The role of stress in the comorbidity of migraine and other chronic primary pain

Abstract Background Chronic migraine is one of the most common causes of headache, belonging to the chronic primary pain (CPP) classification, along with fibromyalgia syndrome (FMS), temporomandibular disorders (TMD), and irritable bowel syndrome (IBS), based on the International Classification of Diseases‐11. The comorbidity between these pain disorders is commonly seen in the clinic. Stress directly and indirectly affects the pathophysiological mechanisms related to migraine and plays an important role in the co‐occurrence and development of migraine, FMS, TMD, and IBS. Methods We systematically searched PubMed and Web of Science databases, using combined keywords: stress, migraine, comorbidity, fibromyalgia syndrome, temporomandibular disorders, irritable bowel syndrome, pathological mechanisms, animal models, and treatment strategies, while emphasizing high impact studies. Literature was screened based on relevance, scientific rigor, and evidence level, prioritizing studies on stress‐related comorbidity mechanisms, models, or treatments. Exclusion criteria included single case reports, non‐full‐text conference abstracts, non‐English articles, low‐relevance studies, low‐quality methodologies, and general opinions (except authoritative consensus/guidelines). Results Clinical and preclinical studies support that potential stress‐related mechanisms underlie these comorbidities, including dysfunction of hypothalamic–pituitary–adrenal axis, dysregulation of autonomic nervous system, and central sensitization. We highlight the development and application of preclinical stress‐induced comorbid models as crucial tools for investigating these shared mechanisms. Stress targeted interventions have potential in managing these conditions, but mechanisms and efficacy stability remain to be clarified. Conclusion Stress may be a key driver of migraine and CPP comorbidities. Stress induced preclinical models support mechanism exploration, and stress‐targeted therapies hold promise for improving patient prognosis. Future research should deepen mechanistic studies and optimize models/therapies to enhance clinical care.