Clinical and Molecular Barriers to Understanding the Pathogenesis, Diagnosis, and Treatment of Complex Regional Pain Syndrome (CRPS)

Complex regional pain syndrome (CRPS) is an idiopathic, highly debilitating chronic disorder with persistent regional pain accompanied by a combination of sensory, motor, and autonomic abnormalities. It is not only difficult to treat but also difficult to study. This scoping review aimed to identify the key clinical and molecular challenges encountered in CRPS research and to examine the assessment tools currently employed. A comprehensive search was conducted across PubMed/Medline, Science Direct, Scopus, Wiley Online Library, and Google Scholar using a combination of free text and MeSH terms related to CRPS, clinical and molecular aspects, neuroinflammation, biomarkers, and research challenges. We analyzed 55 original clinical research papers on CRPS and 17 studies of immunological/biochemical/molecular aspects of CRPS. A significant degree of heterogeneity was observed in the methodologies employed across the reviewed studies. The most frequently reported challenges included difficulties in participant recruitment and controlling confounding factors (reported in 62% of studies), such as the heterogeneity of the patient population, the influence of pain coping strategies and psychological factors, and the impact of sociocultural factors (reported in 62% of studies). Research into diagnostic and prognostic markers for CRPS also faces numerous challenges. Recruiting participants is difficult due to the rarity of the condition, resulting in small sample sizes for studies. In vitro models often fail to replicate the complexity of in vivo inflammation, limiting their applicability. Findings from early CRPS stages may not generalize to chronic CRPS because of differing pathophysiological mechanisms and symptom profiles. Additional obstacles include the disorder's heterogeneity, difficulties in controlling confounding factors, variability in treatment approaches, and the lack of standardized tools and baseline comparisons. These issues hinder the development of reliable biomarkers and evidence-based treatments. Due to these difficulties, the exact cause of CRPS is still not fully understood, making it difficult to develop effective, specific treatments and conduct targeted research.