An integrated systemic approach to chronic primary pain from epigenome to brain: a narrative review

Chronic pain is the most prevalent disease worldwide, leading to substantial disability and enormous societal costs. Breakthrough science led to the recognition by the WHO of chronic pain as a disease. Despite growing evidence, the scientific knowledge and efforts are scattered across a variety of disciplines, making it challenging for scientists and clinicians to have a holistic understanding of chronic pain. Recent discoveries support the close interaction between the multiple physiological dysfunctions involved. Chronic primary pain entails epigenetic modifications in inflammation-related genes, genes encoding for neurotrophic factors, neurotransmitters, ion channels and catecholamine-degrading enzymes that potentially explain neuroinflammation, features of sensory hypersensitivity, and stress intolerance, respectively. Chronic primary pain is characterised by structural and functional central nervous system changes that relate to sensory hypersensitivity, stress intolerance and sleep disturbance. Chronic primary pain is also characterised by neuroinflammation, which relates to altered functional connectivity, depressed feelings, and increased pain (sensitivity). We propose that understanding chronic pain requires an integrated systemic approach, connecting the available evidence from diverse scientific fields to create a more holistic understanding of chronic primary pain. We present an integrated systemic approach to chronic primary pain that was developed from a high-level view to focus on 1) the interplay between the relevant physiological dysfunctions (i.e. structural and functional brain changes, neuroinflammation, immune alterations, genetic and epigenetic changes) involved in chronic primary pain; 2) the links between these physiological dysfunctions and clinical features (i.e. sensory changes, psychological problems, neurocognitive disorders, stress intolerance, and sleep impairments) of chronic primary pain; and 3) human studies. The integrated framework of chronic primary pain aims to bridge the gap between areas of cutting-edge science of various fields. The integrated systemic approach to chronic primary pain allows clinicians and researchers to gain a more comprehensive understanding of chronic primary pain that can be used for therapeutic considerations and future research studies.