Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: pain in fibromyalgia syndrome

Nature Clinical Practice Rheumatology volume 2, pages 90–98 (2006)Cite this article

Abstract

Despite extensive research, the pathogenesis of pain in fibromyalgia syndrome is incompletely understood. Fibromyalgia pain is consistently felt in deep tissues including ligaments, joints and muscles. Increasing evidence points towards these tissues as relevant contributors of nociceptive input that might either initiate or maintain central sensitization, or both. Persistent or intense nociception can lead to transcriptional and translational changes in the spinal cord and brain resulting in central sensitization and pain. This mechanism represents a hallmark of fibromyalgia and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established, only minimal nociceptive input is required for the maintenance of the chronic pain state. Other factors, including pain-related negative affect, have been shown to significantly contribute to clinical fibromyalgia pain. An improved understanding of the mechanisms that characterize central sensitization and clinical pain will provide new approaches for the prevention and treatment of fibromyalgia and other chronic pain syndromes.

Key Points

  • Fibromyalgia represents the extreme end of the spectrum of chronic musculoskeletal pain syndromes and is characterized by chronic widespread pain, insomnia, fatigue, distress and mechanical allodynia

  • Although patients with fibromyalgia display extensive cutaneous hyperalgesia, most of their pain complaints are related to deep tissues like muscles, joints and ligaments

  • Abnormal pain sensitivity in fibromyalgia is not limited to mechanical stimuli, but also includes sensitivity to thermal, electrical, and chemical stimuli

  • Pain-processing abnormalities in fibromyalgia include temporal summation (wind-up) of second pain as well as peripheral and central sensitization

  • There is evidence for abnormal antinociceptive mechanisms in fibromyalgia

  • Effective fibromyalgia treatments include cognitive behavioral therapy, aerobic exercise and pharmacologic therapies

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathogenesis of pain in fibromyalgia syndrome.
Figure 2: Immediate and delayed central sensitization.
Figure 3: Ratings of wind-up of second pain in normal control subjects.
Figure 4: Wind-up comparisons between normal controls and patients with fibromyalgia.

Similar content being viewed by others

References

  1. Wolfe F et al. (1990) The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 33: 160–172

    Article  CAS  Google Scholar 

  2. Russell IJ et al. (1994) Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 37: 1593–1601

    Article  CAS  Google Scholar 

  3. Sorensen J et al. (1998) Hyperexcitability in fibromyalgia. J Rheumatol 25: 152–155

    CAS  PubMed  Google Scholar 

  4. Kosek E et al. (1995) Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue. Pain 63: 335–339

    Article  CAS  Google Scholar 

  5. Wolfe F et al. (1995) The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 38: 19–28

    Article  CAS  Google Scholar 

  6. Loeser JD (1991) What is chronic pain? Theor Med 12: 213–225

    Article  CAS  Google Scholar 

  7. Merskey H and Bogduk N (Eds.; 1994) Classification of chronic pain: description of chronic pain syndromes and definition of pain terms. Seattle: IASP Press

    Google Scholar 

  8. Bayer TL et al. (1991) Situational and psychophysiological factors in psychologically induced pain. Pain 44: 45–50

    Article  CAS  Google Scholar 

  9. Graven-Nielsen T et al. (2002) Peripheral and central sensitization in musculoskeletal pain disorders: an experimental approach. Curr Rheumatol Rep 4: 313–321

    Article  Google Scholar 

  10. Granot M et al. (2001) Simultaneous recording of late and ultra-late pain evoked potentials in fibromyalgia. Clin Neurophysiol 112: 1881–1887

    Article  CAS  Google Scholar 

  11. Kosek E et al. (1996) Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 68: 375–383

    Article  CAS  Google Scholar 

  12. Staud R et al. (2003) Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 102: 87–95

    Article  Google Scholar 

  13. Acasuso-Diaz M et al. (1998) Topical capsaicin versus ketoprofen in primary fibromyalgia syndrome. Br J Rheumatol 37: S151

    Google Scholar 

  14. Reddy SS et al. (2000) Tender point injections are beneficial in fibromyalgia syndrome: a descriptive, open study. J Musculoskelet Pain 8: 7–18

    Article  Google Scholar 

  15. Arendt-Nielsen L et al. (2003) Central sensitization in fibromyalgia and other musculoskeletal disorders. Curr Pain Headache Rep 7: 355–361

    Article  Google Scholar 

  16. Desmeules JA et al. (2003) Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 48: 1420–1429

    Article  CAS  Google Scholar 

  17. Staud R (2004) New evidence for central sensitization in patients with fibromyalgia. Curr Rheumatol Rep 6: 259

    PubMed  Google Scholar 

  18. Simms RW (1998) Fibromyalgia is not a muscle disorder. Am J Med Sci 315: 346–350

    CAS  PubMed  Google Scholar 

  19. Sprott H et al. (1998) Immunohistochemical and molecular studies of serotonin, substance P, galanin, pituitary adenylyl cyclase-activating polypeptide, and secretoneurin in fibromyalgic muscle tissue. Arthritis Rheum 41: 1689–1694

    Article  CAS  Google Scholar 

  20. Sprott H et al. (2004) Increased DNA fragmentation and ultrastructural changes in fibromyalgic muscle fibres. Ann Rheum Dis 63: 245–251

    Article  CAS  Google Scholar 

  21. Salemi S et al. (2003) Detection of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor-α in skin of patients with fibromyalgia. J Rheumatol 30: 146–150

    CAS  PubMed  Google Scholar 

  22. Graven-Nielsen T et al. (2002) Is there a relation between intramuscular hypoperfusion and chronic muscle pain? J Pain 3: 261–263

    Article  Google Scholar 

  23. Wall PD et al. (1984) Muscle but not cutaneous C-afferent input produces prolonged increases in the excitability of the flexion reflex in the rat. J Physiol 356: 443–458

    Article  CAS  Google Scholar 

  24. Hunt IM et al. (1999) The prevalence and associated features of chronic widespread pain in the community using the 'Manchester' definition of chronic widespread pain. Rheumatology 38: 275–279

    Article  CAS  Google Scholar 

  25. Benjamin S et al. (2000) The association between chronic widespread pain and mental disorder— a population-based study. Arthritis Rheum 43: 561–567

    Article  CAS  Google Scholar 

  26. Forseth KO et al. (1999) A 5.5 year prospective study of self-reported musculoskeletal pain and of fibromyalgia in a female population: significance and natural history. Clin Rheumatol 18: 114–121

    Article  CAS  Google Scholar 

  27. McBeth J et al. (2001) Features of somatization predict the onset of chronic widespread pain: results of a large population-based study. Arthritis Rheum 44: 940–946

    Article  CAS  Google Scholar 

  28. Arnold LM et al. (2004) Family study of fibromyalgia. Arthritis Rheum 50: 944–952

    Article  Google Scholar 

  29. Raphael KG et al. (2004) Familial aggregation of depression in fibromyalgia: a community-based test of alternate hypotheses. Pain 110: 449–460

    Article  Google Scholar 

  30. Woolf CJ (1996) Windup and central sensitization are not equivalent. Pain 66: 105–108

    Article  CAS  Google Scholar 

  31. Li J et al. (1999) Windup leads to characteristics of central sensitization. Pain 79: 75–82

    Article  CAS  Google Scholar 

  32. Granovsky Y et al. (2005) Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis. Pain 115: 238–247

    Article  Google Scholar 

  33. Staud R et al. (2001) Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91: 165–175

    Article  CAS  Google Scholar 

  34. Dickenson AH et al. (1987) Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 26: 1235–1238

    Article  CAS  Google Scholar 

  35. Mendell LM et al. (1965) Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature 206: 97–99

    Article  CAS  Google Scholar 

  36. Price DD et al. (1977) Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3: 57–68

    Article  CAS  Google Scholar 

  37. Staud R et al. (2005) Effects of the NDMA receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal controls. J Pain 6: 323–332

    Article  CAS  Google Scholar 

  38. Price DD et al. (1994) The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 59: 165–174

    Article  CAS  Google Scholar 

  39. Vierck CJ et al. (1997) Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode. J Neurophysiol 78: 992–1002

    Article  Google Scholar 

  40. Staud R (2002) Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Curr Rheumatol Rep 4: 299–305

    Article  Google Scholar 

  41. Price DD et al. (2002) Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 99: 49–59

    Article  Google Scholar 

  42. Staud R et al. (2001) Evidence for abnormal pain processing in fibromyalgia syndrome. Pain Med 2: 208–215

    Article  CAS  Google Scholar 

  43. Staud R et al. (2003) Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome. Pain 105: 215–222

    Article  Google Scholar 

  44. Watkins LR et al. (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24: 450–455

    Article  CAS  Google Scholar 

  45. Watkins LR et al. (2003) When good pain turns bad. Curr Dir Psycholog Sci 12: 232–236

    Article  Google Scholar 

  46. Cook AJ et al. (1987) Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature 325: 151–153

    Article  CAS  Google Scholar 

  47. Bengtsson A et al. (1986) Muscle biopsy in primary fibromyalgia. Light-microscopical and histochemical findings. Scand J Rheumatol 15: 1–6

    Article  CAS  Google Scholar 

  48. Bengtsson A et al. (1986) Primary fibromyalgia. A clinical and laboratory study of 55 patients. Scand J Rheumatol 15: 340–347

    Article  CAS  Google Scholar 

  49. Lund N et al. (1986) Muscle tissue oxygen pressure in primary fibromyalgia. Scan J Rheumatol 15: 165–173

    Article  CAS  Google Scholar 

  50. Sluka KA et al. (2001) Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve 24: 37–46

    Article  CAS  Google Scholar 

  51. Park JH et al. (1998) Use of P-31 magnetic resonance spectroscopy to detect metabolic abnormalities in muscles of patients with fibromyalgia. Arthritis Rheum 41: 406–413

    Article  CAS  Google Scholar 

  52. Crofford LJ (2002) The hypothalamic–pituitary–adrenal axis in fibromyalgia: where are we in 2001? J Musculoskelet Pain 10: 215–220

    Article  Google Scholar 

  53. Riedel W et al. (2002) Blunted ACTH and cortisol responses to systemic injection of corticotropin-releasing hormone (CRH) in fibromyalgia: role of somatostatin and CRH-binding protein. Ann NY Acad Sci 966: 483–490

    Article  CAS  Google Scholar 

  54. Martinez-Lavin M (2002) The autonomic nervous system and fibromyalgia. J Musculoskelet Pain 10: 221–228

    Article  Google Scholar 

  55. Cohen H et al. (2001) Abnormal sympathovagal balance in men with fibromyalgia. J Rheumatol 28: 581–589

    CAS  PubMed  Google Scholar 

  56. Martinez-Lavin M et al. (1998) Circadian studies of autonomic nervous balance in patients with fibromyalgia—a heart rate variability analysis. Arthritis Rheum 41: 1966–1971

    Article  CAS  Google Scholar 

  57. Crofford LJ et al. (1996) Neurohormonal perturbations in fibromyalgia. Clin Rheumatol 10: 365–378

    CAS  Google Scholar 

  58. Pillemer SR et al. (1997) The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum 40: 1928–1939

    Article  CAS  Google Scholar 

  59. Price DD (2000) Psychological and neural mechanisms of the affective dimension of pain. Science 288: 1769–1772

    Article  CAS  Google Scholar 

  60. Fields HL and Basbaum AI (1999) Central nervous system mechanisms of pain modulation. In Textbook of Pain, 309–329 (Eds Wall PD and Melzack R) Edinburgh: Churchill Livingstone

    Google Scholar 

  61. Gebhart GF (2004) Descending modulation of pain. Neurosci Biobehav Rev 27: 729–737

    Article  CAS  Google Scholar 

  62. Lautenbacher S et al. (1997) Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 13: 189–196

    Article  CAS  Google Scholar 

  63. Julien N et al. (2005) Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 114: 295–302

    Article  Google Scholar 

  64. Calejesan AA et al. (2000) Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur J Pain 4: 83–96

    Article  CAS  Google Scholar 

  65. Oliver K et al. (2001) A review of multidisciplinary interventions for fibromyalgia patients: where do we go from here? J Musculoskelet Pain 9: 63–80

    Article  Google Scholar 

  66. Sorensen J et al. (1997) Fibromyalgia—are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol 24: 1615–1621

    CAS  PubMed  Google Scholar 

  67. Arnold LM et al. (2004) A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 50: 2974–2984

    Article  CAS  Google Scholar 

  68. Crofford LJ et al. (2005) Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52: 1264–1273

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are supported by the NIH, the American Fibromyalgia Syndrome Association, and in part by the Clinical Research Center.

Author information

Authors and Affiliations

  1. Division of Rheumatology & Clinical Immunology, of the University of Florida, Gainesville, USA

    Roland Staud & Miguel E Rodriguez

Authors
  1. Roland Staud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miguel E Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roland Staud.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staud, R., Rodriguez, M. Mechanisms of Disease: pain in fibromyalgia syndrome. Nat Rev Rheumatol 2, 90–98 (2006). https://doi.org/10.1038/ncprheum0091

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0091

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing