
Updates & Features
Central Sensitisation: From Physical Examination To Clinical Significance
July 2019
Dr Emilio Quetglas, The PainSolve Team
One of the mechanisms used to describe the genesis of chronic pain is peripheral sensitisation. This constitutes a decreased threshold and increased responsiveness of nociceptors due to post-translational changes in, and altered trafficking of, transducer receptors and ion channels. Clinincal characteristics of peripheral clinical pain are pain after the end of a stimulus and a spread of sensitivity to normal tissue induced by local inflammatory mediators. This is referred to as the zone of primary hyperalgesia.1
In contrast, in chronic neuropathic pain the mechanically sensitive skin area often extends beyond the area of the initially involved root or nerve to create a zone of secondary hyperalgesia. This area is unaffected by the primary nerve lesion, which often becomes independent of the initial noxious event.
Frequently, there is a disparity between the pain intensity and the severity of the lesion that causes the pain. One reason is likely the various sensitisation processes that occur and, particularly, the amplification of central excitatory signaling. This concept is described by the IASP as an “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input”.2 Activity-dependent mechanisms of central sensitisation (CS) include homosynaptic long-term potentiation (i.e. exaggeration of nociceptor responsiveness) and heterosynaptic potentiation (i.e. recruiting low threshold A[β] fibre inputs into the pain pathway). These mechanisms might be driven and sustained by ectopic activity in the injured nerve.3 In addition to the strengthening excitatory synapses in the spinal cord, reduced inhibition by decreasing gamma aminobutiryic acid (GABA)-ergic and glycinergic tone also contributes to central hyperexcitability and can be caused by peripheral nerve lesions. An increased responsiveness to thermal and mechanical stimuli at the site of injury is mediated through unmyelinated C-fibre primary afferent neurons. At the same time, low threshold A(β) afferents, which normally do not serve to transmit a pain response, become recruited to transmit spontaneous and movement-induced pain.4 This central hyperexcitability is characterised by a “windup” response of repetitive C-fibre stimulation, expanding receptive field areas and spinal neurons taking on properties of wide dynamic-range neurons.5
Segmental and extrasegmental sensitisation are expressed by punctuate/pressure secondary hyperalgesia (thermal sensitivity in some cases) in the clinical setting. Heterosynaptic potentiation and temporal summation are the mechanisms underlying dynamic tactile allodynia. Temporal summation: when a painful stimulus that is repeated 1–3 times per second for 5 to 10 seonds, the pain integrates and becomes more painful at the end of the stimulus train.6 However, an alternative hypothesis is that allodynia is caused by a decrease in central inhibition of the mechanically induced nociceptive input. In addition, it is hypothesised that collateral sprouting of primary afferent neurons within the spinal cord might occur. According to this model, nerve fibres in deeper laminae that do not normally transmit pain sprout into more superficial regions of the dorsal horn (e.g. laminae I and II) and become receptive to nociceptive input.7
Central Sensitisation Features In Chronic Pain Conditions
The pathways involved in CS and pain amplification have been demonstrated in very diverse pain conditions, such as neuropathic pain, but also myofascial pain syndromes, chronic pelvic pain including vulvodynia, certain forms of chronic headache, non-specific low-back pain and more recently even in osteoarthritic conditions.8,9 One major commonality of these chronic conditions is the intensity of symptom experience and its negative impact on the quality of life of the patient, which frequently result in long‐lasting disability. Time‐related changes in neuronal function have been shown in animals with neuropathy, ultimately spreading to the right amygdala and the cingulate cortex; areas heavily implicated in emotional memories, fear and aversion.10,11 Any sensory experience greater in amplitude, duration and spatial extent than would be expected from a defined peripheral input under normal circumstances, potentially reflects a central amplification due to increased excitation or reduced inhibition. Specific sensory changes could include a reduction in nociceptive threshold, mechanical punctate hyperalgesia and dynamic mechanical allodynia, long‐lasting pain after the end of a stimulus and a spread of (hyper‐) sensitivity to normal tissue (spatial summation).3,12 Individual differences in pain ratings and the extent of CS seem to depend on genetic and environmental factors, as well as the underlying disease entity. Furthermore, it is hypothesised that pain intensity and CS may be influenced by cognitive factors, such as catastrophising.13
Abbreviations: PHN, post-herpetic neuralgia; NP, neuropathic pain; CRPS, complex regional pain syndrome; SCI, spinal cord injury; DPN, diabetic peripheral neuropathy; IBS, irritable bowel syndrome; BPS-IC, bladder pain syndrome-interstitial cystitis
The Role Of Central Sensitisation In The Development Of Chronic Post-Surgical Pain
Considering the three same mechanisms for other conditions involved in the development of CS
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Assessing widespread hyperalgesia by pressure pain thresholds seems to be indicative of chronic post-surgical pain outcome after knee48 and hip49 replacements, and breast cancer surgery.50
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Temporal summation is a normal response that occurs in healthy humans, but is enhanced in patients with central sensitisation, and has been shown to predict pain outcomes after surgery.51-53 For example, patients with osteoarthritis that report chronic pain after joint replacement surgery have significantly higher temporal summation pre-surgically and post-surgically, compared with patients that experience pain relief.54-56 This suggests that enhanced temporal summation may be a marker for vulnerable individuals that develop CS who respond poorly to peripherally directed pain interventions. Conditioning pain modulation (CPM) and temporal summation paradigms can also be used in combination to better characterise the balance of pro‐ and anti-nociceptive processing within individuals.48,57,58
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Decreased CPM is associated with a variety of clinical outcomes, including increased post-surgical pain and analgesia requirements, and the effectiveness of some centrally-acting analgesics.59-61
Conclusion
Advances in the knowledge on pain pathophysiology have highlighted the role of CS on pain chronification. Both sources of pain, nociceptive and neuropathic, seem to depend on the peripheral drive of nociceptive afferents, not only to initiate the process of central sensitisation, but also to maintain and modulate it. Nevertheless, in many patients the changes induced by this phenomenon at the CNS level, and consequently the sensory symptoms perceived by the patients, do not reverse accordingly once the peripheral driver has disappeared. This is thought to be due to an abnormal central processing and consequent descending modulation, influenced by genetic and environmental factors and psychosocial vulnerabilities. This is similar to what has been described in a few clinical disease states like fibromyalgia, chronic fatigue and IBS. Regarding chronic post-surgical pain, there increasingly seems to be an agreement in the scientific community concerning how to reduce the risk of chronic pain states: aggressively treating acute pain episodes and employing multimodal analgesic techniques that target peripheral and central mechanisms, as well as any psychological risk factors that increase a patient’s likelihood of developing these syndromes.
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