Korean J Pain.  2025 Jan;38(1):4-13. 10.3344/kjp.24257.

Nociplastic pain: controversy of the concept

• Macionis V

• KMID: 2563867
• DOI: http://doi.org/10.3344/kjp.24257

Abstract

Classically, pain can be of a nociceptive or neuropathic nature, which refers to non-neural or neural tissue lesions, respectively. Chronic pain in conditions such as migraine, fibromyalgia, and complex regional pain syndrome (CRPS), is thought to perpetuate without a noxious input. Pain in such patients can be assigned neither to the nociceptive nor neuropathic category. Therefore, a third pain descriptor, named “nociplastic pain”, has been adopted by the International Association for the Study of Pain. The current controversy-focused narrative review updates littledebated aspects of the new pain concept. The most disputable feature of nociplastic pain is its autonomous persistence, i.e., existence without causative tissue damage, presumably because of a malfunction of pain pathways and processing. This contradicts the fact that nociplastic pain is accompanied by persistent central sensitization that has been shown to require a continuing noxious input, e.g., nerve injury. Even if sensitization occurs without a lesion, e.g., in psychogenic and emotional pain, peripheral stimulus is necessary to produce pain. A logical weakness of the concept is that the word “plastic” in biology refers to adaptation rather than to maladaptation. The pathophysiologic mechanism of nociplastic pain may, in fact, be associated with background conditions that elude diagnosis because of the limitations of current diagnostic means. Misapplication of the nociplastic pain category may weaken diagnostic alertness toward occult causes of pain. Possible diagnostic errors could be avoided by understanding that nociplastic pain is a mechanism of pain rather than a diagnosis. Clinical use of this pain descriptor deserves a wider critical discussion.

Keyword

Central Nervous System Sensitization; Chronic Pain; Complex Regional Pain Syndromes; Diagnosis; Fibromyalgia; Hypersensitivity; Neuralgia; Nociception

Reference

1. Jackson T, Thomas S, Stabile V, Shotwell M, Han X, McQueen K. 2016; A systematic review and meta-analysis of the global burden of chronic pain without clear etiology in low- and middle-income countries: trends in heterogeneous data and a proposal for new assessment methods. Anesth Analg. 123:739–48. DOI: 10.1213/ANE.0000000000001389. PMID: 27537761.

2. Tsang A, Von Korff M, Lee S, Alonso J, Karam E, Angermeyer MC, et al. 2008; Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J Pain. 9:883–91. Erratum in: J Pain 2009; 10: 553. DOI: 10.1016/j.jpain.2008.05.005. PMID: 18602869.

3. International Association for the Study of Pain. 2021. Terminology [Internet]. International Association for the Study of Pain. Available at: https://www.iasp-pain.org/resources/terminology/.

4. Kosek E, Clauw D, Nijs J, Baron R, Gilron I, Harris RE, et al. 2021; Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system. Pain. 162:2629–34. DOI: 10.1097/j.pain.0000000000002324. PMID: 33974577.

5. Kosek E, Cohen M, Baron R, Gebhart GF, Mico JA, Rice ASC, et al. 2016; Do we need a third mechanistic descriptor for chronic pain states? Pain. 157:1382–6. DOI: 10.1097/j.pain.0000000000000507. PMID: 26835783.

6. Moloney N, Rabey M, Nijs J, Hush J, Slater H. 2017; Support for extended classification of pain states. Pain. 158:1395. DOI: 10.1097/j.pain.0000000000000882. PMID: 28622275.

7. Brummett C, Clauw D, Harris R, Harte S, Hassett A, Williams D. 2016; We agree with the need for a new term but disagree with the proposed terms. Pain. 157:2876. DOI: 10.1097/j.pain.0000000000000717. PMID: 27841842.

8. Granan LP. 2017; We do not need a third mechanistic descriptor for chronic pain states! Not yet. Pain. 158:179. DOI: 10.1097/j.pain.0000000000000735. PMID: 27984528. PMCID: PMC5175995.

9. Martínez-Lavín M. 2022; Centralized nociplastic pain causing fibromyalgia: an emperor with no cloths? Clin Rheumatol. 41:3915–7. DOI: 10.1007/s10067-022-06407-5. PMID: 36239845. PMCID: PMC9561334.

10. Hoegh M, Schmid AB, Hansson P, Finnerup NB. 2022; Not being able to measure what is important, does not make things we can measure important. Pain. 163:e963. DOI: 10.1097/j.pain.0000000000002662. PMID: 35838649.

11. Cohen M, Quintner J, Weisman A. 2023; "Nociplastic pain": a challenge to nosology and to nociception. J Pain. 24:2131–9. DOI: 10.1016/j.jpain.2023.07.019. PMID: 37482233.

12. Toda K. 2019; Pure nociceptive pain is very rare. Curr Med Res Opin. 35:1991. DOI: 10.1080/03007995.2019.1638761. PMID: 31259612.

13. Herman MA, Aiello BR, DeLong JD, Garcia-Ruiz H, González AL, Hwang W, et al. 2022; A unifying framework for understanding biological structures and functions across levels of biological organization. Integr Comp Biol. 61:2038–47. DOI: 10.1093/icb/icab167. PMID: 34302339. PMCID: PMC8990247.

14. Fitzcharles MA, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. 2021; Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet. 397:2098–110. DOI: 10.1016/S0140-6736(21)00392-5. PMID: 34062144.

15. Nijs J, Lahousse A, Kapreli E, Bilika P, Saraçoğlu İ, Malfliet A, et al. 2021; Nociplastic pain criteria or recognition of central sensitization? Pain phenotyping in the past, present and future. J Clin Med. 10:3203. DOI: 10.3390/jcm10153203. PMID: 34361986. PMCID: PMC8347369.

16. Yoo YM, Kim KH. 2024; Current understanding of nociplastic pain. Korean J Pain. 37:107–18. DOI: 10.3344/kjp.23326. PMID: 38504389. PMCID: PMC10985487.

17. Costigan M, Scholz J, Woolf CJ. 2009; Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 32:1–32. DOI: 10.1146/annurev.neuro.051508.135531. PMID: 19400724. PMCID: PMC2768555.

18. Marvizon JC, Walwyn W, Minasyan A, Chen W, Taylor BK. 2015; Latent sensitization: a model for stress-sensitive chronic pain. Curr Protoc Neurosci. 71:9.50.1–9.50.14. DOI: 10.1002/0471142301.ns0950s71. PMID: 25829356. PMCID: PMC4532319.

19. Gerum M, Simonin F. 2022; Behavioral characterization, potential clinical relevance and mechanisms of latent pain sensitization. Pharmacol Ther. 233:108032. DOI: 10.1016/j.pharmthera.2021.108032. PMID: 34763010.

20. Brazenor GA, Malham GM, Teddy PJ. 2022; Can central sensitization after injury persist as an autonomous pain generator? A comprehensive search for evidence. Pain Med. 23:1283–98. DOI: 10.1093/pm/pnab319. PMID: 34718773.

21. Bove GM, Dilley A. 2010; The conundrum of sensitization when recording from nociceptors. J Neurosci Methods. 188:213–8. DOI: 10.1016/j.jneumeth.2010.02.010. PMID: 20171245. PMCID: PMC2854223.

22. Malick A, Burstein R. 2000; Peripheral and central sensitization during migraine. Funct Neurol. 15 Suppl 3:28–35.

23. Satkeviciute I, Goodwin G, Bove GM, Dilley A. 2018; Time course of ongoing activity during neuritis and following axonal transport disruption. J Neurophysiol. 119:1993–2000. DOI: 10.1152/jn.00882.2017. PMID: 29465329. PMCID: PMC7938769.

24. Dilley A, Bove GM. 2008; Resolution of inflammation-induced axonal mechanical sensitivity and conduction slowing in C-fiber nociceptors. J Pain. 9:185–92. DOI: 10.1016/j.jpain.2007.10.012. PMID: 18309534.

25. Bove GM, Ransil BJ, Lin HC, Leem JG. 2003; Inflammation induces ectopic mechanical sensitivity in axons of nociceptors innervating deep tissues. J Neurophysiol. 90:1949–55. DOI: 10.1152/jn.00175.2003. PMID: 12724363.

26. Greening J, Dilley A. Fernández de las Peñas C, Cleland JA, Huijbregts PA, editors. 2011. Peripheral mechanisms of chronic upper limb pain: nerve dynamics, inflammation and neurophysiology. In: Neck and arm pain syndromes. Churchill Livingstone;p. 476–95. DOI: 10.1016/B978-0-7020-3528-9.00037-6.

27. Boada MD, Martin TJ, Parker R, Houle TT, Eisenach JC, Ririe DG. 2020; Recovery from nerve injury induced behavioral hypersensitivity in rats parallels resolution of abnormal primary sensory afferent signaling. Pain. 161:949–59. DOI: 10.1097/j.pain.0000000000001781. PMID: 32040074. PMCID: PMC7166146.

28. Von Korff M, Ormel J, Keefe FJ, Dworkin SF. 1992; Grading the severity of chronic pain. Pain. 50:133–49. DOI: 10.1016/0304-3959(92)90154-4. PMID: 1408309.

29. Matuska W, Matuska J, Skorupska E, Siwek M, Herrero P, Santafé MM. 2023; Can myofascial trigger points involve nociplastic pain? A scoping review on animal models. J Pain Res. 16:3747–58. DOI: 10.2147/JPR.S422885. PMID: 38026452. PMCID: PMC10640827.

30. Sugimoto M, Takahashi Y, Sugimura YK, Tokunaga R, Yajima M, Kato F. 2021; Active role of the central amygdala in widespread mechanical sensitization in rats with facial inflammatory pain. Pain. 162:2273–86. DOI: 10.1097/j.pain.0000000000002224. PMID: 33900711. PMCID: PMC8280967.

31. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. 2019; Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain. 160:19–27. DOI: 10.1097/j.pain.0000000000001384. PMID: 30586067.

32. Álvarez-Pérez B, Deulofeu M, Homs J, Merlos M, Vela JM, Verdú E, et al. 2022; Long-lasting reflexive and nonreflexive pain responses in two mouse models of fibromyalgia-like condition. Sci Rep. 12:9719. DOI: 10.1038/s41598-022-13968-7. PMID: 35691979. PMCID: PMC9189106.

33. Hankerd K, McDonough KE, Wang J, Tang SJ, Chung JM, La JH. 2022; Postinjury stimulation triggers a transition to nociplastic pain in mice. Pain. 163:461–73. DOI: 10.1097/j.pain.0000000000002366. PMID: 34285154. PMCID: PMC8669020.

34. Biggs JE, Lu VB, Stebbing MJ, Balasubramanyan S, Smith PA. 2010; Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain. 6:44. DOI: 10.1186/1744-8069-6-44. PMID: 20653959. PMCID: PMC2918544.

35. McDonough KE. 2022. Male-specific mechanisms in a murine model of nociplastic pain. [Doctoral dissertation]. University of Texas Medical Branch;Galveston, TX:

36. Govindaraju SR, Curry BD, Bain JLW, Riley DA. 2008; Nerve damage occurs at a wide range of vibration frequencies. Int J Ind Ergon. 38:687–92. DOI: 10.1016/j.ergon.2007.10.008.

37. Kajita Y, Suetomi K, Okada T, Ikeuchi M, Arai YC, Sato K, et al. 2013; Behavioral and neuropathological changes in animal models of chronic painful scar. J Orthop Sci. 18:1005–11. DOI: 10.1007/s00776-013-0453-7. PMID: 23963587. PMCID: PMC3838578.

38. Reddy KS, Naidu MU, Rani PU, Rao TR. 2012; Human experimental pain models: a review of standardized methods in drug development. J Res Med Sci. 17:587–95.

39. Terkelsen AJ, Bach FW, Jensen TS. 2008; Experimental forearm immobilization in humans induces cold and mechanical hyperalgesia. Anesthesiology. 109:297–307. DOI: 10.1097/ALN.0b013e31817f4c9d. PMID: 18648239.

40. Liu Y, Liang Y, Gao M, Li Y, Zhao T, Zhao Y. 2021; Animal models of complex regional pain syndrome type I. J Pain Res. 14:3711–21. DOI: 10.2147/JPR.S333270. PMID: 34899000. PMCID: PMC8654689.

41. Mawla IA. 2022. A multimodal examination of functional brain and neurochemical mechanisms underlying nociplastic pain. [Doctoral dissertation]. University of Michigan;Ann Arbor, MI:

42. Mawla I, Huang Z, Kaplan CM, Ichesco E, Waller N, Larkin TE, et al. 2023; Large-scale momentary brain co-activation patterns are associated with hyperalgesia and mediate focal neurochemistry and cross-network functional connectivity in fibromyalgia. Pain. 164:2737–48. DOI: 10.1097/j.pain.0000000000002973. PMID: 37751539. PMCID: PMC10652715.

43. Huynh V, Rosner J, Curt A, Kollias S, Hubli M, Michels L. 2020; Disentangling the effects of spinal cord injury and related neuropathic pain on supraspinal neuroplasticity: a systematic review on neuroimaging. Front Neurol. 10:1413. DOI: 10.3389/fneur.2019.01413. PMID: 32116986. PMCID: PMC7013003.

44. Johnston KJA, Signer R, Huckins LM. 2024; Chronic overlapping pain conditions and nociplastic pain. HGG Adv. 6:100381. DOI: 10.1016/j.xhgg.2024.100381. PMID: 39497418. PMCID: PMC11617767.

45. Macionis V. 2023; Chronic pain and local pain in usually painless conditions including neuroma may be due to compressive proximal neural lesion. Front Pain Res (Lausanne). 4:1037376. DOI: 10.3389/fpain.2023.1037376. PMID: 36890855. PMCID: PMC9986610.

46. Macionis V. 2023; Neurovascular compression-induced intracranial allodynia may be the true nature of migraine headache: an interpretative review. Curr Pain Headache Rep. 27:775–91. DOI: 10.1007/s11916-023-01174-7. PMID: 37837483.

47. Goodwin G. 2018. The role of axonal transport disruption in the development of axonal mechanical sensitivity in intact C-fibre neurons. [Doctoral dissertation]. University of Brighton;Brighton:

48. Dilley A, Bove GM. 2008; Disruption of axoplasmic transport induces mechanical sensitivity in intact rat C-fibre nociceptor axons. J Physiol. 586:593–604. DOI: 10.1113/jphysiol.2007.144105. PMID: 18006580. PMCID: PMC2375581.

49. Eliav E, Benoliel R, Tal M. 2001; Inflammation with no axonal damage of the rat saphenous nerve trunk induces ectopic discharge and mechanosensitivity in myelinated axons. Neurosci Lett. 311:49–52. DOI: 10.1016/S0304-3940(01)02143-7. PMID: 11585565.

50. Chacur M, Milligan ED, Gazda LS, Armstrong C, Wang H, Tracey KJ, et al. 2001; A new model of sciatic inflammatory neuritis (SIN): induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats. Pain. 94:231–44. DOI: 10.1016/S0304-3959(01)00354-2. PMID: 11731060.

51. Dilley A, Lynn B, Pang SJ. 2005; Pressure and stretch mechanosensitivity of peripheral nerve fibres following local inflammation of the nerve trunk. Pain. 117:462–72. DOI: 10.1016/j.pain.2005.08.018. PMID: 16154692. PMCID: PMC1402335.

52. Bułdyś K, Górnicki T, Kałka D, Szuster E, Biernikiewicz M, Markuszewski L, et al. 2023; What do we know about nociplastic pain? Healthcare (Basel). 11:1794. DOI: 10.3390/healthcare11121794. PMID: 37372912. PMCID: PMC10298569.

53. Ferro Moura Franco K, Lenoir D, Dos Santos Franco YR, Jandre Reis FJ, Nunes Cabral CM, Meeus M. 2021; Prescription of exercises for the treatment of chronic pain along the continuum of nociplastic pain: a systematic review with meta-analysis. Eur J Pain. 25:51–70. DOI: 10.1002/ejp.1666. PMID: 32976664.

54. Borchers AT, Gershwin ME. 2017; The clinical relevance of complex regional pain syndrome type I: The Emperor's New Clothes. Autoimmun Rev. 16:22–33. DOI: 10.1016/j.autrev.2016.09.024. PMID: 27666818.

55. Trescot AM, Krashin D. Trescot AM, editor. 2016. Consequences of peripheral nerve entrapment. In: Peripheral nerve entrapments: clinical diagnosis and management. Springer Cham;p. 15–7. DOI: 10.1007/978-3-319-27482-9_3.

56. Harden RN, McCabe CS, Goebel A, Massey M, Suvar T, Grieve S, et al. 2022; Complex regional pain syndrome: practical diagnostic and treatment guidelines, 5th edition. Pain Med. 23(Suppl 1):S1–53. DOI: 10.1093/pm/pnac046. PMID: 35687369. PMCID: PMC9186375.

57. van der Laan L, ter Laak HJ, Gabreëls-Festen A, Gabreëls F, Goris RJ. 1998; Complex regional pain syndrome type I (RSD): pathology of skeletal muscle and peripheral nerve. Neurology. 51:20–5. DOI: 10.1212/WNL.51.1.20. PMID: 9674773.

58. Oaklander AL, Fields HL. 2009; Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol. 65:629–38. DOI: 10.1002/ana.21692. PMID: 19557864.

59. Dellon L, Andonian E, Rosson GD. 2010; Lower extremity complex regional pain syndrome: long-term outcome after surgical treatment of peripheral pain generators. J Foot Ankle Surg. 49:33–6. DOI: 10.1053/j.jfas.2009.08.003. PMID: 20123284.

60. Dellon AL, Andonian E, Rosson GD. 2009; CRPS of the upper or lower extremity: surgical treatment outcomes. J Brachial Plex Peripher Nerve Inj. 4:1.

61. On AY, Tanigor G, Baydar DA. 2022; Relationships of autonomic dysfunction with disease severity and neuropathic pain features in fibromyalgia: is it really a sympathetically maintained neuropathic pain? Korean J Pain. 35:327–35. DOI: 10.3344/kjp.2022.35.3.327. PMID: 35768988. PMCID: PMC9251392.

62. Viceconti A, Geri T, De Luca S, Maselli F, Rossettini G, Sulli A, et al. 2021; Neuropathic pain and symptoms of potential small-fiber neuropathy in fibromyalgic patients: a national on-line survey. Joint Bone Spine. 88:105153. DOI: 10.1016/j.jbspin.2021.105153. PMID: 33561533.

63. Di Carlo M, Cesaroni P, Salaffi F. 2021; Neuropathic pain features suggestive of small fibre neuropathy in fibromyalgia syndrome: a clinical and ultrasonographic study on female patients. Clin Exp Rheumatol. 39 Suppl 130:102–7. DOI: 10.55563/clinexprheumatol/r0kho4. PMID: 33666162.

64. Hulens M, Bruyninckx F, Rasschaert R, Vansant G, De Mulder P, Stalmans I, et al. 2020; Electrodiagnostic abnormalities associated with fibromyalgia. J Pain Res. 13:737–44. DOI: 10.2147/JPR.S234475. PMID: 32308473. PMCID: PMC7154040.

65. Staud R, Price DD, Robinson ME, Vierck CJ Jr. 2004; Body pain area and pain-related negative affect predict clinical pain intensity in patients with fibromyalgia. J Pain. 5:338–43. DOI: 10.1016/j.jpain.2004.05.007. PMID: 15336638.

66. Staud R, Vierck CJ, Robinson ME, Price DD. 2006; Overall fibromyalgia pain is predicted by ratings of local pain and pain-related negative affect--possible role of peripheral tissues. Rheumatology (Oxford). 45:1409–15. DOI: 10.1093/rheumatology/kel121. PMID: 16621922.

67. Ge HY. 2010; Prevalence of myofascial trigger points in fibromyalgia: the overlap of two common problems. Curr Pain Headache Rep. 14:339–45. DOI: 10.1007/s11916-010-0127-5. PMID: 20607459.

68. Fernandez-de-las-Penas C. 2012. Clinical evidence of generalised mechanical hypersensitivity in local musculoskeletal pain syndromes and headaches. [Doctoral dissertation]. Aalborg University;Aalborg:

69. Chiarotto A, Clijsen R, Fernandez-de-Las-Penas C, Barbero M. 2016; Prevalence of myofascial trigger points in spinal disorders: a systematic review and meta-analysis. Arch Phys Med Rehabil. 97:316–37. DOI: 10.1016/j.apmr.2015.09.021. PMID: 26475933.

70. Cerezo-Téllez E, Torres-Lacomba M, Mayoral-Del Moral O, Sánchez-Sánchez B, Dommerholt J, Gutiérrez-Ortega C. 2016; Prevalence of myofascial pain syndrome in chronic non-specific neck pain: a population-based cross-sectional descriptive study. Pain Med. 17:2369–77. DOI: 10.1093/pm/pnw114. PMID: 28025371.

71. Akamatsu FE, Saleh S, Pinesi HT, Rodrigues KR, Zandoná CB, Andrade M, et al. 2013; Anatomical basis of the myofascial trigger points of the trapezius muscle. Int J Morphol. 31:915–20. DOI: 10.4067/S0717-95022013000300023.

72. Akamatsu FE, Yendo TM, Rhode C, Itezerote AM, Hojaij F, Andrade M, et al. 2017; Anatomical basis of the myofascial trigger points of the gluteus maximus muscle. Biomed Res Int. 2017:4821968. DOI: 10.1155/2017/4821968. PMID: 29349073. PMCID: PMC5733974.

73. Wada JT, Akamatsu F, Hojaij F, Itezerote A, Scarpa JC, Andrade M, et al. 2020; An anatomical basis for the myofascial trigger points of the abductor hallucis muscle. Biomed Res Int. 2020:9240581. DOI: 10.1155/2020/9240581. PMID: 32076620. PMCID: PMC6998759.

74. Procópio Pinheiro R, Gaubeur MA, Itezerote AM, Saleh SO, Hojaij F, Andrade M, et al. 2020; Anatomical study of the innervation of the masseter muscle and its correlation with myofascial trigger points. J Pain Res. 13:3217–26. DOI: 10.2147/JPR.S265717. PMID: 33299345. PMCID: PMC7719441.

75. Gautschi RU. Schleip R, Stecco C, Driscoll M, Huijing P, editors. 2021. Trigger points as a fascia-related disorder. In: Fascia: the tensional network of the human body. 2nd ed. Elsevier;p. 329–40.

76. Jorge LL, Amaro E Jr. 2012; Brain imaging in fibromyalgia. Curr Pain Headache Rep. 16:388–98. DOI: 10.1007/s11916-012-0284-9. PMID: 22717698.

77. Suñol M, Payne MF, Tong H, Maloney TC, Ting TV, Kashikar-Zuck S, et al. 2022; Brain structural changes during juvenile fibromyalgia: relationships with pain, fatigue, and functional disability. Arthritis Rheumatol. 74:1284–94. DOI: 10.1002/art.42073. PMID: 35076177. PMCID: PMC9247027.

78. Lee DH, Lee KJ, Cho KI, Noh EC, Jang JH, Kim YC, et al. 2015; Brain alterations and neurocognitive dysfunction in patients with complex regional pain syndrome. J Pain. 16:580–6. DOI: 10.1016/j.jpain.2015.03.006. PMID: 25840331.

79. Hasan H, Irfan Waheed R, Bin Arif T, Saleem S, Anwar A. 2020; Gray and white matter changes in migraineurs: a review of literature. SN Compr Clin Med. 2:2185–96. DOI: 10.1007/s42399-020-00576-7.

80. Kim SK, Nikolova S, Schwedt TJ. 2021; Structural aberrations of the brain associated with migraine: a narrative review. Headache. 61:1159–79. DOI: 10.1111/head.14189. PMID: 34407215.

81. Ashina S, Bentivegna E, Martelletti P, Eikermann-Haerter K. 2021; Structural and functional brain changes in migraine. Pain Ther. 10:211–23. DOI: 10.1007/s40122-021-00240-5. PMID: 33594593. PMCID: PMC8119592.

82. DePauw R, Coppieters I, Meeus M, Caeyenberghs K, Danneels L, Cagnie B. 2017; Is traumatic and non-traumatic neck pain associated with brain alterations? - A systematic review. Pain Physician. 20:245–60. DOI: 10.36076/ppj.2017.260.

83. Kregel J, Meeus M, Malfliet A, Dolphens M, Danneels L, Nijs J, et al. 2015; Structural and functional brain abnormalities in chronic low back pain: a systematic review. Semin Arthritis Rheum. 45:229–37. DOI: 10.1016/j.semarthrit.2015.05.002. PMID: 26092329.

84. Ng SK, Urquhart DM, Fitzgerald PB, Cicuttini FM, Hussain SM, Fitzgibbon BM. 2018; The relationship between structural and functional brain changes and altered emotion and cognition in chronic low back pain brain changes: a systematic review of MRI and fMRI studies. Clin J Pain. 34:237–61. DOI: 10.1097/AJP.0000000000000534. PMID: 28719509.

85. Weaver KR, Sherwin LB, Walitt B, Melkus GD, Henderson WA. 2016; Neuroimaging the brain-gut axis in patients with irritable bowel syndrome. World J Gastrointest Pharmacol Ther. 7:320–33. DOI: 10.4292/wjgpt.v7.i2.320. PMID: 27158548. PMCID: PMC4848255.

86. van Alfen N, van Engelen BG. 2006; The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain. 129(Pt 2):438–50. DOI: 10.1093/brain/awh722. PMID: 16371410.

87. Kaji R. 2003; Physiology of conduction block in multifocal motor neuropathy and other demyelinating neuropathies. Muscle Nerve. 27:285–96. DOI: 10.1002/mus.10273. PMID: 12635114.

88. Hofmeijer J, Franssen H, van Schelven LJ, van Putten MJ. 2013; Why are sensory axons more vulnerable for ischemia than motor axons? PLoS One. 8:e67113. DOI: 10.1371/journal.pone.0067113. PMID: 23840596. PMCID: PMC3688630.

89. Creavin ST, Dunn KM, Mallen CD, Nijrolder I, van der Windt DA. 2010; Co-occurrence and associations of pain and fatigue in a community sample of Dutch adults. Eur J Pain. 14:327–34. DOI: 10.1016/j.ejpain.2009.05.010. PMID: 19540139.

90. Moisset X, Bouhassira D, Avez Couturier J, Alchaar H, Conradi S, Delmotte MH, et al. 2020; Pharmacological and non-pharmacological treatments for neuropathic pain: systematic review and French recommendations. Rev Neurol (Paris). 176:325–52. DOI: 10.1016/j.neurol.2020.01.361. PMID: 32276788.

91. Li L, Chen J, Li YQ. 2023; The downregulation of opioid receptors and neuropathic pain. Int J Mol Sci. 24:5981. DOI: 10.3390/ijms24065981. PMID: 36983055. PMCID: PMC10053236.

92. Holman A, Parikh N, Clauw DJ, Williams DA, Tapper EB. 2023; Contemporary management of pain in cirrhosis: toward precision therapy for pain. Hepatology. 77:290–304. DOI: 10.1002/hep.32598. PMID: 35665522. PMCID: PMC9970025.

93. Pereira J, Bruera E. 1997; Emerging neuropsychiatric toxicities of opioids. J Pharm Care Pain Symptom Control. 5:3–29. DOI: 10.1300/J088v05n04_02.

94. Mao J, Sung B, Ji RR, Lim G. 2002; Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci. 22:7650–61. DOI: 10.1523/JNEUROSCI.22-17-07650.2002. PMID: 12196588. PMCID: PMC6757968.

95. Cunha-Oliveira T, Rego AC, Oliveira CR. 2008; Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev. 58:192–208. DOI: 10.1016/j.brainresrev.2008.03.002. PMID: 18440072.

96. Niedzielska E, Rospond B, Pomierny-Chamioło L, Sadakierska-Chudy A, Filip M. Kostrzewa RM, editor. 2014. Neurotoxicity in psychostimulant and opiate addiction. In: Handbook of neurotoxicity. Springer New York;p. 455–512. DOI: 10.1007/978-1-4614-5836-4_179.

97. Youn DH, Jun J, Kim TW, Park K. 2022; Spinal orexin A attenuates opioid-induced mechanical hypersensitivity in the rat. Korean J Pain. 35:433–9. DOI: 10.3344/kjp.2022.35.4.433. PMID: 36175342. PMCID: PMC9530684.

98. Mercadante S, Arcuri E, Santoni A. 2019; Opioid-induced tolerance and hyperalgesia. CNS Drugs. 33:943–55. DOI: 10.1007/s40263-019-00660-0. PMID: 31578704.

99. Santoni A, Arcuri E. 2020; The ambiguity of opioids revealed by immunology is changing the knowledge and the therapeutic approach in cancer and non-cancer pain: a narrative review. Immunol Lett. 226:12–21. DOI: 10.1016/j.imlet.2020.06.011. PMID: 32590120.

100. Covington EC. 2000; Psychogenic pain-what it means, why it does not exist, and how to diagnose it. Pain Med. 1:287–94. DOI: 10.1046/j.1526-4637.2000.00049.x. PMID: 15101873.

101. de Greck M. Boeker H, Hartwich P, Northoff G, editors. 2018. Somatization and bodily distress disorder. In: Neuropsychodynamic psychiatry. Springer Cham;p. 319–34. DOI: 10.1007/978-3-319-75112-2_15.

102. Tossani E. 2013; The concept of mental pain. Psychother Psychosom. 82:67–73. DOI: 10.1159/000343003. PMID: 23295405.

103. Egloff N, Cámara RJ, von Känel R, Klingler N, Marti E, Ferrari ML. 2014; Hypersensitivity and hyperalgesia in somatoform pain disorders. Gen Hosp Psychiatry. 36:284–90. DOI: 10.1016/j.genhosppsych.2014.01.011. PMID: 24650586.

104. Mohammadi F, Kohlmeier KA, Jeddi S, Ahmadi-Zeidabadi M, Shabani M. 2020; Affective dimensions of pain and region -specific involvement of nitric oxide in the development of empathic hyperalgesia. Sci Rep. 10:10141. DOI: 10.1038/s41598-020-66930-w. PMID: 32576847. PMCID: PMC7311399.

105. Shulman LM. 2020; Emotional traumatic brain injury. Cogn Behav Neurol. 33:301–3. DOI: 10.1097/WNN.0000000000000243. PMID: 32947370. PMCID: PMC7774817.

106. Vachon-Presseau E, Centeno MV, Ren W, Berger SE, Tétreault P, Ghantous M, et al. 2016; The emotional brain as a predictor and amplifier of chronic pain. J Dent Res. 95:605–12. DOI: 10.1177/0022034516638027. PMID: 26965423. PMCID: PMC4924545.

107. Popkirov S, Enax-Krumova EK, Mainka T, Hoheisel M, Hausteiner-Wiehle C. 2020; Functional pain disorders - more than nociplastic pain. NeuroRehabilitation. 47:343–53. DOI: 10.3233/NRE-208007. PMID: 32986624.

108. Fitzcharles MA, Petzke F, Tölle TR, Häuser W. 2021; Cannabis-based medicines and medical cannabis in the treatment of nociplastic pain. Drugs. 81:2103–16. DOI: 10.1007/s40265-021-01602-1. PMID: 34800285.

109. Hendler N. 2016; Why chronic pain patients are misdiagnosed 40 to 80% of the time? J Recent Adv Pain. 2:94–8. DOI: 10.5005/jp-journals-10046-0051.

110. Hendler NH, Kozikowski JG. 1993; Overlooked physical diagnoses in chronic pain patients involved in litigation. Psychosomatics. 34:494–501. DOI: 10.1016/S0033-3182(93)71823-X. PMID: 8284339.

111. Kosek E, Clauw D, Nijs J, Baron R, Gilron I, Harris RE, et al. 2023; Reply to Hoegh et al. Pain. 164:e116. DOI: 10.1097/j.pain.0000000000002823. PMID: 36638308.

112. Flores C. 2008. Plastic intellectual breeze: the contribution of Ralph Cudworth to S. T. Coleridge's early poetics of the symbol. Peter Lang.

113. van der Laan JM. 2001; Plastic words: words without meaning. Bull Sci Technol Soc. 21:349–53. DOI: 10.1177/027046760102100503.

114. Skipper M, Weiss U, Gray N. 2010; Plasticity. Nature. 465:703. DOI: 10.1038/465703a. PMID: 20535198.

115. von Bernhardi R, Bernhardi LE, Eugenín J. 2017; What is neural plasticity? Adv Exp Med Biol. 1015:1–15. DOI: 10.1007/978-3-319-62817-2_1. PMID: 29080018.

116. Walters ET. 1991; A functional, cellular, and evolutionary model of nociceptive plasticity in aplysia. Biol Bull. 180:241–51. DOI: 10.2307/1542394. PMID: 29304696.

117. McQuay HJ, Dickenson AH. 1990; Implications of nervous system plasticity for pain management. Anaesthesia. 45:101–2. DOI: 10.1111/j.1365-2044.1990.tb14270.x. PMID: 2157345.