A hierarchical framework for nociplastic pain mechanisms

Nociplastic pain refers to pain arising from altered nociceptive processing in the absence of tissue damage or somatosensory system lesion sufficient to explain the symptoms. Despite the high prevalence and clinical burden of conditions characterized by nociplastic pain, current treatment strategies remain only partially effective, partly because the mechanisms sustaining nociplastic pain are heterogeneous and incompletely defined. Central sensitization remains an important neurophysiological construct, particularly when used to describe activity-dependent amplification of nociceptive processing, but it should not be treated as a complete explanation for pain persistence and heterogeneity. Here, we propose a hierarchical framework in which nociplastic pain mechanisms are conceptualized as interacting processes spanning spinal gain amplification, brainstem descending modulation, thalamocortical sensory gating, intrinsic network integration, corticolimbic affective-motivational processing, and perceptual inference. Neuroimmune signaling is considered a putative cross-level modulator of excitability and plasticity. The framework also illustrates how non-selective pharmacological perturbations could be used to test selected model components in prospective biomarker-defined studies. The framework generates falsifiable predictions linking pre-treatment sensory, neurophysiological, neuroimaging, molecular, affective, and behavioral profiles to treatment response and functional recovery. Overall, this review proposes a mechanism-informed structure for patient stratification and for the future design of multimodal interventions targeting specific contributors to nociplastic pain rather than relying on diagnostic labels or single-mechanism explanations alone.