Experimental Brain Research

, Volume 233, Issue 8, pp 2391–2399 | Cite as

Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain: a case–control study

  • Juliana Barbosa Corrêa
  • Leonardo Oliveira Pena Costa
  • Naiane Teixeira Bastos de Oliveira
  • Kathleen A. Sluka
  • Richard Eloin LiebanoEmail author
Research Article


Quantitative sensory testing is widely used in human research to investigate the state of the peripheral and central nervous system contributions in pain processing. It is a valuable tool to help identify central sensitization and may be important in the treatment of low back pain. The aim of this study was to evaluate changes in local and segmental hypersensitivity and endogenous pain inhibition in people with chronic nonspecific low back pain. Thirty patients with chronic low back pain and thirty healthy subjects were studied. Pressure pain thresholds (PPTs) were measured from the lumbar region and over the tibialis anterior muscle (TA). A cold pressor test was used to assess the activation of conditioned pain modulation (CPM), and PPTs in the lumbar region were recorded 30 s after immersion of participant’s foot in a bucket with cold water. People with chronic low back pain have significantly lower PPT than controls at both the lumbar region [89.5 kPa (mean difference) 95 % CI 40.9–131.1 kPa] and TA [59.45 kPa (mean difference) 95 % CI 13.49–105.42 kPa]. During CPM, people with chronic low back pain have significantly lower PPT than controls in lumbar region [118.6 kPa (mean difference) 95 % CI 77.9–159.2 kPa]. Women had significantly lower PPTs than men in both lumbar region [101.7 kPa (mean difference) 95 % CI 37.9–165.7 kPa] and over the TA [189.7 kPa (mean difference) 95 % CI 14.2–145.2 kPa]. There was no significant difference in PPTs in men between healthy controls and those with low back pain, suggesting the significant differences are mediated primarily by difference between women.


Low back pain Central nervous system sensitization Hyperalgesia Diffuse noxious inhibitory controls Pain inhibition 



This study was supported by the São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP), Brazil, funder approval number: 2012/13910-2 and the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq), Brazil, funder approval number: 473929/2012-0.

Conflict of interest

The authors have no conflict of interest to disclose.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. Airaksinen O, Brox JI, Cedraschi C et al (2006) Chapter 4. European guidelines for the management of chronic nonspecific low back pain. Eur Spine J 15(Suppl 2):S192–S300PubMedCentralPubMedCrossRefGoogle Scholar
  2. Arendt-Nielsen L, Sluka KA, Nie HL (2008) Experimental muscle pain impairs descending inhibition. Pain 140:465–471PubMedCentralPubMedCrossRefGoogle Scholar
  3. 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 149:573–581PubMedCrossRefGoogle Scholar
  4. Arendt-Nielsen L, Fernandez-de-Las-Penas C, Graven-Nielsen T (2011) Basic aspects of musculoskeletal pain: from acute to chronic pain. J Man Manip Ther 19:186–193PubMedCentralPubMedCrossRefGoogle Scholar
  5. Baad-Hansen L, Poulsen HF, Jensen HM, Svensson P (2005) Lack of sex differences in modulation of experimental intraoral pain by diffuse noxious inhibitory controls (DNIC). Pain 116:359–365PubMedCrossRefGoogle Scholar
  6. 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 107:7–15PubMedCrossRefGoogle Scholar
  7. Bement MK, Sluka KA (2005) Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner. Arch Phys Med Rehabil 86:1736–1740PubMedCrossRefGoogle Scholar
  8. Berkley KJ (1997) Sex differences in pain. Behav Brain Sci 20:371–380 discussion 435–513 PubMedGoogle Scholar
  9. Bouhassira D, Villanueva L, Bing Z, le Bars D (1992) Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat. Brain Res 595:353–357PubMedCrossRefGoogle Scholar
  10. Boyan BD, Tosi LL, Coutts RD, Enoka RM et al (2013) Addressing the gaps: sex differences in osteoarthritis of the knee. Biol Sex Differ 4(1):4PubMedCentralPubMedCrossRefGoogle Scholar
  11. Carli G, Suman AL, Biasi G, Marcolongo R (2002) Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 100:259–269PubMedCrossRefGoogle Scholar
  12. Chou R, Qaseem A, Owens DK, Shekelle P (2011) Diagnostic imaging for low back pain: advice for high-value health care from the American College of Physicians. Ann Intern Med 154:181–189PubMedCrossRefGoogle Scholar
  13. Clauw DJ, Williams D, Lauerman W et al (1999) Pain sensitivity as a correlate of clinical status in individuals with chronic low back pain. Spine (Phila Pa 1976) 24:2035–2041CrossRefGoogle Scholar
  14. Correa JB, Costa LO, de Oliveira NT, Sluka KA, Liebano RE (2013) Effects of the carrier frequency of interferential current on pain modulation in patients with chronic nonspecific low back pain: a protocol of a randomised controlled trial. BMC Musculoskelet Disord 14:195PubMedCentralPubMedCrossRefGoogle Scholar
  15. Costa LO, Maher CG, Latimer J, Ferreira PH, Ferreira ML, Pozzi GC, Freitas LM (2008) Clinimetric testing of three self-report outcome measures for low back pain patients in Brazil: Which one is the best? Spine (Phila Pa 1976) 33:2459–2463CrossRefGoogle Scholar
  16. Dailey DL, Rakel BA, Vance CG et al (2013) Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia. Pain 154:2554–2562PubMedCentralPubMedCrossRefGoogle Scholar
  17. Delitto A, George SZ, Van Dillen LR et al (2012) Low back pain. J Orthop Sports Phys Ther 42:A1–A57PubMedCrossRefGoogle Scholar
  18. DeSantana JM, Walsh DM, Vance C et al (2008) Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Curr Rheumatol Rep 10:492–499PubMedCentralPubMedCrossRefGoogle Scholar
  19. Diers M, Koeppe C, Diesch E et al (2007) Central processing of acute muscle pain in chronic low back pain patients: an EEG mapping study. J Clin Neurophysiol 24:76–83PubMedCrossRefGoogle Scholar
  20. Fernandez-de-Las-Penas C, Ge HY, Arendt-Nielsen L, Cuadrado ML, Pareja JA (2007) The local and referred pain from myofascial trigger points in the temporalis muscle contributes to pain profile in chronic tension-type headache. Clin J Pain 23:786–792PubMedCrossRefGoogle Scholar
  21. France CR, Suchowiecki S (1999) A comparison of diffuse noxious inhibitory controls in men and women. Pain 81:77–84PubMedCrossRefGoogle Scholar
  22. Ge HY, Madeleine P, Arendt-Nielsen L (2004) Sex differences in temporal characteristics of descending inhibitory control: an evaluation using repeated bilateral experimental induction of muscle pain. Pain 110:72–78PubMedCrossRefGoogle Scholar
  23. Giesbrecht RJ, Battie MC (2005) A comparison of pressure pain detection thresholds in people with chronic low back pain and volunteers without pain. Phys Ther 85:1085–1092PubMedGoogle Scholar
  24. Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F, Williams DA, Clauw DJ (2004) Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum 50:613–623PubMedCrossRefGoogle Scholar
  25. Granot M, Weissman-Fogel I, Crispel Y, Pud D, Granovsky Y, Sprecher E, Yarnitsky D (2008) Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: Do conditioning stimulus painfulness, gender and personality variables matter? Pain 136:142–149PubMedCrossRefGoogle Scholar
  26. Greenspan JD, Craft RM, LeResche L et al (2007) Studying sex and gender differences in pain and analgesia: a consensus report. Pain 132(Suppl 1):S26–S45PubMedCentralPubMedCrossRefGoogle Scholar
  27. Gregory NS, Gibson-Corley K, Frey-Law L, Sluka KA (2013) Fatigue-enhanced hyperalgesia in response to muscle insult: induction and development occur in a sex-dependent manner. Pain 154:2668–2676PubMedCentralPubMedCrossRefGoogle Scholar
  28. 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 5:366–376PubMedCrossRefGoogle Scholar
  29. Huppe A, Brockow T, Raspe H (2004) Chronic widespread pain and tender points in low back pain: a population-based study. Z Rheumatol 63:76–83PubMedCrossRefGoogle Scholar
  30. Imamura M, Chen J, Matsubayashi SR, Targino RA, Alfieri FM, Bueno DK, Hsing WT (2013) Changes in pressure pain threshold in patients with chronic nonspecific low back pain. Spine (Phila Pa 1976) 38:2098–2107CrossRefGoogle Scholar
  31. Jensen OK, Nielsen CV, Stengaard-Pedersen K (2010) Low back pain may be caused by disturbed pain regulation: a cross-sectional study in low back pain patients using tender point examination. Eur J Pain 14:514–522PubMedCrossRefGoogle Scholar
  32. John MT (2011) Whiplash is likely to be associated with temporomandibular disorder symptoms, but the magnitude of this association is not known. J Evid Based Dent Pract 11:127–128PubMedCrossRefGoogle Scholar
  33. Julien N, Goffaux P, Arsenault P, Marchand S (2005) Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 114:295–302PubMedCrossRefGoogle Scholar
  34. King CD, Wong F, Currie T, Mauderli AP, Fillingim RB, Riley JL 3rd (2009) Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder. Pain 143:172–178PubMedCentralPubMedCrossRefGoogle Scholar
  35. Knudsen L, Drummond PD (2009) Cold-induced limb pain decreases sensitivity to pressure-pain sensations in the ipsilateral forehead. Eur J Pain 13:1023–1029PubMedCrossRefGoogle Scholar
  36. Koldas Dogan S, Sonel Tur B, Kurtais Y, Atay MB (2008) Comparison of three different approaches in the treatment of chronic low back pain. Clin Rheumatol 27:873–881PubMedCrossRefGoogle Scholar
  37. Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926PubMedCentralPubMedCrossRefGoogle Scholar
  38. 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 9:267–275PubMedCrossRefGoogle Scholar
  39. Lautenbacher S, Rollman GB (1997) Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 13:189–196PubMedCrossRefGoogle Scholar
  40. Leffler AS, Hansson P, Kosek E (2002) Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia. Eur J Pain 6:149–159PubMedCrossRefGoogle Scholar
  41. Lemley KJ, Hunter SK, Bement MK (2015) Conditioned pain modulation predicts exercise-induced hypoalgesia in healthy adults. Med Sci Sports Exerc 47:176–184PubMedCrossRefGoogle Scholar
  42. LeResche L, Turner JA, Saunders K, Shortreed SM, Von Korff M (2013) Psychophysical tests as predictors of back pain chronicity in primary care. J Pain 14:1663–1670PubMedCrossRefGoogle Scholar
  43. Lewis GN, Rice DA, McNair PJ (2012) Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 13:936–944PubMedCrossRefGoogle Scholar
  44. Liebano RE, Rakel B, Vance CG, Walsh DM, Sluka KA (2011) An investigation of the development of analgesic tolerance to TENS in humans. Pain 152:335–342PubMedCentralPubMedCrossRefGoogle Scholar
  45. Liebano RE, Vance CG, Rakel BA et al (2013) Transcutaneous electrical nerve stimulation and conditioned pain modulation influence the perception of pain in humans. Eur J Pain 17:1539–1546PubMedCentralPubMedGoogle Scholar
  46. Maixner W, Fillingim R, Sigurdsson A, Kincaid S, Silva S (1998) Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain: evidence for altered temporal summation of pain. Pain 76:71–81PubMedCrossRefGoogle Scholar
  47. Martel MO, Wasan AD, Edwards RR (2013) Sex differences in the stability of conditioned pain modulation (CPM) among patients with chronic pain. Pain Med 14:1757–1768PubMedCrossRefGoogle Scholar
  48. Meeus M, Nijs J, Van de Wauwer N, Toeback L, Truijen S (2008) Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: an experimental study. Pain 139:439–448PubMedCrossRefGoogle Scholar
  49. Meeus M, Roussel NA, Truijen S, Nijs J (2010) Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study. J Rehabil Med 42:884–890PubMedCrossRefGoogle Scholar
  50. Mlekusch S, Schliessbach J, Camara RJ, Arendt-Nielsen L, Juni P, Curatolo M (2013) Do central hypersensitivity and altered pain modulation predict the course of chronic low back and neck pain? Clin J Pain 29:673–680PubMedCrossRefGoogle Scholar
  51. Naugle KM, Riley JL (2014) Self-reported physical activity predicts pain inhibitory and facilitatory function. Med Sci Sports Exerc 46:622–629PubMedCentralPubMedCrossRefGoogle Scholar
  52. 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 153:311–318PubMedCrossRefGoogle Scholar
  53. Nijs J, Van Houdenhove B, Oostendorp RA (2010) Recognition of central sensitization in patients with musculoskeletal pain: application of pain neurophysiology in manual therapy practice. Man Ther 15:135–141PubMedCrossRefGoogle Scholar
  54. Nijs J, Meeus M, Van Oosterwijck J, Roussel N, De Kooning M, Ickmans K, Matic M (2011) Treatment of central sensitization in patients with ‘unexplained’ chronic pain: What options do we have? Expert Opin Pharmacother 12:1087–1098PubMedCrossRefGoogle Scholar
  55. Nir RR, Yarnitsky D (2015) Conditioned pain modulation. Curr Opin Support Palliat Care Feb 19. [Epub ahead of print]Google Scholar
  56. 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 11:415–420PubMedCrossRefGoogle Scholar
  57. O’Neill S, Kjaer P, Graven-Nielsen T, Manniche C, Arendt-Nielsen L (2011) Low pressure pain thresholds are associated with, but does not predispose for, low back pain. Eur Spine J 20:2120–2125PubMedCentralPubMedCrossRefGoogle Scholar
  58. O’Neill S, Manniche C, Graven-Nielsen T, Arendt-Nielsen L (2014) Association between a composite score of pain sensitivity and clinical parameters in low-back pain. Clin J Pain 30:831–838PubMedCrossRefGoogle Scholar
  59. Peters ML, Schmidt AJ, Van den Hout MA (1989) Chronic low back pain and the reaction to repeated acute pain stimulation. Pain 39:69–76PubMedCrossRefGoogle Scholar
  60. 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 50:177–187PubMedCrossRefGoogle Scholar
  61. Pielsticker A, Haag G, Zaudig M, Lautenbacher S (2005) Impairment of pain inhibition in chronic tension-type headache. Pain 118:215–223PubMedCrossRefGoogle Scholar
  62. Pollard LC, Ibrahim F, Choy EH, Scott DL (2012) Pain thresholds in rheumatoid arthritis: the effect of tender point counts and disease duration. J Rheumatol 39:28–31PubMedCrossRefGoogle Scholar
  63. Popescu A, LeResche L, Truelove EL, Drangsholt MT (2010) Gender differences in pain modulation by diffuse noxious inhibitory controls: a systematic review. Pain 150:309–318PubMedCrossRefGoogle Scholar
  64. Pud D, Sprecher E, Yarnitsky D (2005) Homotopic and heterotopic effects of endogenous analgesia in healthy volunteers. Neurosci Lett 380:209–213PubMedCrossRefGoogle Scholar
  65. Pud D, Granovsky Y, Yarnitsky D (2009) The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans. Pain 144:16–19PubMedCrossRefGoogle Scholar
  66. Rolke R, Baron R, Maier C et al (2006) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123:231–243PubMedCrossRefGoogle Scholar
  67. Roussel NA, Nijs J, Meeus M, Mylius V, Fayt C, Oostendorp R (2013) Central sensitization and altered central pain processing in chronic low back pain: Fact or myth? Clin J Pain 29:625–638PubMedCrossRefGoogle Scholar
  68. Sarlani E, Garrett PH, Grace EG, Greenspan JD (2007) Temporal summation of pain characterizes women but not men with temporomandibular disorders. J Orofac Pain 21:309–317PubMedGoogle Scholar
  69. Schenk P, Laeubli T, Klipstein A (2007) Validity of pressure pain thresholds in female workers with and without recurrent low back pain. Eur Spine J 16:267–275PubMedCentralPubMedCrossRefGoogle Scholar
  70. Shah JP, Danoff JV, Desai MJ, Parikh S, Nakamura LY, Phillips TM, Gerber LH (2008) Biochemicals associated with pain and inflammation are elevated in sites near to and remote from active myofascial trigger points. Arch Phys Med Rehabil 89:16–23PubMedCrossRefGoogle Scholar
  71. Staud R (2011) Evidence for shared pain mechanisms in osteoarthritis, low back pain, and fibromyalgia. Curr Rheumatol Rep 13:513–520PubMedCrossRefGoogle Scholar
  72. Staud R, Robinson ME, Vierck CJ Jr, Price DD (2003) Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 101:167–174PubMedCrossRefGoogle Scholar
  73. Tamcan O, Mannion AF, Eisenring C, Horisberger B, Elfering A, Muller U (2010) The course of chronic and recurrent low back pain in the general population. Pain 150:451–457PubMedCrossRefGoogle Scholar
  74. Vance CG, Rakel BA, Blodgett NP, DeSantana JM, Amendola A, Zimmerman MB, Walsh DM, Sluka KA (2012) Effects of transcutaneous electrical nerve stimulation on pain, pain sensitivity, and function in people with knee osteoarthritis: a randomized controlled trial.Phys Ther 92(7):898-910PubMedCentralPubMedCrossRefGoogle Scholar
  75. Villanueva L (2009) Diffuse Noxious Inhibitory Control (DNIC) as a tool for exploring dysfunction of endogenous pain modulatory systems. Pain 143:161–162PubMedCrossRefGoogle Scholar
  76. Villanueva L, Bouhassira D, Le Bars D (1996) The medullary subnucleus reticularis dorsalis (SRD) as a key link in both the transmission and modulation of pain signals. Pain 67:231–240PubMedCrossRefGoogle Scholar
  77. Yarnitsky D, Arendt-Nielsen L, Bouhassira D et al (2010) Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14:339PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Juliana Barbosa Corrêa
    • 1
  • Leonardo Oliveira Pena Costa
    • 1
    • 2
  • Naiane Teixeira Bastos de Oliveira
    • 1
  • Kathleen A. Sluka
    • 3
  • Richard Eloin Liebano
    • 1
    Email author
  1. 1.Master’s and Doctoral Programs in Physical TherapyUniversidade Cidade de São PauloTatuapéBrazil
  2. 2.Musculoskeletal DivisionThe George Institute for Global HealthSydneyAustralia
  3. 3.Graduate Program in Physical Therapy and Rehabilitation Science, College of MedicineUniversity of IowaIowa CityUSA

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