When we talk about central sensitization, we usually think of a phenomenon with a pathological framework. However, we often forget that central pain sensitization is a normal adaptive mechanism that allows the protection of an injured area. When we get hurt, the body’s first response is generally a stereotypical and lively one, which has the task of alarming the system. Under normal conditions this process is absolutely reversible: when the peripheral stimulus ceases, both the nociceptor and the central neuron return to normal activity.
However, it may happen that when peripheral inflammation stops, the central neuron does not return to its initial state. In this case, then, the central sensitization is configured as a paraphysiological phenomenon, supported by neuroplastic changes.
What is central sensitization?
Central sensitization is configured as an increase in the reactivity of nociceptive neurons of the central nervous system to their normal or sub-threshold afferent input (1). This increased reactivity of second order neurons is an adaptive response that has the task of protecting us from actual or potential damage. However, if intense, lasting and repeated nociceptive stimuli are present, the central neuron may remain sensitized even after the stimulus that triggered it has ceased. The sensitization of the fibers is responsible for a series of manifestations such as secondary hyperalgesia (increased response to painful stimuli outside the area of injury or inflammation), allodynia (increased response to normally painless stimuli even outside the area of injury or inflammation ), enlargement of the receptor field of the neuron (2).
All this translates into a fairly typical clinical picture, characterized by:
- pain that is often discontinuous, unpredictable and inconsistent between stimulus and response;
- pain with variable anatomic distribution;
- Irritability and hyperalgesia
- hypersensitivity to light, sounds, touch;
- pain that does not respond to NSAIDs;
- very low reliability of clinical examinations (3) (4).
To understand if we are facing a central sensitization picture, first of all we must exclude hypothetical neuropathic pain. Once this option is excluded, we can rely on an algorithm based on three fundamental criteria (5): the first criterion has to do with the non-proportionality between pain and the nature and extent of the injury and is a mandatory criterion for the classification of pain to be central awareness raising.
The second criterion concerns the inconsistent pain distribution. In particular, we can find widespread and poorly localized pain, non-segmental distribution of pain, pain that often changes anatomical location, bilateral pain or mirror pain and hyperalgesia or allodynia outside the primary nociception areas. If both of these criteria are present, a central awareness framework can be confirmed.
If the situation is unclear, the third criterion is investigated, using Part A of the Central Sensitization Inventory (CSI) (6). Here the presence of central nervous system hypersensitivity to other stimuli such as smells, light, sounds, touch, sensation of heat and cold is investigated. A CSI score ≥ 40 strongly indicates the presence of central nervous system sensitization. In addition to these criteria, central sensitization is strongly linked to other signs and symptoms such as numbness, muscle weakness, attention deficit and sleep disturbance. In the medical history, patients often report a history of therapeutic failures, intolerability to certain types of treatment or lack of benefit of the same. Finally, there is a strong association with maladaptive psychosocial factors, such as negative emotions, low level of self-efficacy, erroneous beliefs, avoidance behaviors, fear of movement, catastrophization, stress. The use of the Central Sensitization Inventory helps us to understand how emotional factors intervene in reinforcing the mechanisms of central sensitization.
The advantage of having these classification criteria lies in the ability to be able to implement appropriate therapeutic strategies for the type of pain presented by the patient. The treatment goals for central sensitization pain will be very different from those for nociceptive pain! It is not easy to make the patient understand that the problem no longer resides at the tissue level, but concerns the way in which the pain experience is processed (7). Phenotypically, central sensitization syndrome can take many forms, including fibromyalgia, irritable bowel syndrome, tension headache, temporomandibular disorders, restless legs syndrome, chronic fatigue syndrome, interstitial cystitis, rheumatoid arthritis, osteoarthritis, complex regional pain syndrome (CRPS) (8). Susceptibility to developing central nervous system hypersensitivity is also partly linked to an inherited genetic component (9) (10).
The neurophysiological mechanisms underlying central sensitization
At the basis of central sensitization there are neurophysiological changes supported by neuroplastic modifications of neuronal excitability (11). When a nerve receives information it begins to adapt: its activation threshold is reduced and the number of receptors increases to improve the nerve’s ability to receive information. From a molecular point of view, the number of sodium channels in the synaptic increases and with them the ease with which they are willing to open. As the nerve becomes more responsive, it happens that a single stimulus can activate multiple receptors with lower activation thresholds. These mechanisms are supported by the wind-up phenomenon, where constant and repeated stimuli over time increase the responsiveness of the C fibers (12), and by the Long Term Potentiation (LTP), where the increased responsiveness remains even after the stimulus has ceased ( 13). The result is a hyperresponsiveness of the peripheral neuron, as an adaptive response with the intent of protecting us from damage or injury. All this is absolutely physiological. With the same incoming stimuli, if the peripheral neuron is sensitized, it will send an increased message to the spinal neuron. These fibers, High threshold (HT), Low-threshold (LH), Wide-dynamic-range (WDR), receive more information and also begin to adapt. The phenomenon of sensitization begins to receive pathological connotations when the second order neuron remains sensitized when the stimulus coming from the first order neuron ceases. The plastic mechanisms in this case are no longer activity-dependent but become activity-independent, as if the spinal neuron were self-maintaining (11). In this case, the functional change is still reversible.
The state of sensitization is maintained and enhanced by the release of pro-inflammatory cytokines from the glial cells which, when hyperactivated, cause a real neuro-inflammation (14). In addition to cytokines, it also increases the release of another neurotransmitter, glutamate. Glutamate, produced in maintained stress situations, increases the excitatory effect on the central nervous system, with a toxic effect on inhibitory descending neurons (15). An excess of glutamate in fact causes its death and as a consequence there is an enlargement of the receptor field of the spinal neuron, with possible referred pain (16). At this point, real structural changes begin to take place in the hippocampus and in the pre-frontal cortex. The decrease in gray matter in these areas is associated with a contralateral increase in the gray matter of the amygdala, responsible for the emotional coloring of pain (17). Negative emotions, anxiety, fear, catastrophization and anticipation of the consequences will only keep all these dysfunctional cortical changes active (18). Thus there is a real alteration of the inhibitory descending modulation.
Central and peripheral sensitization
We therefore know that the second order neuron can remain sensitized when it receives intense, lasting and repeated stimuli. But what happens to the first order neuron?
The set of changes that occur in first-order neurons is called peripheral sensitization. Following damage or injury, an inflammatory process is activated with the release of chemical mediators such as serotonin, bradykinins, prostaglandins and cytokines. These mediators activate and sensitize afferent fibers, creating an increase in activity and a reduction in the activation threshold of nociceptors. This triggers the phenomenon of primary hyperalgesia, i.e. an increase in the response to nociceptive stimuli, necessary for the protection of the lesion during the healing process (19). Peripheral sensitization, being due to the stimulation of algogenic substances, is a transitory and protective sensitization. The two types of sensitization differ in their basic neurophysiological mechanisms and in the type of clinical manifestation (20).
Central Sensitization and Nociplastic Pain: What’s the Difference?
By definition of the IASP, nociplastic pain is given by an alteration of nociception, in the absence of a clear sign of actual or potential tissue damage that causes the activation of peripheral nociceptors or in the absence of an injury to the somatosensory system (21). It is due to the plasticity of the nociceptor and nocineuron which have become hypersensitive. This new definition justifies the presence of pain which is not specifically nociceptive or neuropathic, but which can be considered a middle ground between the two (22). However, it refers only to those patients in whom an alteration of nociception can be demonstrated and cannot be applied to patients who have pain without hypersensitivity (23). In addition, the exact criteria for establishing an altered nociception have not yet been defined by the IASP (24). The debate on the term “nociplastic” is still heated and some authors have proposed changing the term to “centralized pain” (25). However, this definition cannot be considered correct as it implies an anatomical description compared to the other two definitions (nociceptive and neuropathic) which describe pain from a physiological point of view. Furthermore, it implies that all forms of nociplastic pain are of central origin, but this has yet to be proven (26).
The term “nociplastic pain” is therefore useful in the clinic, but cannot be used as a diagnosis or as a synonym for central sensitization (27).
Central sensitization is a pain processing mechanism in which there is an increase in the responsiveness of spinal neurons, accompanied by a decrease in inhibitory descending modulation. Clinically it is responsible for phenomena such as secondary hyperalgesia, allodynia and enlargement of the receptor field. Unlike peripheral sensitization, it does not depend on an alteration of nociception but rather on a change in the properties of the CNS neurons. The protracted sensitization of 2nd order neurons beyond tissue healing causes structural and functional changes in the cortical matrix, responsible for the development and maintenance of chronic pain (28) (29).
Translated from “Sensibilizzazione Centrale: una panoramica centrale” written by Nicole Schenato, PT, BSc, OMPT
- IASP Terminology “Part III: Pain Terms, A Current List with Definitions and Notes on Usage” (pp 209-214) Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy, edited by H. Merskey and N. Bogduk, IASP Press, Seattle, 1994
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- Nijs J, Torres-cueco R, Van wilgen CP, et al. Applying modern pain neuroscience in clinical practice: criteria for the classification of central sensitization pain. Pain Physician. 2014;17(5):447-57.
- Smart KM, Blake C, Staines A, Doody C. The Discriminative validity of “nociceptive,” “peripheral neuropathic,” and “central sensitization” as mechanisms-based classifications of musculoskeletal pain. Clin J Pain. 2011;27(8):655-63.
- Nijs J, Goubert D, Ickmans K. Recognition and Treatment of Central Sensitization in Chronic Pain Patients: Not Limited to Specialized Care. J Orthop Sports Phys Ther. 2016;46(12):1024-1028.
- Chiarotto A, Viti C, Sulli A, Cutolo M, Testa M, Piscitelli D. Cross-cultural adaptation and validity of the Italian version of the Central Sensitization Inventory. Musculoskelet Sci Pract. 2018;37:20-28.
- Woolf CJ. What is this thing called pain?. J Clin Invest. 2010;120(11):3742-4.
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