Skip to main content
Log in

Central sensitization in fibromyalgia and other musculoskeletal disorders

  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Muscle hyperalgesia and referred pain play an important role in chronic musculoskeletal pain. New knowledge on the involved basic mechanisms and better methods to assess muscle pain in the clinic are needed to revise and optimize treatment regimens. Increased muscle sensitivity is manifested as pain evoked by a normally non-nociceptive stimulus (allodynia), increased pain intensity evoked by nociceptive stimuli (hyperalgesia), or increased referred pain areas with associated somatosensory changes. Some manifestations of sensitization, such as expanded referred muscle pain areas in patients with chronic musculoskeletal pain, can be explained from animal experiments showing extrasegmental spread of sensitization. An important part of the pain manifestations (eg, tenderness and referred pain) related to chronic musculoskeletal disorders may result from peripheral and central sensitization, which may play a role in the transition from acute to chronic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Kellgren JH: Observation on referred pain arising from muscle. Clin Sci 1938, 3:175–190.

    Google Scholar 

  2. Mense S: Referral of muscle pain. APS J 1994, 3:1–9.

    Article  Google Scholar 

  3. Marchettini P, Simone DA, Caputi G, Ochoa JL: Pain from excitation of identified muscle nociceptors in humans. Brain Res 1996, 740:109–116.

    Article  PubMed  CAS  Google Scholar 

  4. Simone DA, Marchettini P, Caputi G, Ochoa JL: Identification of muscle afferents subserving sensation of deep pain in humans. J Neurophysiol 1994, 72:883–889.

    PubMed  CAS  Google Scholar 

  5. Bendtsen L, Jensen R, Olesen J: Qualitatively altered nociception in chronic myofascial pain. Pain 1996, 65:259–264.

    Article  PubMed  CAS  Google Scholar 

  6. Kosek E, Ekholm J, Hansson P: Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls. Pain 1996, 64:415–423.

    Article  PubMed  CAS  Google Scholar 

  7. Lautenbacher S, Rollman GB, McCain GA: Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain 1994, 59:45–53.

    Article  PubMed  CAS  Google Scholar 

  8. Nørregaard J, Bendtsen L, Lykkegaard J, Jensen R: Pressure and heat pain thresholds and tolerances in patients with fibromyalgia. J Musculoskel Pain 1997, 5:43–53.

    Article  Google Scholar 

  9. Sörensen J, Bengtsson A, Ahlner J, et al.: Fibromyalgia: Are there different mechanisms in the processing of pain? A double-blind crossover comparison of analgesic drugs. J Rheumatol 1997, 24:1615–1621.

    PubMed  Google Scholar 

  10. Svensson P, Arendt-Nielsen L, Nielsen H, Larsen JK: Effect of chronic and experimental jaw muscle pain on pain-pressure thresholds and stimulus-response curves. J Orofac Pain 1995, 9:347–356.

    PubMed  CAS  Google Scholar 

  11. Vecchiet L, Giamberardino MA, de Bigontina P, Dragani L: Comparative sensory evaluation of parietal tissues in painful and nonpainful areas in fibromyalgia and myofascial pain syndrome. In Proceedings of the 7th World Congress on Pain. Edited by Gebhart GF, Hammond DL, Jensen TS. Seattle: IASP Press; 1994:177–185.

    Google Scholar 

  12. Vecchiet L, Giamberardino MA, Saggini R: Myofascial pain syndromes: clinical and pathophysiological aspects. Clin J Pain 1991, 7:16–22.

    Google Scholar 

  13. Gibson SJ, Littlejohn GO, Gorman MM, et al.: Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome. Pain 1994, 58:185–193.

    Article  PubMed  CAS  Google Scholar 

  14. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: Referred pain is dependent on sensory input from the periphery: a psychophysical study. Eur J Pain 1997, 1:261–269.

    Article  PubMed  CAS  Google Scholar 

  15. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: The effect of compression and regional anaesthetic block on referred pain intensity in humans. Pain 1999, 80:257–263. Determines to which degree referred pain is dependent on peripheral or central mechanisms by blocking sensory input from the referred pain area. Despite the regional anesthesia, referred pain was still present, although the referred pain intensity was decreased. Thus, referred pain is based mainly on a central mechanism and partly dependant on peripheral sensory input.

    Article  PubMed  CAS  Google Scholar 

  16. Head H: On disturbances of sensation with especial reference to the pain of visceral disease. Brain 1893, 16:1–136.

    Article  Google Scholar 

  17. Bonica JJ: General considerations of acute pain. In The Management of Pain, edn 2. Edited by Bonica JJ. Philadelphia and London: Lea & Febiger; 1990:159–179.

    Google Scholar 

  18. Lewis T: Suggestions relating to the study of somatic pain. BMJ 1938, 1:321–325.

    Article  PubMed  Google Scholar 

  19. Inman VT, Saunders JB: Referred pain from skeletal structures. J Nerv Ment Dis 1944, 99:660–667.

    Article  Google Scholar 

  20. Foerster O: The dermatomes in man. Brain 1933, 56:1–39.

    Article  Google Scholar 

  21. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS: Stimulus-response functions in areas with experimentally induced referred muscle pain: a psychophysical study. Brain Res 1997, 744:121–128.

    Article  PubMed  CAS  Google Scholar 

  22. Leffler AS, Kosek E, Hansson P: Injection of hypertonic saline into musculus infraspinatus resulted in referred pain and sensory disturbances in the ipsilateral upper arm. Eur J Pain 2000, 4:73–82.

    Article  PubMed  CAS  Google Scholar 

  23. Tuveson B, Lindblom B, Fruhstorfer H: Experimental muscle pain and sensory changes at the site of referred pain. Proceedings of the SASP 22nd Annual Meeting. Reykjavik, Iceland: UtgSted; 1999:77.

    Google Scholar 

  24. Witting N, Svensson P, Gottrup H, et al.: Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain. Pain 2000, 84:407–412.

    Article  PubMed  CAS  Google Scholar 

  25. Babenko V, Graven-Nielsen T, Svensson P, et al.: Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and bradykinin. Pain 1999, 82:1–8.

    Article  PubMed  CAS  Google Scholar 

  26. Bhave G, Karim F, Carlton SM, Gereau RW: Peripheral group I metabotropic glutamate receptors modulate nociception in mice. Nat Neurosci 2001, 4:417–423.

    Article  PubMed  CAS  Google Scholar 

  27. Carlton SM, Hargett GL, Coggeshall RE: Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neuroscience Lett 1995, 197:25–28.

    Article  CAS  Google Scholar 

  28. Cairns BE, Hu JW, Arendt-Nielsen L, et al.: Human pain perception and rat afferent discharge evoked by injection of glutamate into the masseter muscle: evidence of sex-related differences. J Neurophysiol 2001, 86:782–791.

    PubMed  CAS  Google Scholar 

  29. Carlton SM, Shou S, Coggeshall RE: Evidence for the interaction of glutamate and NK1 receptors in the periphery. Brain Res 1998, 790:160–169.

    Article  PubMed  CAS  Google Scholar 

  30. Vecchiet L, Galletti R, Giamberardino MA, et al.: Modifications of cutaneous, subcutaneous and muscular sensory and pain thresholds after the induction of an experimental allgogenic focus in the skeletal muscle. Clin J Pain 1988, 4:55–59.

    Article  Google Scholar 

  31. Asmussen E: Observations on experimental muscular soreness. Acta Rheumatol Scand 1956, 2:109–116.

    PubMed  CAS  Google Scholar 

  32. Bajaj P, Graven-Nielsen T, Arendt-Nielsen L: Post-exercise muscle soreness after eccentric exercise: psychophysical effects and implications on mean arterial pressure. Scand J Med Sci Sports 2001, 11:266–273.

    Article  PubMed  CAS  Google Scholar 

  33. Howell JN, Chleboun G, Conatser R: Muscle stiffness, strength loss, swelling and soreness following exercise-induced injury in humans. J Physiol (Lond) 1993, 464:183–196.

    CAS  Google Scholar 

  34. Newham DJ: The consequences of eccentric contractions and their relation to delayed onset muscle pain. Eur J Appl Physiol 1988, 57:353–359.

    Article  CAS  Google Scholar 

  35. Vecchiet L, Giamberardino MA, Marini I: Immediate muscular pain from physical activity. In Pain and Mobility. Edited by Tiengo M, Eccles J, Cuello AC, Ottoson D. New York: Raven Press; 1987:193–218.

    Google Scholar 

  36. Slater H, Arendt-Nielsen L, Wright A, Graven-Nielsen T: Deep tissue pain in wrist extensors: a model of lateral epicondylalgia. Proceedings of the Myopain World Congress. Portland: September 9–13, 2001.

  37. Fischer AA: Muscle Pain Syndromes and Fibromyalgia: Pressure Algometry for Quantification of Diagnosis and Treatment Outcome. New York: Haworth Medical Press; 1998:1–158.

    Google Scholar 

  38. Gracely RH, Reid KI: Orofacial pain measurement. In Orofacial Pain and Temporomandibular Disorders: Advances in Pain Research and Therapy, vol 21. Edited by Fricton JR, Dubner R. New York: Raven Press; 1995:117–143.

    Google Scholar 

  39. Jensen K: Quantification of Tenderness by palpation and use of pressure algometers. Advances in Pain Research and Therapy. New York: Raven Press Ltd; 1990:165–180.

    Google Scholar 

  40. Goulet J-P, Clark GT, Flack VF, Liu C: The reproducibility of muscle and joint tenderness detection methods and maximum mandibular movement measurement for the temporomandibular system. J Orofacial Pain 1998, 12:17–26.

    PubMed  CAS  Google Scholar 

  41. Isselee H, De Laat A, Bogaerts K, Lysens R: Short-term reproducibility of pressure pain thresholds in masticatory muscles measured with a new algometer. J Orofacial Pain 1998, 12:203–209.

    PubMed  CAS  Google Scholar 

  42. Jensen K, Andersen HØ, Olesen J, Lindblom U: Pressure-pain threshold in human temporal region: evaluation of a new pressure algometer. Pain 1986, 25:313–323.

    Article  PubMed  CAS  Google Scholar 

  43. List T, Helkimo M, Karlsson R: Influence of pressure rates on the reliability of a pressure threshold meter. J Craniomandib Disord 1991, 5:173–178.

    PubMed  CAS  Google Scholar 

  44. Ohrbach R, Gale EN: Pressure pain thresholds in normal muscles: reliability, measurement effects and topographic differences. Pain 1989, 37:257–263.

    Article  PubMed  CAS  Google Scholar 

  45. Reeves JL, Jaeger B, Graff-Radford SB: Reliability of the pressure algometer as a measure of myofascial trigger point sensitivity. Pain 1986, 24:313–321.

    Article  PubMed  CAS  Google Scholar 

  46. Lavigne GJ, Thon MT, Rompré P, et al.: Sensory descriptors from touch to pressure-pain and experimental variables: a psychophysiological study in humans on pressure-pain threshold. Proceedings of the 7th World Congress on Pain: Progress in Pain Research and Management, vol 2. Edited by Gebhart GF, Hammond DL, Jensen TS. Seattle: IASP Press; 1994:831–842.

    Google Scholar 

  47. McMillan AS, Lawson ET: Effect of tooth clenching and jaw opening on pain-pressure thresholds in the human jaw muscles. J Orofacial Pain 1994, 8:250–257.

    PubMed  CAS  Google Scholar 

  48. Ohrbach R, Crow H, Kamer A: Examiner expectancy effects in the measurement of pressure pain thresholds. Pain 1998, 74:163–170.

    Article  PubMed  CAS  Google Scholar 

  49. Polianskis R, Graven-Nielsen T, Arendt-Nielsen L: Pressurepain function in desensitized and hypersensitized muscle and skin assessed by cuff algometry. J Pain 2002, 3:28–37.

    Article  PubMed  Google Scholar 

  50. Whitty CM, Willison RG: Some aspects of referred pain. Lancet 1958, 2:226–231.

    Article  PubMed  CAS  Google Scholar 

  51. Feinstein B, Langton JNK, Jameson RM, Schiller F: Experiments on pain referred from deep tissues. J Bone Joint Surg 1954, 36:981–997.

    PubMed  Google Scholar 

  52. Hockaday JM, Whitty CM: Patterns of referred pain in the normal subject. Brain 1967, 90:481–496.

    Article  PubMed  CAS  Google Scholar 

  53. Klingon GH, Jeffreys WH: Distribution of cutaneous hyperalgesia. Neurology 1958, 8:272–276.

    PubMed  CAS  Google Scholar 

  54. Sinclair DC, Wenddell G, Feindel WH: Referred pain and associated phenomena. Brain 1948, 71:184–211.

    Article  PubMed  CAS  Google Scholar 

  55. Cook AJ, Woolf CJ, Wall PD, McMahon SB: Dynamic receptive field plasticity in rat spinal cord dorsal horn following Cprimary afferent input. Nature 1987, 325:151–153.

    Article  PubMed  CAS  Google Scholar 

  56. Hoheisel U, Mense S, Simons DG, Yu XM: Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle: a model for referral of muscle pain? Neurosci Lett 1993, 153:9–12.

    Article  PubMed  CAS  Google Scholar 

  57. Hu JW, Sessle BJ, Raboisson P, et al.: Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in Trigeminal nociceptive brainstem neurons. Pain 1992, 48:53–60.

    Article  PubMed  CAS  Google Scholar 

  58. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS: Quantification of local and referred muscle pain in humans after sequential i.m. injections of hypertonic saline. Pain 1997, 69:111–117.

    Article  PubMed  CAS  Google Scholar 

  59. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: Quantification of local and referred pain in humans induced by intramuscular electrical stimulation. Eur J Pain 1997, 1:105–113.

    Article  PubMed  CAS  Google Scholar 

  60. Lewis T, Kellgren JH: Observations relating to referred pain, viscero-motor reflexes and other associated phenomena. Clin Sci 1939, 4:47–71.

    Google Scholar 

  61. Torebjörk HE, Ochoa JL, Schady W: Referred pain from intraneural stimulation of muscle fascicles in the median nerve. Pain 1984, 18:145–156.

    Article  PubMed  Google Scholar 

  62. Simone DA, Baumann TK, LaMotte RH: Dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989, 38:99–107.

    Article  PubMed  CAS  Google Scholar 

  63. Steinbrocker O, Isenberg SA, Silver M, et al.: Observations on pain produced by injections of hypertonic saline into muscles and other supportive tissues. J Clin Invest 1953, 32:1045–1051.

    PubMed  CAS  Google Scholar 

  64. Arendt-Nielsen L, Graven-Nielsen T, Svensson P, Jensen TS: Temporal summation in muscles and referred pain areas: an experimental human study. Muscle Nerve 1997, 20:1311–1313.

    Article  PubMed  CAS  Google Scholar 

  65. Graven-Nielsen T, Gibson SJ, Laursen RJ, et al.: Opioid-insensitive hypoalgesia to mechanical stimuli at sites ipsilateral and contralateral to experimental muscle pain in human volunteers. Exp Brain Res 2002, 146:213–222.

    Article  PubMed  CAS  Google Scholar 

  66. Graven-Nielsen T, Babenko V, Svensson P, Arendt-Nielsen L: Experimentally induced muscle pain induces hypoalgesia in heterotopic deep tissues, but not in homotopic deep tissues. Brain Res 1998, 787:203–210.

    Article  PubMed  CAS  Google Scholar 

  67. Svensson P, Graven-Nielsen T, Arendt-Nielsen L: Mechanical hyperesthesia of human facial skin induced by tonic painful stimulation of jaw-muscles. Pain 1998, 74:93–100.

    Article  PubMed  CAS  Google Scholar 

  68. Mense S, Simons DG: Muscle Pain: Understanding Its Nature, Diagnosis, and Treatment. Baltimore: Lippincott Williams & Wilkins; 2001:62–83.

    Google Scholar 

  69. Simons DG: Clinical and etiological update of myofascial pain from trigger points. J Musculoskel Pain 1996, 4:93–121.

    Article  Google Scholar 

  70. Travell JG, Simons DG: Myofascial Pain and Dysfunction: The Trigger Point Manual. Baltimore: Williams & Williams; 1982.

    Google Scholar 

  71. Sörensen J, Graven-Nielsen T, Henriksson KG, et al.: Hyperexcitability in fibromyalgia. J Rheumatol 1998, 25:152–155.

    PubMed  Google Scholar 

  72. Staud R, Vierck CJ, Cannon RL, et al.: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001, 91:165–175. Assessed temporal summation to heat stimulation in patients with fibromyalgia and control subjects. It was concluded that fibromyalgia patients had increased pain responses to repeated heat stimuli compared with control subjects, suggesting the involvement of central sensitization in fibromyalgia.

    Article  PubMed  CAS  Google Scholar 

  73. Wright A, Graven-Nielsen T, Davies I, Arendt-Nielsen L: Temporal summation of pain from skin, muscle and joint following nociceptive ultrasonic stimulation in humans. Exp Brain Res 2002, 144:475–482.

    Article  PubMed  CAS  Google Scholar 

  74. Graven-Nielsen T, Kendall SA, Henriksson KG, et al.: Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 2000, 85:483–491. The exaggerated referred pain areas evoked by hypertonic saline and facilitated temporal summation to intramuscular electrical stimulation previously found in patients with fibromyalgia (71) was pharmacologically decreased by ketamine (an NMDA-antagonist), which targeted central sensitization. The facilitated mechanisms for referred pain and temporal summation were reduced by ketamine compared with placebo, which strongly indicates involvement of central sensitization in fibromyalgia.

    Article  PubMed  CAS  Google Scholar 

  75. Johansen MK, Graven-Nielsen T, Olesen AS, Arendt-Nielsen L: Generalized muscular hyperalgesia in chronic whiplash syndrome. Pain 1999, 83:229–234. Assess referred pain pattern to intramuscular infusion of hypertonic saline and the muscle sensitivity to pressure in areas within and outside the region involved in the whiplash trauma. Hyperalgesia to pressure and enlarged referred pain areas were found in patients with chronic whiplash syndrome compared with control subjects within and outside the traumatized area suggesting central sensitization.

    Article  Google Scholar 

  76. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, et al.: Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain 2001, 17:306–315.

    Article  PubMed  CAS  Google Scholar 

  77. Bajaj P, Bajaj P, Graven-Nielsen T, Arendt-Nielsen L: Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study. Pain 2001, 93:107–114. This study shows that persistent joint chronic nociceptive input can facilitate the central processing of muscle nociceptive input in humans. Muscle sensitivity and referred pain pattern were assessed in patients with knee osteoarthritis by intramuscular infusion of hypertonic saline into the tibialis anterior muscle. Increased pain intensity and enlarged pain areas were found in patients versus control subjects, suggesting involvement of central sensitization.

    Article  PubMed  CAS  Google Scholar 

  78. Svensson P, List T, Hector G: Analysis of stimulus-evoked pain in patients with myofascial temporomandibular pain disorders. Pain 2001, 92:399–409.

    Article  PubMed  CAS  Google Scholar 

  79. Leffler AS, Kosek E, Lerndal T, et al.: Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis. Eur J Pain 2002, 6:161–176. This study describes the influence of ongoing rheumatoid arthritic pain, with two different disease durations, on somatosensory sensitivity and descending inhibitory pain control mechanism. In addition to hyperalgesia to pressure over the painful joint, widespread hyperalgesia to pressure also was found in the patient group with the longest disease duration compared with control subjects. The descending inhibitory control of pain was not affected in any of the patient groups compared with control subjects. The widespread hyperalgesia to pressure detected in the group with long-term pain conditions indicated development of central sensitization.

    Article  PubMed  Google Scholar 

  80. Leffler AS: Pain influences somatosensory perception: an experimental and clinical study [PhD Thesis]. Stockholm: Karolinska Institute and Hospital; 2002.

  81. Leffler AS, Kosek E, Hansson P: The influence of pain intensity on somatosensory perception in patients suffering from subacute/ chronic lateral epicondylalgia. Eur J Pain 2000, 4:57–71.

    Article  PubMed  CAS  Google Scholar 

  82. Bajaj P, Bajaj P, Graven-Nielsen T, Arendt-Nielsen L: Trigger points in patients with lower limb osteoarthritis. J Musculoskel Pain 2001, 9:17–33.

    Article  Google Scholar 

  83. Carli G, Suman AL, Biasi G, Marcolongo R: Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 2002, 100:259–269.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arendt-Nielsen, L., Graven-Nielsen, T. Central sensitization in fibromyalgia and other musculoskeletal disorders. Current Science Inc 7, 355–361 (2003). https://doi.org/10.1007/s11916-003-0034-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-003-0034-0

Keywords

Navigation