The Four-Route Central Sensitization Framework: Clinical Framework (Version 2.1)

Central sensitization (CS) is widely recognized as a key mechanism underlying chronic pain and related nociplastic conditions, including fibromyalgia. Despite decades of research, a coherent mechanistic framework remains absent: neuroimmune activation, glutamate-GABA imbalance, stress-HPA-axis dysregulation, and persistent peripheral nociceptive input have each been proposed as primary drivers, yet no unifying architecture has emerged. This paper proposes a multidimensional mechanistic framework in which central sensitization is understood as a convergent regulatory state, defined by a persistent shift toward excitatory dominance within central sensory networks. Within this framework, four distinct biological routes deliver sustained excitatory input to the central nervous system, where shared feedback mechanisms stabilize and maintain the sensitized state. By reframing previously competing explanations as complementary pathways converging on a shared end-state, the model resolves longstanding inconsistencies in the literature and provides a structural explanation for clinical heterogeneity and variable treatment response. Each route is associated with recognizable phenotypic patterns, differential pharmacological responsiveness, and distinct empirical predictions. The framework introduces Regulatory State Profiling (RSP) as a multidimensional approach to identifying dominant biological pathways and early-stage dysregulation prior to full central sensitization. This enables a transition from syndrome-based classification toward mechanism-based stratification and targeted intervention. This version represents the clinically oriented formulation of the framework (Version 2.x), focused on phenotyping, diagnosis, and treatment stratification. It is conceptually complementary to the system-theoretical formulation presented separately (Version 3.0), which addresses underlying regulatory dynamics and formal modeling. The model is explicitly testable and falsifiable, generating pathway-specific and cross-route predictions that can be evaluated through stratified clinical studies and multimodal biomarker assessment. This work is intended as a conceptual foundation for future empirical validation, mechanism-based trial design, and the development of precision approaches to nociplastic pain and related multisystem conditions.