Chronic pain and stress: unravelling the common neuroinflammatory, immune and endocrine mechanisms for novel therapeutic approaches.

Chronic pain and stress often co-exist and are driven by overlapping neurobiological, immunological, and psychosocial mechanisms. In this review, we provide a mechanistic and translational overview of the common pathways underlying chronic pain-stress comorbidity. We summarize key mechanisms, including dysfunction of the sympatho-adrenomedullary system and HPA axis, neuroimmune crosstalk, neurotransmitter imbalances (e.g., monoamines, neuropeptides, and cytokines), maladaptive neuroplasticity within the stress-pain matrix, as well as peripheral immune activation and autoantibody-mediated sensitization. Together these processes contribute to a bidirectional, self-perpetuating cycle observed in conditions such as fibromyalgia, complex regional pain syndrome, low back pain, irritable bowel syndrome, and rheumatoid arthritis. Current therapeutic options remain insufficient, with many patients showing resistance to traditional treatments. We highlight the importance of a multidisciplinary biopsychosocial strategy integrating pharmacological interventions targeting shared neurotransmitter systems (antidepressants, anticonvulsants), with non-pharmacological modalities (cognitive behavioral therapy, mindfulness, physical activity, neuromodulation). Furthermore, emerging mechanism-based targets, including the endocannabinoid system, neurotrophic factors, and stress-related hormonal pathways, are discussed as promising novel therapeutic approaches. In conclusion, chronic pain and stress should be conceptualized as interconnected neuroinflammatory disorders driven by common neuroimmune and neuroendocrine dysregulation. A mechanism-oriented, integrative framework may support the development of more effective, individualized therapeutic strategies to improve patient outcomes.