Updates & Features
Central Sensitisation: Involvement In Different Sources Of Pain
Dr Emilio Quetglas, The PainSolve Team
In recent years, there have not been many publications on the involvement of peripheral sensitisation on the development and maintenance of central sensitisation, although central sensitisation has been suggested to play a role in almost every chronic painful and other medical conditions.1
Peripheral sensitisation represents a reduction in threshold and an amplification in the responsiveness of nociceptors, that occurs when the peripheral terminals are exposed to inflammatory mediators and damaged tissue and, in consequence, is restricted to the site of tissue injury.2 Peripheral sensitisation certainly contributes to the sensitisation of the nociceptive system and thereby to inflammatory pain hypersensitivity at inflamed sites (primary hyperalgesia). Nevertheless, peripheral sensitisation represents a form of pain elicited by activation of nociceptors, albeit one with a lower threshold due to the increased peripheral transduction sensitivity, and generally requires ongoing peripheral pathology for its maintenance. Peripheral sensitisation appears to play a major role in altered heat but not mechanical sensitivity, which is a major feature of central sensitisation.
Central sensitisation has been defined as the incorporation of novel inputs to nociceptive pathways including those that did not normally drive them, to produce Aβ fibre–mediated pain.3 Central sensitisation also produces pain hypersensitivity in noninflamed tissue by changing the sensory response elicited by normal inputs and increases pain sensitivity long after the initiating cause may have disappeared and when no peripheral pathology may be present. Acute nociceptive pain is ordinarily coupled to the presence, intensity or duration of particular peripheral stimuli, however, because central sensitisation results from changes in the properties of neurons in the CNS, it is not necessarily coupled in this way.
During the last years, different publications have asserted that the generation of this abnormal pain sensitivity is seen in individuals where there has been clearly an ongoing nociceptive input, at least in the first instance.4 This population will display features of central sensitisation: pain arising spontaneously, being elicited by normally innocuous stimuli (allodynia), being exaggerated and prolonged in response to noxious stimuli (hyperalgesia) and spreading beyond the site of injury (secondary hyperalgesia). This phenomenon can show up in autoimmune disorders, any type of arthritis, cancer, chronic low back pain (cLBP), Ehler-Danlos and hypermobility syndromes5–8 and is characterised by a partial or entire lack of remission when the input is removed.9,10 Comparatively, something similar has been described in neuropathic pain conditions. In post-herpetic neuralgia (PHN), the area of mechanical hypersensitivity has been shown to be a dynamic phenomenon that depends on peripheral input. In these patients, the application of cutaneous capsaicin to the primary affected skin area leads to an increase of the allodynic area, into previously non-affected skin.11 According to the authors, the observation supports the hypothesis that allodynia in some PHN patients is maintained by input from intact and possibly 'irritable' primary afferent nociceptors to a sensitised CNS. Furthermore, in patients with complex regional pain syndrome, although not a proper neuropathic pain condition (due to redefinition and grading system of neuropathic pain),12 a local anaesthetic block of painful foci associated with previous trauma abolishes the mechanical allodynia and spontaneous pain, whereas tactile and thermal perception in the previously allodynic area is preserved.13 When the local anaesthetic block wanes, spontaneous pain and allodynia return. Large network studies also support the concept that mechanical allodynia essentially depends on peripheral nociceptive input. Of 110 patients in the German Neuropathic Pain database suffering from heat hyperalgesia—a classical sign of peripheral nociceptor sensitisation—only 9% did not develop any form of mechanical hypersensitivity, so did not present any sign of central sensitisation.14
It has also been stated that central sensitisation may become more pathological in situations when it becomes autonomous and is maintained even in the absence of active peripheral event (resolved long ago, or not identified at all). Central sensitisation is not only a state where pain may be triggered by less intense stimuli, but also where it can be maintained by a different type of stimulus.15 This is probably the reasoning used to subscribe the first definition of central sensitisation given in this article, but it could also reflect the need why the International Association for the Study of Pain (IASP) had to adopt the term “nociplastic”, “algopathic” or “nocipathic” pain.
In November 2017, the IASP Council adopted the proposal for a third mechanistic descriptor of pain,16 electing to include the term “nociplastic pain” in the IASP terminology.17 The Task Force on Taxonomy defined nociplastic pain as “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain”.
There is a family of conditions characterised in part by pain and varied constitutional symptoms, that play a significant role in the societal burden of chronic pain, as they are both prevalent and difficult to treat. In this case, peripheral pathology corresponds poorly to the location and severity of pain.18,19 Many researchers favour a primary (but not exclusive) role for central nervous system (CNS) mechanisms in their aetiology and maintenance.20 Functional, chemical and structural neuroimaging studies reveal abnormalities in the brains of patients with these conditions,21-29 and the drugs that are effective in these conditions are believed to work primarily in the CNS.30,31 This does not mean that peripheral factors, or low-grade inflammation that is not identifiable clinically, do not play some role in these entities. It is, however, relevant that clinicians who care for individuals with these conditions, and who are quite adept at identifying (with blood tests, imaging or endoscopy) peripheral damage or inflammation, have generally concluded that these are not inflammatory or peripheral-based disorders. A recent term, Chronic Overlapping Pain Conditions (COPCs), already discussed in a previous article has been coined by the NIH to indicate that fibromyalgia (FM), irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), headache, interstitial cystitis/bladder pain syndrome (IC/BPS), temporo-mandibular disorders (TMD), endometriosis, low back pain and dry-eye disease may all represent conditions with overlapping clinical and pathophysiological features (i.e., those related to central sensitisation), where central factors may be playing a prominent or exclusive role in their pathogenesis.32,33
Individuals who develop COPCs begin developing pain and other related central sensitisation symptoms (fatigue, sleep disturbance, sensory sensitivity) in early life. For example, individuals who eventually go on to develop FM are more likely to experience headaches, dysmenorrhea, TMD, chronic fatigue, IBS and other functional GI disorders, IC/BPS, endometriosis and other regional pain syndromes (especially back and neck pain).34,35 What often appears clinically as a new episode of acute or subacute pain is just the most recent region of the body experiencing pain.36 Consequently, many pain experts have suggested that COPCs are best understood as a single lifelong disease that merely tends to manifest in different bodily regions over time.37-39
Nevertheless, this approach presents several inconsistencies. In the case of IBS, around a 15% of the cases believe their symptoms started following a gastroenteritis.40,41 For IC/BPS, patients are twice as likely to report a history of recurrent UTI before the onset of IC/BPS symptoms compared with patients who do not have IC/BPS and 10- to 12-times as likely to have a history of childhood urinary tract disorders.42 There appears to be a positive relationship between yeast infections preceding and following the diagnosis of vulvodynia, but this relationship varies from strong to non-existent depending on the relative accuracy of the recalled diagnosis of yeast infections among cases and controls.43 Up to 70% of TMD patients suffer from pathology or mispositioning of the temporo-mandibular joint disc, termed “internal derangement”.44,45 In the case of endometriosis, it is not reasonable to talk about “centralised pain” when implants of endometrial-like tissue are found outside the uterus that can cause pelvic pain and/or infertility.46 Finally, only non-specific LBP, and after a discogenic origin has been discarded, should be included under this COPC consideration.
According to these new definitions and concepts we propose the following diagram to classify the most relevant 50 pain conditions:
Pain conditions surrounded by a blue rectangle indicate evidence of central sensitisation (presumably secondary central sensitisation)
Summary and Conclusions
Peripheral nociceptive input is the ultimate cause of nociceptive or neuropathic pain. In the majority of patients, once this peripheral input is resolved, the pain disappears. Nevertheless, there is a proportion of patients in which pain remains. Those, who have developed central sensitisation that does not reverse despite an adequate treatment of the original lesion, will usually continue to experience extensive hypersensitivity, dynamic mechanical allodynia and secondary hyperalgesia. Ultimately, the pathophysiological mechanism in these pain indications could be similar to that adopted by the IASP: define pain that arises in certain conditions and that has been defined as nociplastic pain, in which central sensitisation is not preceded by any peripheral stimulus.
- Harte SE, Harris RE, Clauw DJ. J Appl Behav Res. 2018;23:e12137.
- Latremoliere A, Woolf CJ. J Pain 2009;10(9):895-926.
- Woolf CJ, Salter MW. Science 2000;288:1765-1769.
- Kosek E, Cohen M, Baron R, et al. Pain, 2016;157(7), 1382–1386.
- Gwilym SE, Keltner JR, Warnaby CE, et al. Arthritis Rheum. 2009;61(9):1226-34.
- Henry NL, Clauw DJ. Breast Cancer Res Treat. 2012;133(2):413-6.
- Phillips K, Clauw DJ. Arthritis Rheum. 2013;65(2):291-302.
- Owens MA, Bulls HW, Trost Z, et al. Pain Med 2016;17, 1452–1464.
- Gwilym SE, Filippini N, Douaud G, et al. Arthritis Rheum. 2010;62(10):2930-40.
- Kosek E, Ordeberg G. Eur J Pain. 2000;4(3):229-38
- Petersen KL, Fields HL, Brennum J, et al. Pain. 2000;88(2):125-33.
- Naleschinski D, Baron R. Curr Pain Headache Rep. 2010;14(3):196-202.
- Gracely RH, Lynch SA, Bennett GJ. Pain 1992;51:175–194.
- Baron R, Hans G, Dickenson AH. Ann Neurol 2013;74:630–636
- Ashmawi HA, Goes-Freire GM. Rev. dor 2016;17(supl 1):S31-4
- IASP Council Adopts Task Force Recommendation for Third Mechanistic Descriptor of Pain [Internet]. Washington DC, USA: International Association for the Study of Pain; c2018 [updated 2017 Nov 14]
- IASP Terminology [Internet]. Washington DC, USA: International Association for the Study of Pain; c2018 [updated 2017 Dec 14]
- Clauw DJ. Pain 2015;156:2115–16.
- Vercellini P, Fedele L, Aimi G, et al. Hum Reprod 2007;22:266–71.
- Woolf CJ. J Appl Biobehavioral Res 2018:e12124.
- Foerster BR, Petrou M, Edden RA, et al. Arthritis Rheum 2012;64:579–83.
- Hampson JP, Reed BD, Clauw DJ, et al. J Pain 2013;14:579–89.
- Harris RE, Clauw DJ, Scott DJ, et al. J Neurosci 2007;27:10000–6.
- Harris RE, Sundgren PC, Craig AD, et al. Arthritis Rheum 2009;60:3146–52.
- Kairys AE, Schmidt-Wilcke T, Puiu T, et al. J Urol 2015;193:131–7.
- Kilpatrick LA, Kutch JJ, Tillisch K, et al. J Urol 2014;192:947–55.
- Kutch JJ, Ichesco E, Hampson JP, et al. Pain 2017;158:1979–91.
- Schrepf A, Harper DE, Harte SE, et al. Pain 2016;157:2217–25.
- Seminowicz DA, Labus JS, Bueller JA, et al. Gastroenterology 2010;139:48–57.e42.
- Clauw DJ. J Clin Psychiatry 2008;69(suppl 2):25–9.
- Harris RE, Napadow V, Huggins JP, et al. Anesthesiology 2013;119:1453–64.
- Levitt AE, Galor A, Chowdhury AR, et al. Mol Pain. 2017;13:1744806917729306.
- Maixner W, Fillingim RB, Williams DA, et al. J Pain, 2016;17(9 Suppl):T93–T107.
- Aaron LA, Buchwald D. Ann Int Med, 2001;134(9), 868–881.
- Hudson JJ, Pope HG. Baillieres Clin Rheumatol, 1994;8(4), 839–856.
- Warren JW, Howard FM, Cross RK, et al. Urology, 2009;73(1), 52–57.
- Tracey I, Bushnell MC. J Pain, 2009;10(11), 1113–1120.
- Williams DA, Clauw DJ. J Pain, 2009;10(8), 777–791.
- Woolf CJ. Pain, 2011;152(3 Suppl), S2–S15.
- Longstreth GF, Hawkey CJ, Mayer EA, et al. Aliment Pharmacol Ther. 2001;15(7):959-64.
- Spiller R, Lam C. J Neurogastroenterol Motil 2012;18:258-268
- Drekonja DM, Johnson JR. Prim Care. 2008;35:345–367.
- Harlow BL, Caron RE, Parker SE, et al. J Womens Health (Larchmt). 2017;26(10):1069-1076.
- Murphy MK, MacBarb RF, Wong ME, et al. Int J Oral Maxillofac Implants 2013; 28 (6): e393-e414.
- Farrar WB, McCarty WL. J Ala Dent Assoc 1979; 63:19–26.
- Johnson NP, Sharpe Timms KL. Hum Reprod 2017; 32 (2): 315-324.