Skip to main content

Advertisement

SpringerLink
Log in

Non-inflammatory Causes of Pain in Patients with Rheumatoid Arthritis

  • Rheumatoid Arthritis (LW Moreland, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Although pain in rheumatoid arthritis (RA) is frequently thought to be inflammatory in nature, the association between measures of inflammation and pain intensity is low. This observation is likely due to the multifactorial nature of pain. In addition to pain from joint inflammation, RA patients may also have pain due to structural damage or central etiologies, such as aberrancies in the central nervous system (CNS) pain regulatory pathways. These CNS pathways include mechanisms that facilitate pain, as well as mechanisms that inhibit pain. Other factors, such as sleep disturbances, depression, anxiety, and catastrophizing, may also impact the perception of pain in RA patients. Since pain is frequently used as a proxy for inflammation in the assessment of RA disease activity, it is important that patients and physicians recognize that not all pain is inflammatory, and alternative management strategies, other than escalating disease-modifying antirheumatic drug treatment, may need to be considered.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Borenstein D, Altman R, Bello A, et al. Report of the American College of Rheumatology Pain Management Task Force. Arthritis Care Res (Hoboken). 2010;62(5):590–9.

    Article  Google Scholar 

  2. Hewlett S, Sanderson T, May J, et al. ‘I’m hurting, i want to kill myself’: rheumatoid arthritis flare is more than a high joint count—an international patient perspective on flare where medical help is sought. Rheumatology (Oxford). 2012;51(1):69–76. doi:10.1093/rheumatology/keq455.

    Article  Google Scholar 

  3. Studenic P, Radner H, Smolen JS, et al. Discrepancies between patients and physicians in the perception of rheumatoid arthritis disease activity. Arthritis Rheum. 2012;64:2814–23.

    Article  PubMed  Google Scholar 

  4. Courvoisier N, Dougados M, Cantagrel A, et al. Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2008;10(5):R106. doi:10.1186/ar2498.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lee YC, Cui J, Lu B, et al. Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study. Arthritis Res Ther. 2011;13(3):R83.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Koop SM, ten Klooster PM, Vonkeman HE, et al. Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis. Arthritis Res Ther. 2015;17:237. doi:10.1186/s13075-015-0761-8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lee YC, Frits ML, Iannaccone CK, et al. Subgrouping of patients with rheumatoid arthritis based on pain, fatigue, inflammation, and psychosocial factors. Arthritis Rheumatol. 2014;66(8):2006–14. doi:10.1002/art.38682.

    Article  PubMed  PubMed Central  Google Scholar 

  8. McWilliams DF, Zhang W, Mansell JS, et al. Predictors of change in bodily pain in early rheumatoid arthritis: an inception cohort study. Arthritis Care Res (Hoboken). 2012;64(10):1505–13. doi:10.1002/acr.21723.

    Article  Google Scholar 

  9. Walsh DA, McWilliams DF. Mechanisms, impact and management of pain in rheumatoid arthritis. Nat Rev Rheumatol. 2014. doi:10.1038/nrrheum.2014.64. Excellent review describing the interelationships between joint pathology and both peripheral and central nervous system processing of pain signals.

    PubMed  Google Scholar 

  10. Stefanik JJ, Gross KD, Guermazi A, et al. The relation of mri-detected structural damage in the medial and lateral patellofemoral joint to knee pain: the multicenter and Framingham osteoarthritis studies. Osteoarthr Cartil. 2015;23(4):565–70. doi:10.1016/j.joca.2014.12.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Roubille C, Raynauld JP, Abram F, et al. The presence of meniscal lesions is a strong predictor of neuropathic pain in symptomatic knee osteoarthritis: a cross-sectional pilot study. Arthritis Res Ther. 2014;16(6):507. doi:10.1186/s13075-014-0507-z.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wesseling J, Bierma-Zeinstra SM, Kloppenburg M, et al. Worsening of pain and function over 5 years in individuals with ‘early’ OA is related to structural damage: data from the osteoarthritis initiative and check (cohort hip & cohort knee) study. Ann Rheum Dis. 2015;74(2):347–53. doi:10.1136/annrheumdis-2013-203829.

    Article  PubMed  Google Scholar 

  13. Sokka T, Kankainen A, Hannonen P. Scores for functional disability in patients with rheumatoid arthritis are correlated at higher levels with pain scores than with radiographic scores. Arthritis Rheum. 2000;43(2):386–9. doi:10.1002/1529-0131(200002)43:2<386::AID-ANR19>3.0.CO;2-Z.

    Article  CAS  PubMed  Google Scholar 

  14. Sarzi-Puttini P, Fiorini T, Panni B, et al. Correlation of the score for subjective pain with physical disability, clinical and radiographic scores in recent onset rheumatoid arthritis. BMC Musculoskelet Disord. 2002;3:18.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lau BK, Vaughan CW. Descending modulation of pain: the GABA disinhibition hypothesis of analgesia. Curr Opin Neurobiol. 2014;29:159–64. doi:10.1016/j.conb.2014.07.010.

    Article  CAS  PubMed  Google Scholar 

  16. Denk F, McMahon SB, Tracey I. Pain vulnerability: a neurobiological perspective. Nat Neurosci. 2014;17(2):192–200. doi:10.1038/nn.3628. Comprehensive review regarding the genetic, epigenetic, and environmental factors that confer risk for chronic pain and the neural mechanisms underlying chronic pain.

    Article  CAS  PubMed  Google Scholar 

  17. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010;23(5):611–5. doi:10.1097/ACO.0b013e32833c348b.

    Article  PubMed  Google Scholar 

  18. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–15. doi:10.1016/j.pain.2010.09.030.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cagnie B, Coppieters I, Denecker S, et al. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum. 2014;44(1):68–75. doi:10.1016/j.semarthrit.2014.01.001.

    Article  PubMed  Google Scholar 

  20. Andersson ML, Svensson B, Bergman S. Chronic widespread pain in patients with rheumatoid arthritis and the relation between pain and disease activity measures over the first 5 years. J Rheumatol. 2013;40(12):1977–85. doi:10.3899/jrheum.130493.

    Article  PubMed  Google Scholar 

  21. Walitt B, Nahin RL, Katz RS, et al. The prevalence and characteristics of fibromyalgia in the 2012 national health interview survey. PLoS One. 2015;10(9), e0138024. doi:10.1371/journal.pone.0138024.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Pollard LC, Kingsley GH, Choy EH, et al. Fibromyalgic rheumatoid arthritis and disease assessment. Rheumatology (Oxford). 2010;49(5):924–8.

    Article  Google Scholar 

  23. Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia. J Rheumatol. 2011;38:1113–22.

    Article  PubMed  Google Scholar 

  24. Wolfe F, Hauser W, Hassett AL, et al. The development of fibromyalgia—i: examination of rates and predictors in patients with rheumatoid arthritis (RA). Pain. 2011;152(2):291–9.

    Article  PubMed  Google Scholar 

  25. Joharatnam N, McWilliams DF, Wilson D, et al. A cross sectional study of pain sensitivity, disease activity assessment, mental health and fibromyalgia status in rheumatoid arthritis. Arthritis Res Ther. 2015;17(1):11. doi:10.1186/s13075-015-0525-5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lee YC, Nassikas NJ, Clauw DJ. The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia. Arthritis Res Ther. 2011;13(2):211.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wolfe F, Michaud K. Outcome and predictor relationships in fibromyalgia and rheumatoid arthritis: evidence concerning the continuum versus discrete disorder hypothesis. J Rheumatol. 2009;36(4):831–6. doi:10.3899/jrheum.080897.

    Article  PubMed  Google Scholar 

  28. Hauser W, Schmutzer G, Brahler E, et al. A cluster within the continuum of biopsychosocial distress can be labeled “fibromyalgia syndrome”—evidence from a representative German population survey. J Rheumatol. 2009;36(12):2806–12. doi:10.3899/jrheum.090579.

    Article  PubMed  Google Scholar 

  29. Wolfe F, Brahler E, Hinz A, et al. Fibromyalgia prevalence, somatic symptom reporting, and the dimensionality of polysymptomatic distress: results from a survey of the general population. Arthritis Care Res (Hoboken). 2013;65(5):777–85. doi:10.1002/acr.21931.

    Article  Google Scholar 

  30. Edwards RR. Individual differences in endogenous pain modulation as a risk factor for chronic pain. Neurology. 2005;65(3):437–43. doi:10.1212/01.wnl.0000171862.17301.84.

    Article  PubMed  Google Scholar 

  31. Cruz-Almeida Y, Fillingim RB. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med. 2014;15(1):61–72. doi:10.1111/pme.12230.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Meeus M, Vervisch S, De Clerck LS, et al. Central sensitization in patients with rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2012;41(4):556–67. doi:10.1016/j.semarthrit.2011.08.001.

    Article  PubMed  Google Scholar 

  33. 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(2):161–76.

    Article  PubMed  Google Scholar 

  34. Edwards RR, Wasan AD, Bingham 3rd CO, et al. Enhanced reactivity to pain in patients with rheumatoid arthritis. Arthritis Res Ther. 2009;11(3):R61.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lee YC, Lu B, Edwards RR, et al. The role of sleep problems in central pain processing in rheumatoid arthritis. Arthritis Rheum. 2013;65(1):59–68. doi:10.1002/art.37733.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Garcia-Fernandez E, Godoy-Izquierdo D, Perez-Garcia M, et al. Differences in pressure-pain threshold between healthy women and patients with fibromyalgia syndrome, systemic lupus erythematosus, and rheumatoid arthritis. J Musculoskelet Pain. 2009;17(2):139–54.

    Article  Google Scholar 

  37. Lee YC, Chibnik LB, Lu B, et al. The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2009;11(5):R160.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain. 2015;156 Suppl 1:S24–31. doi:10.1097/01.j.pain.0000460343.46847.58.

    Article  PubMed  Google Scholar 

  39. Meeus M, Ickmans K, Struyf F, et al. Does acetaminophen activate endogenous pain inhibition in chronic fatigue syndrome/fibromyalgia and rheumatoid arthritis? A double-blind randomized controlled cross-over trial. Pain Physician. 2013;16(2):E61–70.

    PubMed  Google Scholar 

  40. Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol. 2010;6(10):599–606. doi:10.1038/nrrheum.2010.107.

    Article  PubMed  Google Scholar 

  41. Vladimirova N, Jespersen A, Bartels EM, et al. Pain sensitisation in women with active rheumatoid arthritis: a comparative cross-sectional study. Arthritis. 2015;2015:434109. doi:10.1155/2015/434109.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Meeus M, Hermans L, Ickmans K, et al. Endogenous pain modulation in response to exercise in patients with rheumatoid arthritis, patients with chronic fatigue syndrome and comorbid fibromyalgia, and healthy controls: a double-blind randomized controlled trial. Pain Pract. 2015;15(2):98–106. doi:10.1111/papr.12181.

    Article  PubMed  Google Scholar 

  43. Son CN, Choi G, Lee SY, et al. Sleep quality in rheumatoid arthritis, and its association with disease activity in a Korean population. Korean J Intern Med. 2015;30(3):384–90. doi:10.3904/kjim.2015.30.3.384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nicassio PM, Wallston KA. Longitudinal relationships among pain, sleep problems, and depression in rheumatoid arthritis. J Abnorm Psychol. 1992;101(3):514–20.

    Article  CAS  PubMed  Google Scholar 

  45. Taylor-Gjevre RM, Gjevre JA, Nair B, et al. Components of sleep quality and sleep fragmentation in rheumatoid arthritis and osteoarthritis. Musculoskelet Care. 2011;9(3):152–9.

    CAS  Google Scholar 

  46. Luyster FS, Chasens ER, Wasko MC, et al. Sleep quality and functional disability in patients with rheumatoid arthritis. J Clin Sleep Med. 2011;7(1):49–55.

    PubMed  PubMed Central  Google Scholar 

  47. Purabdollah M, Lakdizaji S, Rahmani A, et al. Relationship between sleep disorders, pain and quality of life in patients with rheumatoid arthritis. J Caring Sci. 2015;4(3):233–41. doi:10.15171/jcs.2015.024.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Irwin MR, Olmstead R, Carrillo C, et al. Sleep loss exacerbates fatigue, depression, and pain in rheumatoid arthritis. Sleep. 2012;35(4):537–43.

    PubMed  PubMed Central  Google Scholar 

  49. Odegard S, Finset A, Mowinckel P, et al. Pain and psychological health status over a 10-year period in patients with recent onset rheumatoid arthritis. Ann Rheum Dis. 2007;66(9):1195–201.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kekow J, Moots R, Khandker R, et al. Improvements in patient-reported outcomes, symptoms of depression and anxiety, and their association with clinical remission among patients with moderate-to-severe active early rheumatoid arthritis. Rheumatology (Oxford). 2011;50(2):401–9. doi:10.1093/rheumatology/keq327.

    Article  Google Scholar 

  51. Zyrianova Y, Kelly BD, Gallagher C, et al. Depression and anxiety in rheumatoid arthritis: the role of perceived social support. Ir J Med Sci. 2006;175(2):32–6.

    Article  CAS  PubMed  Google Scholar 

  52. Zautra AJ, Parrish BP, Van Puymbroeck CM, et al. Depression history, stress, and pain in rheumatoid arthritis patients. J Behav Med. 2007;30(3):187–97.

    Article  PubMed  Google Scholar 

  53. Kojima M, Kojima T, Suzuki S, et al. Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis Rheum. 2009;61(8):1018–24.

    Article  PubMed  Google Scholar 

  54. Rathbun AM, Harrold LR, Reed GW. Temporal effect of depressive symptoms on the longitudinal evolution of rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken). 2015;67(6):765–75. doi:10.1002/acr.22515. Important longitudinal study examining the effects of prevalent and incident depressive symptoms on pain and disease activity in individuals with RA. Depressive symptoms predicted slower rates of improvement in pain, patient global assessment and tender joint count but not swollen joint count or acute phase reactants.

    Article  Google Scholar 

  55. Graham-Engeland JE, Zawadzki MJ, Slavish DC, et al. Depressive symptoms and momentary mood predict momentary pain among rheumatoid arthritis patients. Ann Behav Med. 2016;50(1):12–23. doi:10.1007/s12160-015-9723-2.

    Article  PubMed  Google Scholar 

  56. Smith BW, Zautra AJ. The effects of anxiety and depression on weekly pain in women with arthritis. Pain. 2008;138(2):354–61.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Edwards RR, Cahalan C, Mensing G, et al. Pain, catastrophizing, and depression in the rheumatic diseases. Nat Rev. 2011;7(4):216–24.

    CAS  Google Scholar 

  58. Edwards RR, Giles J, Bingham 3rd CO, et al. Moderators of the negative effects of catastrophizing in arthritis. Pain Med. 2010;11(4):591–9.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ranzolin A, Brenol JC, Bredemeier M, et al. Association of concomitant fibromyalgia with worse disease activity score in 28 joints, health assessment questionnaire, and short form 36 scores in patients with rheumatoid arthritis. Arthritis Rheum. 2009;61(6):794–800.

    Article  PubMed  Google Scholar 

  60. Wolfe F, Cathey MA, Kleinheksel SM. Fibrositis (fibromyalgia) in rheumatoid arthritis. J Rheumatol. 1984;11(6):814–8.

    CAS  PubMed  Google Scholar 

  61. Naranjo A, Ojeda S, Francisco F, et al. Fibromyalgia in patients with rheumatoid arthritis is associated with higher scores of disability. Ann Rheum Dis. 2002;61(7):660–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize ra patients with fibromyalgia. J Rheumatol. 2004;31(4):695–700.

    PubMed  Google Scholar 

  63. Leeb BF, Andel I, Sautner J, et al. The DAS28 in rheumatoid arthritis and fibromyalgia patients. Rheumatology (Oxford). 2004;43(12):1504–7.

    Article  CAS  Google Scholar 

  64. Coury F, Rossat A, Tebib A, et al. Rheumatoid arthritis and fibromyalgia: a frequent unrelated association complicating disease management. J Rheumatol. 2009;36(1):58–62. doi:10.3899/jrheum.080366.

    PubMed  Google Scholar 

  65. Wolfe F, Michaud K, Busch RE, et al. Polysymptomatic distress in patients with rheumatoid arthritis: understanding disproportionate response and its spectrum. Arthritis Care Res (Hoboken). 2014. doi:10.1002/acr.22300.

    Google Scholar 

  66. Lage-Hansen PR, Chrysidis S, Lage-Hansen M, et al. Concomitant fibromyalgia in rheumatoid arthritis is associated with the more frequent use of biological therapy: a cross-sectional study. Scand J Rheumatol. 2015:1–4. doi:10.3109/03009742.2015.1046484

  67. Lee YC, Massarotti E, Edwards RR, et al. Effect of milnacipran on pain in patients with rheumatoid arthritis with widespread pain: a randomized blinded crossover trial. J Rheumatol. 2016;43(1):38–45. doi:10.3899/jrheum.150550. Randomized clinical trial showing that milnacipran, a serotonin-norepinephrine reuptake inhibitor, did not significantly lessen average pain among individuals with RA and widespread pain but was associated with decreases in average pain among the subgroup of RA patients with minimal inflammatory disease activity.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA

    Sean D. Boyden, Imtiyaz N. Hossain, Alyssa Wohlfahrt & Yvonne C. Lee

Authors
  1. Sean D. Boyden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Imtiyaz N. Hossain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alyssa Wohlfahrt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yvonne C. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvonne C. Lee.

Ethics declarations

Conflict of Interest

SDB and INH declare that they have no conflicts of interest. AW reports receiving salary support from a grant from Forest Research Institute, outside the submitted work. YCL reports grants from Forest Research Institute, other stock in Merck, stock in Novartis, and stock in Perrigo, outside the submitted work.

Funding

YCL receives funding from the NIH-NIAMS (R01 AR064850).

Human and Animal Rights and Informed Consent

All studies by YCL involving animal or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Additional information

This article is part of the Topical Collection on Rheumatoid Arthritis

Sean D. Boyden and Imtiyaz N. Hossain are co-first authors

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boyden, S.D., Hossain, I.N., Wohlfahrt, A. et al. Non-inflammatory Causes of Pain in Patients with Rheumatoid Arthritis. Curr Rheumatol Rep 18, 30 (2016). https://doi.org/10.1007/s11926-016-0581-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-016-0581-0

Keywords

Search

Navigation