1) tissue injury as an acute injury, which then (2) recruits mast cells, macrophages, neutrophils, and eosinophils to the area. Both these cells and tissue injury all contribute to release of the inflammatory soup (proinflammatory cytokines, prostaglandins, histamine, nitric oxide, serotonin, and NGF), which increases NGF. (3) NGF binds to TrkA at peripheral ends of the sensory nerve fibers (C-fiber and A-δ fibers), leading to upregulation and stimulation of Na⁺ channels and causes peripheral sensitization (A). When NGF binds to TrkA on afferent inputs inside the dorsal root ganglion of the spinal cord, it prolongs their stimulation and increases glutamate release onto NMDA and AMPA receptors, resulting in central sensitization at the level of the spinal cord dorsal root ganglion (B), while neuroinflammation due to increased microglia and astrocyte responses leads to central sensitization (B). This is also facilitated by weaker GABA signaling and increased spontaneous firing. Chronic/recurrent stimulation and activation of PAG results in release of BDNF into the RVM, and BDNF-TrkB signaling leads to pain facilitation (C). Decreases in GABA, glycine, serotonergic, and opioid responses, leading to decreased inhibitory sympathetic output, contributing to pain sensitization, also known as decreased descending inhibition (D). Lastly, maladaptive neuroplasticity (E) takes place, contributing to central sensitization of pain. Pediatric developmental context from available studies is shown in blue: For example, increased growth factor release by tissue injury in neonatal rats [33], nerve injury in neonatal rats produces more anti-inflammatory responses and descending inhibition is not developed [34,35,36], earlier synaptic pruning, altered pain connectivity and myelination [32]. Abbreviations: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), brain-derived neurotrophic factor (BDNF), calcitonin gene-related peptide (CGRP), dorsal root ganglion (DRG), electroencephalography (EEG), functional magnetic resonance imaging (fMRI), γ-aminobutyric acid (GABA), magnetoencephalography (MEG), nerve growth factor (NGF), N-methyl-D-aspartic acid (NMDA), norepinephrine (NE), periaqueductal gray (PAG), prefrontal cortex (PFC), quantitative sensory testing (QST), rostral ventromedial medulla (RVM), tropomyosin-related kinase A (TrkA). Created with BioRender.com.

Figure 2

Genetic and epigenetic evidence of acute to chronic pain transition in the pediatric population. Summary of the genetic and epigenetic evidence found for acute to chronic pain transition in the human pediatric population. (a) Evidence from infant studies [108,109,110], and (b) from child/adolescent studies [4,5,111,112,113]. Abbreviations: Ataxin 1 (ATXN1); brain-derived neurotrophic factor (BDNF); chronic postsurgical pain (CPSP); calcium voltage-gated channel auxiliary subunit gamma 2 (CACNG2); catechol-O-methyltransferase (COMT); 5′-cytosine-phosphate-guanine (CpG); dopamine receptor D2 (DRD2); major histocompatibility complex, class II, DR beta 3 (HLA-DRB3); methylation quantitative trait loci (meQTL); nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1); opioid receptor mu 1 (OPRM1); peptidase M20 domain-containing 1 (PM20D1); polygenic risk score (PRS); potassium inwardly rectifying channel subfamily J member 3 (KCNJ3); potassium inwardly rectifying channel subfamily J member 6 (KCNJ6); potassium two pore domain channel subfamily K member 3 (KCNK3); protein kinase C alpha (PRKCA); RAB7, member RAS oncogene family (RAB7); RAB7, member RAS oncogene family-like 1 (RAB7L1); solute carrier family 6 member 1 (SLC6A); solute carrier family 41 member 1 (SCL41A1); solute carrier family 45 member 3 (SLC45A3). Figure created with BioRender, modified from a template by Ruslan Medzhitov (Creator), Akiko Iwasaki, and Wendy Jiang (See the Supplementary File for details on the search strategy).