Author(s)

Sabrina Alexander¹, Milana Stein², David Matatov², Janae Rasmussen³, Hannah Weber⁴, Natasha Doshi⁵, Ali Osman⁶, Kelly Frasier⁷

¹Herbert Wertheim College of Medicine, Florida International University, Miami, USA.
²College of Osteopathic Medicine, New York Institute of Technology, New York, USA.
³Valley Consortium for Medical Education, Modesto, USA.
⁴Kentucky College of Osteopathic Medicine, Pikeville, USA.
⁵Lake Erie College of Osteopathic Medicine, Bradenton, USA.
⁶Heritage College of Osteopathic Medicine, Ohio University, Dublin, USA.
⁷Northwell, New Hyde Park, NY, USA.

Background: Cutaneous dysesthesia (CD) and complex regional pain syndrome (CRPS) commonly emerge as complications following orthopedic trauma or surgical procedures. Although these conditions are traditionally classified independently, increasing clinical evidence indicates substantial overlap in their underlying neuropathic, neuroimmune, and neuroplastic mechanisms, complicating their diagnosis and management. Objective: This narrative review aims to critically examine current evidence concerning shared pathophysiological mechanisms linking CRPS and CD, specifically focusing on small-fiber neuropathy, central sensitization, neuroimmune dysregulation, and maladaptive neuroplasticity, and to discuss the clinical implications of these overlaps in orthopedic care. Methods: A targeted literature search was conducted using PubMed, Medline, and Google Scholar databases, employing the following keywords: “complex regional pain syndrome”, “cutaneous dysesthesia”, “small-fiber neuropathy”, “central sensitization”, “neuroimmune dysfunction”, and “maladaptive neuroplasticity.” The review prioritized recent peer-reviewed original research, systematic reviews, and meta-analyses published within the past decade. Articles were critically assessed for methodological quality, clinical applicability, and relevance to orthopedic trauma and surgery-related pain syndromes. Key Findings: Analysis identified four central mechanisms consistently shared by CRPS and CD: 1) Small-fiber neuropathy defined by reductions in intraepidermal nerve fiber density and altered peripheral nociceptive signaling; 2) Central sensitization characterized by hyperexcitability of spinal and supraspinal neurons, resulting in amplified and often disproportionate pain responses; 3) Neuroimmune dysfunction involving persistent elevations of pro-inflammatory cytokines and circulating autoantibodies that sustain chronic inflammation and pain; and 4) Maladaptive neuroplasticity, notably cortical reorganization secondary to limb disuse or immobilization, perpetuating chronic sensory abnormalities and pain perception. Clinical Implications: The intersection of these pathophysiological processes contributes significantly to diagnostic ambiguity in distinguishing CD from CRPS, often delaying accurate recognition and appropriate management. Orthopedic clinicians and pain specialists should consider adopting a mechanistic diagnostic framework to differentiate these neuropathic syndromes from conventional post-surgical pain, thereby facilitating timely, targeted therapeutic interventions. Conclusion: Understanding the overlapping pathophysiological mechanisms between CD and CRPS underscores the importance of adopting multidisciplinary, integrative diagnostic and therapeutic strategies within orthopedic settings. Future research efforts should prioritize the development of precise biomarkers, the integration of advanced neuroimaging modalities, and targeted therapeutic approaches to address specific neuropathic, neuroimmune, and neuroplastic mechanisms. These advances hold significant potential to enhance patient outcomes, reduce chronic pain incidence, and optimize functional recovery following orthopedic trauma or surgical interventions.

Complex Regional Pain Syndrome, Cutaneous Dysesthesia, Post-Traumatic Neuropathy, Orthopedic Surgery, Central Sensitization, Neuroimmune Dysfunction

Alexander, S. , Stein, M. , Matatov, D. , Rasmussen, J. , Weber, H. , Doshi, N. , Osman, A. and Frasier, K. (2025) Overlapping Pathophysiology of Cutaneous Dysesthesia and Complex Regional Pain Syndrome. Journal of Biomedical Science and Engineering, 18, 183-201. doi: 10.4236/jbise.2025.186013.