Central and peripheral sensitization
IASP Definitions & Taxonomy
The foundation of any pain chapter must align with the International Association for the Study of Pain (IASP) taxonomy.
- Peripheral Sensitization: “Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields” (Curatolo, 2024). It is clinically associated with primary hyperalgesia at the site of injury.
Peripheral sensitization is driven by inflammation and sodium channel activation; it is treated with NSAIDs and local anaesthetics.
- Central Sensitization: “An increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input” (Curatolo, 2024). It requires changes in function within central neurons only. Clinically, it manifests as secondary hyperalgesia (extending beyond the injury site) and allodynia (pain from non-noxious stimuli).
Central sensitization is driven by calcium influx and NMDA receptor activation in the dorsal horn,it is treated with gabapentinoids and ketamine (Woolf, 2011).
- Nociplastic Pain (Newest Addition, 2017): Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors, nor evidence of somatosensory disease/lesion. Central sensitization is a key mechanism driving nociplastic pain.
Pathophysiology: Peripheral vs. Central Sensitization
Peripheral Sensitization (The “Inflammatory Soup”)
Occurs at the primary afferent terminals (A-delta and C fibers) due to tissue damage or inflammation.
- Mechanism: Release of inflammatory mediators (prostaglandins, bradykinin, substance P, histamine, serotonin, Nerve Growth Factor [NGF]).
- Cellular Level: These mediators bind to G-protein coupled receptors on nociceptor terminals, phosphorylating transient receptor potential (TRP) channels (e.g., TRPV1) and sodium channels (Nav1.7, Nav1.8).
- Result: A lowered threshold for activation (spontaneous firing) and an exaggerated response to noxious stimuli (McGreevy et al., 2011; Puja et al., 2021).
Central Sensitization (The “Wind-Up” Phenomenon)
Occurs at the dorsal horn of the spinal cord (specifically second-order Wide Dynamic Range [WDR] neurons) and higher cortical structures.
- Mechanism: Sustained release of excitatory neurotransmitters (Glutamate, Substance P, BDNF) from C-fibers into the synaptic cleft of the dorsal horn.
- Cellular Level:
- NMDA Receptor Activation: Massive glutamate release removes the plug from NMDA receptors, allowing massive calcium influx.
- Intracellular cascades: Activation of protein kinases (PKA, PKC) and increased intracellular .
- Glial Cell Activation: Microglia and astrocytes release pro-inflammatory cytokines, maintaining the hyperexcitable state.
- Result: Temporal summation (wind-up), mechanical allodynia, and a receptive field expansion that leads to secondary hyperalgesia (Curatolo, 2024).
The transition from acute to chronic pain begins at the site of tissue injury, where the release of inflammatory mediators (such as bradykinin and prostaglandins) lowers the activation threshold of peripheral nociceptors, resulting in primary hyperalgesia. If this peripheral input is severe or sustained, it triggers an overwhelming release of glutamate and substance P in the dorsal horn of the spinal cord.
This massive neurotransmitter release activates NMDA receptors—a phenomenon foundational to the concept of central sensitization (Woolf, 2011).
Consequently, the central nervous system becomes hyperexcitable, amplifying sensory input so that normal, non-noxious stimuli are perceived as painful (allodynia) and the receptive field expands to create secondary hyperalgesia (Curatolo, 2024).
In the critical care setting, preventing this neuroplastic transition relies on early, multimodal analgesic interventions .
References
- ANZCA (Australian and New Zealand College of Anaesthetists). Acute Pain Management: Scientific Evidence (5th Edition, 2020).
- IASP (International Association for the Study of Pain). Global Year Against Pain Guidelines/Fact Sheets. (Specifically noting the 2017 taxonomy update defining nociplastic pain).
- PROSPECT (Procedure-Specific Postoperative Pain Management) Guidelines. (Crucial for procedure-specific multimodal analgesia protocols).
- Curatolo, M. (2024). Central Sensitization and Pain: Pathophysiologic and Clinical Insights. Current Neuropharmacology, 22, 15–22. https://doi.org/10.2174/1570159×20666221012112725
- Woolf, C. J. (2011). Central sensitization: Implications for the diagnosis and treatment of pain. Pain, 152, S2-S15. https://doi.org/10.1016/j.pain.2010.09.030