The American Journal of Medicine
Volume 122, Issue 12, Supplement , Pages S22-S30 , December 2009

Pathophysiology of Fibromyalgia

  • Laurence A. Bradley, PhD

      Affiliations

    • Corresponding Author InformationRequest for reprints should be addressed to Laurence A. Bradley, PhD, Division of Clinical Immunology and Rheumatology, 177A Shelby Research Building, 1825 University Boulevard, Birmingham, Alabama 35294

References 

  1. Hudson JI, Mangweth B, Pope HG, et al. Family study of affective spectrum disorder. Arch Gen Psychiatry. 2003;60:170–177
  2. Hudson JI, Arnold LM, Keck PE, Auchenbach MB, Pope HG. Family study of fibromyalgia and affective spectrum disorder. Biol Psychiatry. 2004;56:884–891
  3. Arnold LM, Hudson JI, Hess EV, et al. Family study of fibromyalgia. Arthritis Rheum. 2004;50:944–952
  4. Aaron LA, Buchwald D. Chronic diffuse musculoskeletal pain, fibromyalgia and co-morbid unexplained clinical conditions. Best Pract Res Clin Rheumatol. 2003;17:563–574
  5. Arnold LM, Hudson JI, Keck PE, Auchenbach MB, Javaras KN, Hess EV. Comorbidity of fibromyalgia and psychiatric disorders. J Clin Psychiatry. 2006;67:1219–1225
  6. Weir PT, Harlan GA, Nkoy FL, et al. The incidence of fibromyalgia and its associated comorbidities: a population-based retrospective cohort study based on International Classification of Diseases, 9th Revision codes. J Clin Rheumatol. 2006;12:124–128
  7. 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
  8. Nielsen LA, Henriksson KG. Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition. Best Pract Res Clin Rheumatol. 2007;21:465–480
  9. Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001;24:450–455
  10. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth. 2001;48:1000–1010
  11. Ledeboer A, Liu T, Shumilla JA, et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol. 2006;2:279–291
  12. Watkins LR, Milligan ED, Maier SF. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol. 2003;521:1–21
  13. Clauw DJ. Fibromyalgia: an overview. Am J Med. 2009;122(suppl):S3–S13
  14. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343
  15. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Javors MA, Bowden CA. Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol. 1992;19:104–109
  16. Russell IJ, Vaerøy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992;35:550–556
  17. Mease PJ. Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors. Am J Med. 2009;122(suppl):S44–S55
  18. McCain GA, Tilbe KS. Diurnal hormone variation in fibromyalgia syndrome: a comparison with rheumatoid arthritis. J Rheumatol Suppl. 1989;19:154–157
  19. Crofford LJ, Pillemer SR, Kalogeras KT, et al. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum. 1994;37:1583–1592
  20. Harris RE, Williams DA, McLean SA, et al. Characterization and consequences of pain variability in individuals with fibromyalgia. Arthritis Rheum. 2005;52:3670–3674
  21. Vaerøy H, Qiao ZG, Morkrid L, Forre O. Altered sympathetic nervous system response in patients with fibromyalgia (fibrositis syndrome). J Rheumatol. 1989;16:1460–1465
  22. Bou-Holaigah I, Calkins H, Flynn JA, et al. Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia. Clin Exp Rheumatol. 1997;15:239–246
  23. Martinez-Lavin M, Hermosillo AG, Rosas M, Soto ME. Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart rate variability analysis. Arthritis Rheum. 1998;41:1966–1971
  24. Stein PK, Domitrovich PP, Ambrose K, et al. Sex effects on heart rate variability in fibromyalgia and Gulf War illness. Arthritis Rheum. 2004;51:700–708
  25. Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum. 2001;44:222–230
  26. Harding SM. Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci. 1998;315:367–376
  27. Van Cauter E, Plat L, Copinschi G. Interrelations between sleep and the somatotropic axis. Sleep. 1998;21:553–566
  28. Prinz PN, Moe KE, Dulberg EM, et al. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. J Gerontol A Biol Sci Med Sci. 1995;50:M222–M226
  29. Bennett RM, Clark SR, Campbell SM, Burckhardt CS. Low levels of somatomedin C in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain. Arthritis Rheum. 1992;35:1113–1116
  30. Davies KA, Macfarlane GJ, Nicholl BI, et al. Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study. Rheumatology (Oxford). 2008;47:1809–1813
  31. Raphael KG, Janal MN, Nayak S, Schwartz JE, Gallagher RM. Familial aggregation of depression in fibromyalgia: a community-based test of alternate hypotheses. Pain. 2004;110:449–460
  32. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160–172
  33. Kato K, Sullivan PF, Evengard B, Pedersen NL. Importance of genetic influences on chronic widespread pain. Arthritis Rheum. 2006;54:1682–1686
  34. Offenbaecher M, Bondy B, de Jonge S, et al. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 1999;42:2482–2488
  35. Cohen H, Buskila D, Neumann L, Ebstein RP. Confirmation of an association between fibromyalgia and serotonin transporter promoter region (5-HTTLPR) polymorphism, and relationship to anxiety-related personality traits. Arthritis Rheum. 2002;46:845–847
  36. Bradley L, Fillingim R, Sotolongo A, et al. Family aggregation of pain sensitivity in fibromyalgia [abstract]. J Pain. 2006;7(suppl 1):S1
  37. Hoefgen B, Schulze TG, Ohlraun S, et al. The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biol Psychiatry. 2005;57:247–251
  38. Eaton WW, Shao H, Nestadt G, Lee HB, Bienvenu OJ, Zandi P. Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry. 2008;65:513–520
  39. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389
  40. Yeo A, Boyd P, Lumsden S, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut. 2004;53:1452–1458
  41. Park JM, Choi MG, Park JA, et al. Serotonin transporter gene polymorphism and irritable bowel syndrome. Neurogastroenterol Motil. 2006;18:995–1000
  42. Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA. Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2006;130:34–43
  43. Camilleri M. Is there a SERT-ain association with IBS?. Gut. 2004;53:1396–1399
  44. Colucci R, Blandizzi C, Bellini M, Ghisu N, Tonini M, Del Tacca M. The genetics of the serotonin transporter and irritable bowel syndrome. Trends Mol Med. 2008;14:295–304
  45. Van Kerkhoven LA, Laheij RJ, Jansen JB. Meta-analysis: a functional polymorphism in the gene encoding for activity of the serotonin transporter protein is not associated with the irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:979–986
  46. Gürsoy S. Absence of association of the serotonin transporter gene polymorphism with the mentally healthy subset of fibromyalgia patients. Clin Rheumatol. 2002;21:194–197
  47. Camilleri M, Busciglio I, Carlson P, et al. Candidate genes and sensory functions in health and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2008;295:G219–G225
  48. Fukudo S, Kanazawa M, Mizuno T, et al. Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention. Neuroimage. 2009;47:946–951
  49. Diatchenko L, Nackley AG, Tchivileva IE, et al. Genetic architecture of human pain perception. Trends Genet. 2007;23:605–613
  50. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240–1243
  51. Diatchenko L, Nackley AG, Slade GD, et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain. 2006;125:216–224
  52. Diatchenko L, Slade GD, Nackley AG, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14:135–143
  53. Gürsoy S, Erdal E, Herken H, Madenci E, Alaşehirli B, Erdal N. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int. 2003;23:104–107
  54. Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors. Pain. 2007;128:199–208
  55. Arnold LM. Strategies for managing fibromyalgia. Am J Med. 2009;122(suppl):S31–S43
  56. Tander B, Gunes S, Boke O, et al. Polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase genes: a study on fibromyalgia susceptibility. Rheumatol Int. 2008;28:685–691
  57. Saito YA, Talley NJ. Genetics of irritable bowel syndrome. Am J Gastroenterol. 2008;103:2100–2104quiz 2105
  58. Buskila D, Cohen H, Neumann L, Ebstein RP. An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits. Mol Psychiatry. 2004;9:730–731
  59. Wood PB, Patterson JC, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain. 2007;8:51–58
  60. Al-Allaf AW, Dunbar KL, Hallum NS, Nosratzadeh B, Templeton KD, Pullar T. A case-control study examining the role of physical trauma in the onset of fibromyalgia syndrome. Rheumatology (Oxford). 2002;41:450–453
  61. Cruz BA, Catalan-Soares B, Proietti F. Higher prevalence of fibromyalgia in patients infected with human T cell lymphotropic virus type I. J Rheumatol. 2006;33:2300–2303
  62. Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci. 1998;840:684–697
  63. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord. 2007;8:27
  64. Harkness EF, Macfarlane GJ, Nahit E, et al. Mechanical injury and psychosocial factors in the work place predict the onset of widespread body pain: a two-year prospective study among cohorts of newly employed workers. Arthritis Rheum. 2004;50:1655–1664
  65. Harkness EF, Macfarlane GJ, Nahit ES, Silman AJ, McBeth J. Risk factors for new-onset low back pain amongst cohorts of newly employed workers. Rheumatology (Oxford). 2003;42:959–968
  66. Harkness EF, Macfarlane GJ, Nahit ES, Silman AJ, McBeth J. Mechanical and psychosocial factors predict new onset shoulder pain: a prospective cohort study of newly employed workers. Occup Environ Med. 2003;60:850–857
  67. Jones GT, Harkness EF, Nahit ES, McBeth J, Silman AJ, Macfarlane GJ. Predicting the onset of knee pain: results from a 2-year prospective study of new workers. Ann Rheum Dis. 2007;66:400–406
  68. Davis MC, Zautra AJ, Reich JW. Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann Behav Med. 2001;23:215–226
  69. Loggia ML, Mogil JS, Bushnell MC. Experimentally induced mood changes preferentially affect pain unpleasantness. J Pain. 2008;9:784–791
  70. Okonkwo R, Bradley L, Sotolongo A, et al. Effect of stressful imagery on thermal pain ratings of patients with fibromyalgia: what mediates this relationship?. J Pain. 2007;8:525;[abstract]

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

 Dr. Bradley has received grant/research support from the National Institutes of Health (NIH), the Agency for Healthcare Research and Quality (AHRQ), and the American Fibromyalgia Syndrome Association (AFSA).

PII: S0002-9343(09)00825-0

doi: 10.1016/j.amjmed.2009.09.008

The American Journal of Medicine
Volume 122, Issue 12, Supplement , Pages S22-S30 , December 2009