Updates & Features

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

1. 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

2. 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

3. 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.

References

1. Vardeh D, Mannion RJ, Woolf CJ, et al. J Pain. 2016;17(9 Suppl):T50–69
2. IASP Task Force. Classification of chronic pain. The IASP taxonomy. Merskey H, Bogduk N, ed. 2012
3. Latremoliere A, Woolf CJ. J Pain. 2009; 10(9): 895–926
4. Devor M. In: Weinstein J, Gordon S, editors. Low Back Pain: A Scientific and Clinical Overview. Rosemont, IL: AAOS, 1986;187-208
5. Cook AJ, Woolf CJ, Wall PD, et al. Nature 1987;325:151-3
6. Arendt-Nielsen L, Brennum J, Sindrup S, et al. Eur J Appl Physiol Occup Physiol. 1994;68(3):266-73
7. Stacey BR. Am J Phys Med Rehabil. 2005;84(3 Suppl):S4–16
8. Meeus M, Nijs J. Clin Rheumatol 2007; 26: 465– 473
9. Woolf CJ. Pain 2011; 152: S2– S15
10. Goncalves L, Dickenson AH. Eur J Neurosci 2012; 36: 3204– 3213
11. Navratilova E, Xie JY, Okun A, et al. Proc Natl Acad Sci USA 2012; 109: 20709– 20713
12. Rocha AP, Kraychete DC, Lemonica L, et al. Rev Bras Anestesiol 2007; 57: 94– 105
13. Nijs J, Paul van Wilgen C, Van Oosterwijck J, et al. Man Ther 2011; 16: 413– 418
14. Aykanat V, Gentgall M, Briggs N, et al. Br J Clin Pharmacol 2012;73, 37–4
15. Konopka K, Harbers M, Houghton A, et al. PLoS ONE 2012;7, e37524
16. Baron R, Saguer M. Neurosci Lett 1994;165, 97–100
17. Eide, PK, Jørum E, Stubhaug A, et al. Pain 1994;58, 347–35
18. Nikolajsen L, Hansen CL, Nielsen J, et al. Pain 1996;67, 69–77
19. Huge V, Lauchart M, Forderreuther S, et al. PLoS ONE 2008 ;3, e2742
20. De-la-Llave-Rincón AI, Fernández-de-las-Peñas C, Palacios-Ceña D, et al. J Orthop Sports Phys Ther. 2009;39(9):658-64
21. Bouhassira D, Danziger N, Attal N, et al. Brain 2003;126, 1068–1078
22. Gruener H, Zeilig G, Laufer Y, et al. Pain 2016;157, 1415–1424
23. Yarnitsky D, Granot M, Nahman-Averbuch H, et al. Pain 153, 1193–1198
24. Giesecke T, Gracely RH, Grant MA, et al. Arthritis Rheum 2004;50, 613–623
25. Puta C, Schulz B, Schoeler S, Magerl W, et al. BMC Neurol 2012;12, 98
26. Owens MA, Bulls HW, Trost Z, et al. Pain Med 2016;17, 1452–1464
27. Arendt-Nielsen L, Nie H, Laursen, MB, et al. Pain 2010;149, 573–581
28. Imamura M, Imamura ST, Kaziyama HH, et al. Arthritis Rheum 2008;59, 1424–1431
29. Skou ST, Graven-Nielsen T, Rasmussen S, et al. Eur J Pain 2014 ;18, 1024–1031
30. Lundblad H, Kreicbergs A, Jansson KA. J Bone Joint Surg Br 2008;90, 166–171
31. Meeus M, Vervisch S, De Clerck LS, et al. Semin Arthritis Rheum. 2012;41(4):556-67
32. Verne G, Price DD. Curr Rheumatol Rep 2002;4, 322–328
33. Bouin M, Meunier P, Riberdy-Poitras M, et al. Dig Dis Sci 46, 2542–2548
34. Drewes AM, Petersen P, Qvist P, et al. Scand J Gastroenterol 1999;34, 765–771
35. Munakata J, Naliboff B, Harraf F, et al. Gastroenterology 1997;112, 55–63
36. Wilder-Smith CH, Schindler D, Lovblad K, et al. Gut 2004;53,1595–1601
37. Bouwense SA, de Vries M, Schreuder LT, et al. World J Gastroenterol. 2015;21(1):47-59
38. Anand P, Aziz Q, Willert R, et al. Neurogastroenterol Motil. 2007;19 (1 Suppl):29-46
39. He W, Liu X, Zhang Y, et al. Reprod Sci. 2010;17(12):1099-111
40. Stratton P, Khachikyan I, Sinaii N, et al. Obstet Gynecol. 2015;125(3):719-28
41. Giesecke J, Reed BD, Haefner HK, et al. Obstet Gynecol. 2004;104(1):126–33
42. Pukall CF, Binik YM, Khalife S, et al. Pain. 2002;96(1–2):163–75
43. Lai H, Gardner V, Ness T, et al. J Pain 2014; 15 (4, Supplement) : S36
44. Do TP, Heldarskard GF, Kolding LT, et al. J Headache Pain. 2018;19(1):84
45. Van Oosterwijck J, Nijs J, Meeus M, et al. Eur J Pain. 2013;17(3):299-31
46. Garrigós-Pedrón M, La Touche R, Navarro-Desentre P, et al. Acta Odontol Scand. 2019;77(3):224-231
47. Sato H, Saisu H, Muraoka W, et al. J Orofac Pain 2012;26, 288–295
48. Bragdon EE, Light KC, Costello NL, et al. Pain 2002;96, 227–237
49. Petersen KK, Graven-Nielsen T, Simonsen O, et al. Pain 2016;157, 1400–1406
50. Wylde V, Sayers A, Lenguerrand E, et al. Pain 2015;156, 47–54
51. van Helmond N, Steegers MA, Filippini-de Moor GP, V, et al. PLoS ONE 2016;11(12): e0166601
52. Arendt‐Nielsen L, Nie H, Laursen MB, et al. Pain, 2010;149( 3), 573– 581
53. Staud R, Craggs JG, Perlstein WM, et al. Eur J Pain, 2008;12( 8), 1078– 1089
54. Weissman‐Fogel I, Granovsky Y, Crispel Y, et al. J Pain, 2009; 10( 6), 628– 636
55. Izumi M, Petersen KK, Laursen MB, et al. Pain, 2017;158( 2), 323– 332
56. Petersen KK, Arendt‐Nielsen L, Simonsen O, et al. Pain, 2015;156( 1), 55– 61
57. Skou ST, Graven‐Nielsen T, Rasmussen S, et al. Pain, 2013;154( 9), 1588– 1594
58. Vaegter HB, Graven‐Nielsen T. Pain, 2016;157( 7), 1480– 1488
59. Yarnitsky D, Crispel Y, Eisenberg E, et al. Pain, 2008 ;138( 1), 22– 28
60. Edwards RR. Neurology, 2005;65( 3), 437– 443
61. Yarnitsky D. Pain, 2015;156( Suppl 1), S24– S31