Pain Control pp 79-102 | Cite as

Central Sensitization in Humans: Assessment and Pharmacology

  • Lars Arendt-NielsenEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 227)


It is evident that chronic pain can modify the excitability of central nervous system which imposes a specific challenge for the management and for the development of new analgesics. The central manifestations can be difficult to quantify using standard clinical examination procedures, but quantitative sensory testing (QST) may help to quantify the degree and extend of the central reorganization and effect of pharmacological interventions. Furthermore, QST may help in optimizing the development programs for new drugs.

Specific translational mechanistic QST tools have been developed to quantify different aspects of central sensitization in pain patients such as threshold ratios, provoked hyperalgesia/allodynia, temporal summation (wind-up like pain), after sensation, spatial summation, reflex receptive fields, descending pain modulation, offset analgesia, and referred pain areas. As most of the drug development programs in the area of pain management have not been very successful, the pharmaceutical industry has started to utilize the complementary knowledge obtained from QST profiling. Linking patients QST profile with drug efficacy profile may provide the fundamentals for developing individualized, targeted pain management programs in the future. Linking QST-assessed pain mechanisms with treatment outcome provides new valuable information in drug development and for optimizing the management regimes for chronic pain.


Pain assessment Quantitative sensory testing Spreading sensitization 


Conflict of Interest

No conflict of interest can be reported.


  1. Andersen OK, Sonnenborg FA, Arendt-Nielsen L (2001) Reflex receptive fields for human withdrawal reflexes elicited by non-painful and painful electrical stimulation of the foot sole. Clin Neurophysiol 112(4):641–649PubMedGoogle Scholar
  2. Andersen OK, Finnerup NB, Spaich EG, Jensen TS, Arendt-Nielsen L (2004) Expansion of nociceptive withdrawal reflex receptive fields in spinal cord injured humans. Clin Neurophysiol 115(12):2798–2810PubMedGoogle Scholar
  3. Arendt-Nielsen L (1997) Induction and assessment of experimental pain from human skin, muscle and viscera. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z (eds) Proceedings of the 8th World Congress on pain, Vancouver, Canada, August 17–22: progress in pain research and management, vol 8. IASP Press, Seattle, pp 393–425Google Scholar
  4. Arendt-Nielsen L, Curatolo M (2013) Mechanistic, translational, quantitative pain assessment tools in profiling of pain patients and for development of new analgesic compounds. Scand J Pain 4(4):226–230Google Scholar
  5. Arendt-Nielsen L, Hoeck HC (2011) Optimizing the early phase development of new analgesics by human pain biomarkers. Expert Rev Neurother 11(11):1631–1651PubMedGoogle Scholar
  6. Arendt-Nielsen L, Yarnitsky D (2009) Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 10(6):556–572PubMedGoogle Scholar
  7. Arendt-Nielsen L, Brennum J, Sindrup SH, Bak P (1994) Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system. Eur J Appl Physiol Occup Physiol 68:266–273PubMedGoogle Scholar
  8. Arendt-Nielsen L, Drewes AM, Hansen JB, Tage-Jensen U (1997a) Gut pain reactions in man: an experimental investigation using short and long duration transmucosal electrical stimulation. Pain 69(3):255–262PubMedGoogle Scholar
  9. Arendt-Nielsen L, Graven-Nielsen T, Svensson P, Jensen TS (1997b) Temporal summation in muscles and referred pain areas: an experimental human study. Muscle Nerve 20(10):1311–1313PubMedGoogle Scholar
  10. Arendt-Nielsen L, Frokjaer JB, Staahl C, Graven-Nielsen T, Huggins JP, Smart TS, Drewes AM (2007) Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth Pain Med 2(5):382–388Google Scholar
  11. Arendt-Nielsen L, Graven-Nielsen T (2008) Muscle pain: sensory implications and interaction with motor control. Clin J Pain 24(4):291–298PubMedGoogle Scholar
  12. Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T (2010) Sensitization in patients with painful knee osteoarthritis. Pain 149(3):573–581PubMedGoogle Scholar
  13. Arendt-Nielsen L, Andresen T, Malver LP, Oksche A, Mansikka H, Drewes AM (2012a) A double-blind, placebo-controlled study on the effect of buprenorphine and fentanyl on descending pain modulation: a human experimental study. Clin J Pain 28(7):623–627PubMedGoogle Scholar
  14. Arendt-Nielsen L, Graven-Nielsen T, Petrini L (2012b) Experimental human models and assessment of pain in non-pain conditions. In: Giamberardino MA, Jensen TS (eds) Pain comorbidities: understanding and treating the complex patient. IASP Press, Seattle, Chapter 3Google Scholar
  15. Atzeni F, Cazzola M, Benucci M, Di Franco M, Salaffi F, Sarzi-Puttini P (2011) Chronic widespread pain in the spectrum of rheumatological diseases. Best Pract Res Clin Rheumatol 25(2):165–171PubMedGoogle Scholar
  16. Aykanat V, Gentgall M, Briggs N, Williams D, Yap S, Rolan P (2012) Intradermal capsaicin as a neuropathic pain model in patients with unilateral sciatica. Br J Clin Pharmacol 73(1):37–45PubMedCentralPubMedGoogle Scholar
  17. Baba Y, Kohase H, Oono Y, Fujii-Abe K, Arendt-Nielsen L (2012) Effects of dexmedetomidine on conditioned pain modulation in humans. Eur J Pain 16(8):1137–1147PubMedGoogle Scholar
  18. Bajaj P, Bajaj P, Graven-Nielsen T, Arendt-Nielsen L (2001a) Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study. Pain 93(2):107–114PubMedGoogle Scholar
  19. Bajaj P, Graven-Nielsen T, Arendt-Nielsen L (2001b) Trigger points in patients with lower limb osteoarthritis. J Musculoskelet Pain 9:17–33Google Scholar
  20. Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L (2003) Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain 4(7):372–380PubMedGoogle Scholar
  21. Balasubramaniam R, de Leeuw R, Zhu H, Nickerson RB, Okeson JP, Carlson CR (2007) Prevalence of temporomandibular disorders in fibromyalgia and failed back syndrome patients: a blinded prospective comparison study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:204–216PubMedGoogle Scholar
  22. Banic B, Petersen-Felix S, Andersen OK, Radanov BP, Villiger PM, Arendt-Nielsen L, Curatolo M (2004) Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. Pain 107:7–15PubMedGoogle Scholar
  23. Baron R, Saguer M (1994) Axon-reflex reactions in affected and homologous contralateral skin after unilateral peripheral injury of thoracic segmental nerves in humans. Neurosci Lett 165(1–2):97–100PubMedGoogle Scholar
  24. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284PubMedCentralPubMedGoogle Scholar
  25. Benson S, Kattoor J, Wegner A, Hammes F, Reidick D, Grigoleit JS, Engler H, Oberbeck R, Schedlowski M, Elsenbruch S (2012) Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans. Pain 153(4):794–799PubMedGoogle Scholar
  26. Biurrun Manresa JA, Neziri AY, Curatolo M, Arendt-Nielsen L, Andersen OK (2013) Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain. Pain 154(8):1318–1324PubMedGoogle Scholar
  27. Bouhassira D, Gall O, Chitour D, Le Bars D (1995) Dorsal horn convergent neurones: negative feedback triggered by spatial summation of nociceptive afferents. Pain 62(2):195–200PubMedGoogle Scholar
  28. Bragdon EE, Light KC, Costello NL, Sigurdsson A, Bunting S, Bhalang K, Maixner W (2002) Group differences in pain modulation: pain-free women compared to pain-free men and to women with TMD. Pain 96:227–237PubMedGoogle Scholar
  29. Burstein R, Yarnitsky D, Goor-Aryeh I et al (2000) An association between migraine and cutaneous allodynia. Ann Neurol 47:614–624PubMedGoogle Scholar
  30. Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, Hargreaves R, Becerra L, Borsook D (2010) Thalamic sensitization transforms localized pain into widespread allodynia. Ann Neurol 68(1):81–91PubMedCentralPubMedGoogle Scholar
  31. Carli G, Suman AL, Biasi G, Marcolongo R (2002) Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 100:259–269PubMedGoogle Scholar
  32. Cavallone LF, Frey K, Montana MC, Joyal J, Regina KJ, Petersen KL, Gereau RW IV (2013) Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers. J Pain Res 6:771–784PubMedCentralPubMedGoogle Scholar
  33. Christidis N, Ioannidou K, Milosevic M, Segerdahl M, Ernberg M (2008) Changes of hypertonic saline-induced masseter muscle pain characteristics, by an infusion of the serotonin receptor type 3 antagonist granisetron. J Pain 9(10):892–901PubMedGoogle Scholar
  34. Crow M, Denk F, McMahon SB (2013) Genes and epigenetic processes as prospective pain targets. Genome Med 5(2):12PubMedCentralPubMedGoogle Scholar
  35. Daenen L, Nijs J, Cras P, Wouters K, Roussel N (2014) Changes in pain modulation occur soon after whiplash trauma but are not related to altered perception of distorted visual feedback. Pain Pract 14(7):588–598Google Scholar
  36. Davis MA, Ettinger WH, Neuhaus JM, Barclay JD, Segal MR (1992) Correlates of knee pain among US adults with and without radiographic knee osteoarthritis. J Rheumatol 19(12):1943–1949PubMedGoogle Scholar
  37. de Goeij M, van Eijk LT, Vanelderen P, Wilder-Smith OH, Vissers KC, van der Hoeven JG, Kox M, Scheffer GJ, Pickkers P (2013) Systemic inflammation decreases pain threshold in humans in vivo. PLoS One 8(12):e84159PubMedCentralPubMedGoogle Scholar
  38. Dimcevski G, Staahl C, Andersen SD, Thorsgaard N, Funch-Jensen P, Arendt-Nielsen L et al (2007) Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis. Pancreas 35(1):22–29PubMedGoogle Scholar
  39. Drewes AM, Petersen P, Qvist P, Nielsen J, Arendt-Nielsen L (1999) An experimental pain model based on electric stimulations of the colon mucosa. Scand J Gastroenterol 34(8):765–771PubMedGoogle Scholar
  40. Eide PK, Jørum E, Stubhaug A, Bremnes J, Breivik H (1994) Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine. A doubleblind, cross-over comparison with morphine and placebo. Pain 58:347–354PubMedGoogle Scholar
  41. Eisenberg E, Kleiser A, Dortort A, Haim T, Yarnitsky D (1998) The NMDA (N-methyl-D-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebo-controlled study. Eur J Pain 2(4):321–327PubMedGoogle Scholar
  42. Fernández Carnero J, Fernández-de-las-Peñas C, Sterling M, Souvlis T, Arendt-Nielsen L, Vicenzino B (2009a) Exploration of the extent of somato-sensory impairment in patients with unilateral lateral epicondylalgia. J Pain 10(11):1179–1185PubMedGoogle Scholar
  43. Fernández Carnero J, Fernández-de-las-Peñas C, De La Llave Rincón AI, Ge HY, Arendt-Nielsen L (2009b) Widespread mechanical pain hyper-sensitivity as sign of central sensitization in unilateral lateral epicondylalgia: a blinded, controlled study. Clin J Pain 2(7):555–561Google Scholar
  44. Fernández-de-las-Peñas C, Ge HY, Cuadrado ML, Madeleine P, Pareja JA, Arendt-Nielsen L (2008) Bilateral pressure pain sensitivity mapping of the temporalis muscle in chronic tension type headache. Headache 48(8):1067–1075PubMedGoogle Scholar
  45. Fernández-de-las-Peñas C, Galán del Río F, Fernández Carnero J, Pesquera J, Arendt-Nielsen L, Svensson P (2009) Bilateral widespread mechanical pain sensitivity in myofascial temporomandibular disorder: evidence of impairment in central nociceptive processing. J Pain 10(11):1170–1178PubMedGoogle Scholar
  46. Fernández-de-las-Peñas C, Galan-del-Rio F, Ortega-Santiago R, Jimenez-Garcia R, Arendt-Nielsen L, Svensson P (2010) Bilateral thermal hyperalgesia in trigeminal and extra-trigeminal regions in patients with myofascial temporomandibular disorders. Exp Brain Res 202:171–179PubMedGoogle Scholar
  47. Fillingim RB, Fillingim LA, Hollins M, Sigurdsson A, Maixner W (1998) Generalized vibrotactile allodynia in a patient with temporomandibular disorder. Pain 78:75–78PubMedGoogle Scholar
  48. Finnerup NB, Sindrup SH, Bach FW, Johannesen IL, Jensen TS (2002) Lamotrigine in spinal cord injury pain: a randomized controlled trial. Pain 96(3):375–383PubMedGoogle Scholar
  49. Foster DC, Dworkin RH, Wood RW (2005) Effects of intradermal foot and forearm capsaicin injections in normal and vulvodynia-afflicted women. Pain 117:128–136PubMedGoogle Scholar
  50. Geber C, Klein T, Azad S, Birklein F, Gierthmühlen J, Huge V, Lauchart M, Nitzsche D, Stengel M, Valet M, Baron R, Maier C, Tölle T, Treede RD (2011) Test-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): a multi-centre study. Pain 152(3):548–556PubMedGoogle Scholar
  51. Giamberardino MA (2003) Referred muscle pain/hyperalgesia and central sensitisation. J Rehabil Med 41(Suppl):85–88PubMedGoogle Scholar
  52. Giamberardino MA, de Bigontina P, Martegiani C, Vecchiet L (1994) Effects of extracorporeal shock-wave lithotripsy on referred hyperalgesia from renal/ureteral calculosis. Pain 56(1):77–83PubMedGoogle Scholar
  53. Giamberardino MA, Costantini R, Affaitati G, Fabrizio A, Lapenna D, Tafuri E, Mezzetti A (2010) Viscero-visceral hyperalgesia: characterization in different clinical models. Pain 151(2):307–322PubMedGoogle Scholar
  54. Gottrup H, Kristensen AD, Bach FW, Jensen TS (2003) Aftersensations in experimental and clinical hypersensitivity. Pain 103(1–2):57–64PubMedGoogle Scholar
  55. Graven-Nielsen T, Aspegren Kendall S, Henriksson KG, Bengtsson M, Sörensen J, Johnson A, Gerdle B, Arendt-Nielsen L (2000) Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 85(3):483–491PubMedGoogle Scholar
  56. Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL (2012) Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 64(9):2907–2916PubMedGoogle Scholar
  57. Grill JD, Coghill RC (2002) Transient analgesia evoked by noxious stimulus offset. J Neurophysiol 87:2205–2208PubMedGoogle Scholar
  58. Haanpää M (2011) Are neuropathic pain screening tools useful for patients with spinal cord injury? Pain 152:715–716PubMedGoogle Scholar
  59. Hannan MT, Felson DT, Pincus T (2000) Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J Rheumatol 27(6):1513–1517PubMedGoogle Scholar
  60. Harris J, Clarke RW (2003) Organisation of sensitisation of hind limb withdrawal reflexes from acute noxious stimuli in the rabbit. J Physiol 546:251–265PubMedCentralPubMedGoogle Scholar
  61. Hayes AG, Arendt-Nielsen L, Tate S (2014) Multiple mechanisms have been tested in pain—how can we improve the chances of success? Curr Opin Pharmacol 14:11–17PubMedGoogle Scholar
  62. Herren-Gerber R, Weiss S, Arendt-Nielsen L, Petersen-Felix S, Di Stefano G, Radanov BP, Curatolo M (2004) Modulation of central hypersensitivity by nociceptive input in chronic pain after whiplash injury. Pain Med 5(4):366–376PubMedGoogle Scholar
  63. Holm LW, Carroll LJ, Cassidy JD, Skillgate E, Ahlbom A (2007) Widespread pain following whiplash-associated disorders: incidence, course, and risk factors. J Rheumatol 34:193–200PubMedGoogle Scholar
  64. Holst H, Arendt-Nielsen L, Mosbech H, Elberling J (2011) Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity. Clin J Pain 27(2):156–162PubMedGoogle Scholar
  65. Honigman L, Yarnitsky D, Sprecher E, Weissman-Fogel I (2013) Psychophysical testing of spatial and temporal dimensions of endogenous analgesia: conditioned pain modulation and offset analgesia. Exp Brain Res 228(4):493–501PubMedGoogle Scholar
  66. Hutchinson MR, Buijs M, Tuke J, Kwok YH, Gentgall M, Williams D, Rolan P (2013) Low-dose endotoxin potentiates capsaicin-induced pain in man: evidence for a pain neuroimmune connection. Brain Behav Immun 30:3–11PubMedGoogle Scholar
  67. Jensen TS, Baron R (2002) Translation of symptoms and signs into mechanisms in neuropathic pain: topical review. Pain 102:1–8Google Scholar
  68. Jespersen A, Amris K, Graven-Nielsen T, Arendt-Nielsen L, Bartels EM, Torp-Pedersen S, Bliddal H, Danneskiold-Samsoe B (2013) Assessment of pressure-pain thresholds and central sensitization of pain in lateral epicondylalgia. Pain Med 14(2):297–304PubMedGoogle Scholar
  69. John MT, Miglioretti DL, LeResche L, Von Korff M, Critchlow CW (2003) Widespread pain as a risk factor for dysfunctional temporomandibular disorder pain. Pain 102:257–263PubMedGoogle Scholar
  70. Koelbaek Johansen M, Graven-Nielsen T, Olesen AS, Arendt-Nielsen L (1999) Generalised muscular hyperalgesia in chronic whiplash syndrome. Pain 83(2):229–234PubMedGoogle Scholar
  71. Kong JT, Johnson KA, Balise RR, Mackey S (2013) Test-retest reliability of thermal temporal summation using an individualized protocol. J Pain 14(1):79–88PubMedCentralPubMedGoogle Scholar
  72. Konopka KH, Harbers M, Houghton A, Kortekaas R, van Vliet A, Timmerman W, den Boer JA, Struys MM, van Wijhe M (2012) Bilateral sensory abnormalities in patients with unilateral neuropathic pain: a quantitative sensory testing (QST) study. PLoS One 7(5):e37524PubMedCentralPubMedGoogle Scholar
  73. Kosek E, Hansson P (1997) Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain 70:41–51PubMedGoogle Scholar
  74. Kosek E, Ordeberg G (2000) Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 88:69–78PubMedGoogle Scholar
  75. Kozin F, McCarty SJ, Sims J, Genant H (1976) The reflex sympathetic dystrophy syndrome. Am J Med 60:320–337Google Scholar
  76. Lapossy E, Maleitzke R, Hrycaj P, Mennet W, Muller W (1995) The frequency of transition of chronic low back pain to fibromyalgia. Scand J Rheumatol 24:29–33PubMedGoogle Scholar
  77. Laursen BS, Bajaj P, Olesen AS, Delmar C, Arendt-Nielsen L (2005) Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain. Eur J Pain 9:267–275PubMedGoogle Scholar
  78. Leblebici B, Pektas ZO, Ortancil O, Hurcan EC, Bagis S, Akman MN (2007) Coexistence of fibromyalgia, temporomandibular disorder, and masticatory myofascial pain syndromes. Rheumatol Int 7:541–544Google Scholar
  79. Lecybyl R, Acosta J, Ghoshdastidar J, Stringfellow K, Hanna M (2010) Validation, reproducibility and safety of trans dermal electrical stimulation in chronic pain patients and healthy volunteers. BMC Neurol 10:5PubMedCentralPubMedGoogle Scholar
  80. Lee J, Ellis B, Price C, Baranowski AP (2014) Chronic widespread pain, including fibromyalgia: a pathway for care developed by the British Pain Society. Br J Anaesth 112(1):16–24PubMedGoogle Scholar
  81. Lemming D, Graven-Nielsen T, Sörensen J, Arendt-Nielsen L, Gerdle B (2012) Widespread pain hypersensitivity and facilitated temporal summation of deep tissue pain in whiplash associated disorder: an explorative study of women. J Rehabil Med 44(8):648–657PubMedGoogle Scholar
  82. Macfarlane GJ (1999) Generalized pain, fibromyalgia and regional pain: an epidemiological view. Baillieres Best Pract Res Clin Rheumatol 13:403–414PubMedGoogle Scholar
  83. Magerl W, Krumova EK, Baron R, Tölle T, Treede RD, Maier C (2010) Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain 151(3):598–605PubMedGoogle Scholar
  84. Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, Gierthmühlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihöfner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uçeyler N, Valet M, Wasner G, Treede RD (2010) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 150(3):439–450PubMedGoogle Scholar
  85. Malan TP, Ossipov MH, Gardell LR, Ibrahim M, Bian D, Lai J, Porreca F (2000) Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats. Pain 86(1–2):185–194PubMedGoogle Scholar
  86. Martucci KT, Eisenach JC, Tong C, Coghill RC (2012a) Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information. Pain 153(6):1232–1243PubMedCentralPubMedGoogle Scholar
  87. Martucci KT, Yelle MD, Coghill RC (2012b) Differential effects of experimental central sensitization on the time-course and magnitude of offset analgesia. Pain 153(2):463–472PubMedCentralPubMedGoogle Scholar
  88. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36PubMedCentralPubMedGoogle Scholar
  89. Miranda A, Peles S, Rudolph C, Shaker R, Sengupta JN (2004) Altered visceral sensation in response to somatic pain in the rat. Gastroenterology 126(4):1082–1089PubMedGoogle Scholar
  90. Morris VH, Cruwys SC, Kidd BL (1997) Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis. Pain 71:179–186PubMedGoogle Scholar
  91. Morris V, Cruwys S, Kidd B (1998) Increased capsaicin-induced secondary hyperalgesia as a marker of abnormal sensory activity in patients with fibromyalgia. Neurosci Lett 250(3):205–207PubMedGoogle Scholar
  92. Mourão AF, Blyth FM, Branco JC (2010) Generalised musculoskeletal pain syndromes. Best Pract Res Clin Rheumatol 24(6):829–840PubMedGoogle Scholar
  93. Naugle KM, Cruz-Almeida Y, Fillingim RB, Riley JL III (2013) Offset analgesia is reduced in older adults. Pain 154(11):2381–2387PubMedCentralPubMedGoogle Scholar
  94. Neogi T, Felson D, Niu J, Nevitt M, Lewis CE, Aliabadi P, Sack B, Torner J, Bradley L, Zhang Y (2009) Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ 339:b2844PubMedCentralPubMedGoogle Scholar
  95. Ness TJ, Lloyd LK, Fillingim RB (2014) An endogenous pain control system is altered in subjects with interstitial cystitis. J Urol 191(2):364–370PubMedGoogle Scholar
  96. Neziri AY, Haesler S, Petersen-Felix S, Müller M, Arendt-Nielsen L, Manresa JB, Andersen OK, Curatolo M (2010) Generalized expansion of nociceptive reflex receptive fields in chronic pain patients. Pain 151(3):798–805PubMedGoogle Scholar
  97. Neziri AY, Scaramozzino P, Andersen OK, Dickenson AH, Arendt-Nielsen L, Curatolo M (2011) Reference values of mechanical and thermal pain tests in a pain-free population. Eur J Pain 15(4):376–383PubMedGoogle Scholar
  98. Neziri AY, Dickenmann M, Scaramozzino P, Andersen OK, Arendt-Nielsen L, Dickenson AH, Curatolo M (2012) Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients. Pain 153(2):311–318PubMedGoogle Scholar
  99. Nie H, Graven-Nielsen T, Arendt-Nielsen L (2009) Spatial and temporal summation of pain evoked by mechanical pressure stimulation. Eur J Pain 13(6):592–599PubMedGoogle Scholar
  100. Nielsen J, Arendt-Nielsen L (1997) Spatial summation of heat induced pain within and between dermatomes. Somatosens Mot Res 14(2):119–125PubMedGoogle Scholar
  101. Niesters M, Hoitsma E, Sarton E, Aarts L, Dahan A (2011a) Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine. Anesthesiology 115(5):1063–1071PubMedGoogle Scholar
  102. Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim RB, Aarts L, Sarton EY (2011b) Effect of ketamine on endogenous pain modulation in healthy volunteers. Pain 152(3):656–663PubMedGoogle Scholar
  103. Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS (1996) The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 67(1):69–77PubMedGoogle Scholar
  104. Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS (2000) Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth Analg 91(4):960–966PubMedGoogle Scholar
  105. Nilsson M, Piasco A, Nissen TD, Graversen C, Gazerani P, Lucas MF, Dahan A, Drewes AM, Brock C (2013) Reproducibility of psychophysics and electroencephalography during offset analgesia. Eur J Pain 18(6):824–834PubMedGoogle Scholar
  106. Nishimura I, Thakor D, Lin A, Ruangsri S, Spigelman I (2010) Molecular strategies for therapeutic targeting of primary sensory neurons in chronic pain syndromes. In: Kruger L, Light AR (eds) Translational pain research: from mouse to man. CRC, Boca Raton, Chapter 6Google Scholar
  107. O’Neill S, Manniche C, Graven-Nielsen T, Arendt-Nielsen L (2007) Generalized deep-tissue hyperalgesia in patients with chronic low-back pain. Eur J Pain 11(4):415–420PubMedGoogle Scholar
  108. Oertel BG, Lötsch J (2013) Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research. Br J Pharmacol 168(3):534–553PubMedCentralPubMedGoogle Scholar
  109. Peters ML, Schmidt AJ, Van den Hout MA, Koopmans R, Sluijter ME (1992) Chronic back pain, acute postoperative pain and the activation of diffuse noxious inhibitory controls (DNIC). Pain 50:177–187PubMedGoogle Scholar
  110. Petersen KL, Fields HL, Brennum J, Sandroni P, Rowbotham MC (2000) Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 88:125–133PubMedGoogle Scholar
  111. Piché M, Arsenault M, Poitras P, Rainville P, Bouin M (2010) Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome. Pain 148(1):49–58PubMedGoogle Scholar
  112. Polianskis R, Graven-Nielsen T, Arendt-Nielsen L (2002) Spatial and temporal aspects of deep tissue pain assessed by cuff algometry. Pain 100:19–26PubMedGoogle Scholar
  113. Porreca F, Ossipov MH, Gebhart GF (2002) Chronic pain and medullary descending facilitation. Trends Neurosci 25:319–325PubMedGoogle Scholar
  114. Price DD, Hayes RL, Ruda M, Dubner R (1978) Neural representation of cutaneous aftersensations by spinothalamic tract neurons. Fed Proc 37(9):2237–2239PubMedGoogle Scholar
  115. Pud D, Eisenberg E, Spitzer A, Adler R, Fried G, Yarnitsky D (1998) The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 75:349–354PubMedGoogle Scholar
  116. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW (2004) Therapeutic outcome in neuropathic pain: relationship to evidence of nervous system lesion. Eur J Neurol 11(8):545–553PubMedGoogle Scholar
  117. Richards N, McMahon SB (2013) Targeting novel peripheral mediators for the treatment of chronic pain. Br J Anaesth 111(1):46–51PubMedGoogle Scholar
  118. Robinson ME, Bialosky JE, Bishop MD, Price DD, George SZ (2010) Supra-threshold scaling, temporal summation, and after-sensation: relationships to each other and anxiety/fear. J Pain Res 3:25–32PubMedCentralPubMedGoogle Scholar
  119. Rolke R, Baron R, Maier C, Tölle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Bötefür IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihöfner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B (2006a) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123(3):231–243PubMedGoogle Scholar
  120. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede RD (2006b) Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain 10(1):77–88PubMedGoogle Scholar
  121. Sandkühler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89(2):707–758PubMedGoogle Scholar
  122. Sandrini G, Rossi P, Milanov I, Serrao M, Cecchini AP, Nappi G (2006) Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients. Cephalalgia 26:782–789PubMedGoogle Scholar
  123. Sarzi-Puttini P, Atzeni F, Mease PJ (2011) Chronic widespread pain: from peripheral to central evolution. Best Pract Res Clin Rheumatol 25(2):133–139PubMedGoogle Scholar
  124. Sato H, Saisu H, Muraoka W, Nakagawa T, Svensson P, Wajima K (2012) Lack of temporal summation but distinct aftersensations to thermal stimulation in patients with combined tension-type headache and myofascial temporomandibular disorder. J Orofac Pain 26(4):288–295PubMedGoogle Scholar
  125. Schliessbach J, Siegenthaler A, Streitberger K, Eichenberger U, Nüesch E, Jüni P, Arendt-Nielsen L, Curatolo M (2013) The prevalence of widespread central hypersensitivity in chronic pain patients. Eur J Pain 17(10):1502–1510PubMedGoogle Scholar
  126. Schneider GM, Smith AD, Hooper A, Stratford P, Schneider KJ, Westaway MD, Frizzell B, Olson L (2010) Minimizing the source of nociception and its concurrent effect on sensory hypersensitivity: an exploratory study in chronic whiplash patients. BMC Musculoskelet Disord 11:29PubMedCentralPubMedGoogle Scholar
  127. Schomberg D, Olson JK (2012) Immune responses of microglia in the spinal cord: contribution to pain states. Exp Neurol 234:262–270PubMedGoogle Scholar
  128. Schouenborg J, Weng HR, Holmberg H (1994) Modular organization of spinal reflexes: a new hypothesis. NIPS 9:261–265Google Scholar
  129. Schouenborg J, Weng H-R, Kalliomäki J, Holmberg H (1995) A survey of spinal dorsal horn neurones encoding the spinal organization of withdrawal reflexes in the rat. Exp Brain Res 106:19–27PubMedGoogle Scholar
  130. Schulte H, Segerdahl M, Graven-Nielsen T, Grass S (2006) Reduction of human experimental muscle pain by alfentanil and morphine. Eur J Pain 10(8):733–741PubMedGoogle Scholar
  131. Scott D, Jull G, Sterling M (2005) Widespread sensory hypersensitivity is a feature of chronic whiplash-associated disorder but not chronic idiopathic neck pain. Clin J Pain 21:175–181PubMedGoogle Scholar
  132. Shimada A, Cairns BE, Vad N, Ulriksen K, Pedersen AM, Svensson P, Baad-Hansen L (2013) Headache and mechanical sensitization of human pericranial muscles after repeated intake of monosodium glutamate (MSG). J Headache Pain 14(1):2PubMedCentralPubMedGoogle Scholar
  133. Skou ST, Graven-Nielsen T, Rasmussen S, Simonsen OH, Laursen MB, Arendt-Nielsen L (2013) Widespread sensitization in patients with chronic pain after revision total knee arthroplasty. Pain 154(9):1588–1594PubMedGoogle Scholar
  134. Smith SB, Maixner DW, Greenspan JD, Dubner R, Fillingim RB, Ohrbach R, Knott C, Slade GD, Bair E, Gibson DG, Zaykin DV, Weir BS, Maixner W, Diatchenko L (2011) Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J Pain 12(11 Suppl):T92–T101PubMedCentralPubMedGoogle Scholar
  135. Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, Zaykin DV, Hyde C, John S, Tan K, Maixner W, Diatchenko L (2012) Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. Arthritis Rheum 64(2):584–593PubMedCentralPubMedGoogle Scholar
  136. Sorensen J, Graven-Nielsen T, Henriksson KG, Bengtsson M, Arendt-Nielsen L (1998) Hyperexcitability in fibromyalgia. J Rheumatol 25(1):152–155PubMedGoogle Scholar
  137. Staud R (2011) Peripheral pain mechanisms in chronic widespread pain. Best Pract Res Clin Rheumatol 25(2):155–164PubMedCentralPubMedGoogle Scholar
  138. Staud R (2012) Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions. Expert Rev Neurother 12(5):577–585PubMedCentralPubMedGoogle Scholar
  139. Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck CJ Jr (2003) Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 102(1–2):87–95PubMedGoogle Scholar
  140. Staud R, Vierck CJ, Robinson ME, Price DD (2004) Spatial summation of heat pain within and across dermatomes in fibromyalgia patients and pain-free subjects. Pain 111(3):342–350PubMedGoogle Scholar
  141. Staud R, Koo E, Robinson ME, Price DD (2007) Spatial summation of mechanically evoked muscle pain and painful aftersensations in normal subjects and fibromyalgia patients. Pain 130(1–2):177–187PubMedCentralPubMedGoogle Scholar
  142. Stawowy M, Rössel P, Bluhme C, Funch-Jensen P, Arendt-Nielsen L, Drewes AM (2002) Somatosensory changes in the referred pain area following acute inflammation of the appendix. Eur J Gastroenterol Hepatol 14(10):1079–1084PubMedGoogle Scholar
  143. Stawowy M, Funch-Jensen P, Arendt-Nielsen L, Drewes AM (2005) Somatosensory changes in the referred pain area in patients with cholecystolithiasis. Eur J Gastroenterol Hepatol 17(8):865–870PubMedGoogle Scholar
  144. Stiasny-Kolster K, Pfau DB, Oertel WH, Treede RD, Magerl W (2013) Hyperalgesia and functional sensory loss in restless legs syndrome. Pain 154(8):1457–1463PubMedGoogle Scholar
  145. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A (1997) Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 41:1124–1132PubMedGoogle Scholar
  146. Sumracki NM, Hutchinson MR, Gentgall M, Briggs N, Williams DB, Rolan P (2012) The effects of pregabalin and the glial attenuator minocycline on the response to intradermal capsaicin in patients with unilateral sciatica. PLoS One 7(6):e3852Google Scholar
  147. Suzan E, Midbari A, Treister R, Haddad M, Pud D, Eisenberg E (2013) Oxycodone alters temporal summation but not conditioned pain modulation: preclinical findings and possible relations to mechanisms of opioid analgesia. Pain 154(8):1413–1418PubMedGoogle Scholar
  148. Suzuki R, Rygh LJ, Dickenson AH (2004) Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci 25(12):613–617PubMedGoogle Scholar
  149. Swarbrick ET, Hegarty JE, Bat L, Williams CB, Dawson AM (1980) Site of pain from the irritable bowel. Lancet 2(8192):443–446PubMedGoogle Scholar
  150. Thompson LR, Boudreau R, Newman AB, Hannon MJ, Chu CR, Nevitt MC, Kent Kwoh C, OAI Investigators (2010) The association of osteoarthritis risk factors with localized, regional and diffuse knee pain. Osteoarthritis Cartilage 18(10):1244–1249PubMedCentralPubMedGoogle Scholar
  151. Treister R, Pud D, Eisenberg E (2013) The dopamine agonist apomorphine enhances conditioned pain modulation in healthy humans. Neurosci Lett 548:115–119PubMedGoogle Scholar
  152. van Rijn MA, Marinus J, Putter H, Bosselaar SR, Moseley GL, van Hilten JJ (2011) Spreading of complex regional pain syndrome: not a random process. J Neural Transm 118(9):1301–1309PubMedCentralPubMedGoogle Scholar
  153. Veldman PH, Goris RJ (1996) Multiple reflex sympathetic dystrophy. Which patients are at risk for developing a recurrence of reflex sympathetic dystrophy in the same or another limb. Pain 64:463–466PubMedGoogle Scholar
  154. Werner MU, Petersen KL, Rowbotham MC, Dahl JB (2013) Healthy volunteers can be phenotyped using cutaneous sensitization pain models. PLoS One 8(5):e62733PubMedCentralPubMedGoogle Scholar
  155. Xu YM, Ge HY, Arendt-Nielsen L (2010) Sustained nociceptive mechanical stimulation of latent myofascial trigger point induces central sensitization in healthy subjects. J Pain 11(12):1348–1355PubMedGoogle Scholar
  156. Yarnitsky D, Arendt-Nielsen L, Bouhassira D, Edwards RR, Fillingim RB, Granot M, Hansson P, Lautenbacher S, Marchand S, Wilder-Smith O (2010) Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14(4):339PubMedGoogle Scholar
  157. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y (2012) Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 153(6):1193–1198PubMedGoogle Scholar
  158. Yelle MD, Rogers JM, Coghill RC (2008) Offset analgesia: a temporal contrast mechanism for nociceptive information. Pain 134:174–186PubMedCentralPubMedGoogle Scholar
  159. You HJ, Colpaert FC, Arendt-Nielsen L (2005) The novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 inhibits nociceptive responses, wind-up, and after-discharges in spinal neurons and withdrawal reflexes. Exp Neurol 191(1):174–183PubMedGoogle Scholar
  160. You HJ, Lei J, Sui MY, Huang L, Tan YX, Tjølsen A, Arendt-Nielsen L (2010) Endogenous descending modulation: spatiotemporal effect of dynamic imbalance between descending facilitation and inhibition of nociception. J Physiol 588(Pt 21):4177–4188PubMedCentralPubMedGoogle Scholar
  161. Zakrzewska JM (2013) Multi-dimensionality of chronic pain of the oral cavity and face. J Headache Pain 14:37–46PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Center for Sensory-Motor Interaction (SMI), Department of Health Science and TechnologySchool of Medicine, Aalborg UniversityAalborgDenmark

Personalised recommendations