Epigenetic and Endocrine Adaptations Linking Chronic Pain, Metabolic Dysregulation, and Cardiovascular Remodeling: A Narrative Review

Chronic pain is not confined to the areas of nociceptive input but activates systemic biological reactions characterized by inflammation, endocrine disequilibrium, and new epigenetic remodeling. The combination of these processes leads to cardiovascular dysfunction and metabolic dysregulation, but there is limited understanding of the integrative processes between them. The available evidence indicates that maladaptive changes in the vascular and metabolic systems are accompanied by sustained neuroendocrine and epigenetic reprogramming and require a one-stop synthesis of information. This narrative review will explain the role of epigenetic and endocrine mediators of the interaction between chronic pain, cardiovascular remodeling, and metabolic dysfunction, and shed light on important understanding of mechanisms and implications of translation. The literature search was performed in PubMed, Scopus, and Web of Science databases, with the keywords related to chronic pain, epigenetics, endocrine adaptation, cardiovascular remodeling, and metabolic health. Both animal and human studies in the English language were incorporated. Synthesis of evidence was done in a narrative fashion with a focus on mechanistic themes, although limited by the fact that heterogeneity of study designs was noted and the possibility of selection bias in narrative reviews was also indicated. Chronic pain has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal axis, which may contribute to sustained elevations in cortisol and catecholamines, insulin resistance, and endothelial dysfunction. Evidence from animal models and observational human studies suggests that epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, are involved in modulating inflammatory and vascular responses, potentially favoring maladaptive gene expression linked to myocardial hypertrophy, vascular constriction, and metabolic syndrome. Moreover, bidirectional interactions between hormonal signaling and epigenetic regulation are thought to exacerbate oxidative stress, inflammation, and metabolic dysregulation, forming a reinforcing loop that may help sustain elevated cardiometabolic risk. The modulation of chronic pain is associated with sustained endocrine and epigenetic restructuring, including chronic activation of the hypothalamic-pituitary-adrenal axis with altered cortisol and catecholamine signaling, alongside epigenetic modifications of stress- and vascular-related genes involved in inflammation, endothelial function, and metabolic regulation (e.g., <i>NR3C1</i> and endothelial nitric oxide synthase). These changes may contribute to cardiovascular remodeling and dysmetabolic states. Accordingly, pain management should be integrated with cardiometabolic risk assessment to provide holistic patient care. Future mechanistic and longitudinal studies should be prioritized to clarify causal pathways and to identify therapeutic targets capable of mitigating the systemic effects of chronic pain.