Skip to main content

Advertisement

SpringerLink
Log in

Does central sensitization help explain idiopathic overactive bladder?

  • Opinion
  • Published:

From Nature Reviews Urology

View current issue Sign up to alerts

Abstract

The pathophysiological mechanisms underlying overactive bladder syndrome (OAB) can include dysfunction of sensory pathways of the peripheral and central nervous systems, resulting in bladder hypersensitivity. Central sensitization describes an induced state of spinal hypersensitivity that is associated with a variety of chronic pain disorders that share many attributes with OAB, albeit without the presence of pain. As such, the concept of central sensitization might be relevant to understanding the mechanisms and clinical manifestations of OAB syndrome. An understanding of the pathophysiology and clinical manifestations of central sensitization, and the evidence that supports a role of central sensitization in OAB, including the potential implications of mechanisms of central sensitization for the treatment of patients with OAB could provide a novel approach to the treatment of patients with this disease. Such an approach would be especially relevant to those patients with central sensitization-related comorbidities, and has the potential to improve the outcomes of these patients in particular.

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

Figure 1: Mechanisms of central sensitization.
Figure 2: Temporal summation.
Figure 3: Hypothetical roles of central sensitization in overactive bladder (OAB).

Similar content being viewed by others

References

  1. Hartmann, K. et al. Treatment of overactive bladder in women. http://www.ahrq.gov/downloads/pub/evidence/pdf/bladder/bladder.pdf (2009).

  2. Milsom, I. et al. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur. Urol. 65, 79–95 (2014).

    PubMed  Google Scholar 

  3. Ju, R., Garrett, J. & Wu, J. M. Anticholinergic medication use for female overactive bladder in the ambulatory setting in the United States. Int. Urogynecol. J. 25, 479–484 (2014).

    PubMed  Google Scholar 

  4. Ganz, M. L. et al. Economic costs of overactive bladder in the United States. Urology 75, 526–532.e18 (2010).

    PubMed  Google Scholar 

  5. Wein, A. J. Overactive bladder: defining the disease. Am. J. Manag. Care 6, S559–S564; discussion S607–S619 (2000).

    CAS  PubMed  Google Scholar 

  6. Abrams, P. et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol. Urodynam. 21, 167–178 (2002).

    Google Scholar 

  7. Clemens, J. Q. Afferent neurourology: a novel paradigm. Neurourol. Urodynam. 29 (Suppl. 1), S29–S31 (2010).

    Google Scholar 

  8. Homma, Y. Hypersensitive bladder: a solution to confused terminology and ignorance concerning interstitial cystitis. Int. J. Urol. 21 (Suppl. 1), 43–47 (2014).

    PubMed  Google Scholar 

  9. Phillips, K. & Clauw, D. J. Central pain mechanisms in chronic pain states — maybe it is all in their head. Best Pract. Res. Clin. Rheumatol. 25, 141–154 (2011).

    PubMed  PubMed Central  Google Scholar 

  10. Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).

    PubMed  Google Scholar 

  11. Yunus, M. B. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin. Arthritis Rheum. 37, 339–352 (2008).

    PubMed  Google Scholar 

  12. The InternationaI Association for the Study of Pain. The IASP pain terminology. http://www.iasp-pain.org/Taxonomy?navItemNumber=576 (2012).

  13. Baron, R., Hans, G. & Dickenson, A. H. Peripheral input and its importance for central sensitization. Ann. Neurol. 74, 630–636 (2013).

    PubMed  Google Scholar 

  14. Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).

    PubMed  PubMed Central  Google Scholar 

  15. Mifflin, K. A. & Kerr, B. J. The transition from acute to chronic pain: understanding how different biological systems interact. Can. J. Anaesth. 61, 112–122 (2014).

    PubMed  Google Scholar 

  16. Kandasamy, R. & Price, T. J. The pharmacology of nociceptor priming. Handb. Exp. Pharmacol. 227, 15–37 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuner, R. Central mechanisms of pathological pain. Nat. Med. 16, 1258–1266 (2010).

    CAS  PubMed  Google Scholar 

  18. Mizumura, K. & Murase, S. Role of nerve growth factor in pain. Handb. Exp. Pharmacol. 227, 57–77 (2015).

    CAS  PubMed  Google Scholar 

  19. Smith, P. A. BDNF: no gain without pain? Neuroscience 283, 107–123 (2014).

    CAS  PubMed  Google Scholar 

  20. Beggs, S., Trang, T. & Salter, M. W. P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 15, 1068–1073 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Old, E. A., Clark, A. K. & Malcangio, M. The role of glia in the spinal cord in neuropathic and inflammatory pain. Handb. Exp. Pharmacol. 227, 145–170 (2015).

    PubMed  Google Scholar 

  22. Arendt-Nielsen, L. & Yarnitsky, D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J. Pain 10, 556–572 (2009).

    PubMed  Google Scholar 

  23. Thakur, M., Dickenson, A. H. & Baron, R. Osteoarthritis pain: nociceptive or neuropathic? Nat. Rev. Rheumatol. 10, 374–380 (2014).

    PubMed  Google Scholar 

  24. Roussel, N. A. et al. Central sensitization and altered central pain processing in chronic low back pain: fact or myth? Clin. J. Pain 29, 625–638 (2013).

    PubMed  Google Scholar 

  25. Zhou, Q. & Verne, G. N. New insights into visceral hypersensitivity — clinical implications in IBS. Nat. Rev. Gastroenterol. Hepatol. 8, 349–355 (2011).

    PubMed  PubMed Central  Google Scholar 

  26. Yunus, M. B. Editorial review: an update on central sensitivity syndromes and the issues of nosology and psychobiology. Curr. Rheumatol. Rev. 11, 70–85 (2015).

    PubMed  Google Scholar 

  27. Kaya, S., Hermans, L., Willems, T., Roussel, N. & Meeus, M. Central sensitization in urogynecological chronic pelvic pain: a systematic literature review. Pain Physician 16, 291–308 (2013).

    PubMed  Google Scholar 

  28. Warren, J. W. Bladder pain syndrome/interstitial cystitis as a functional somatic syndrome. J. Psychosom. Res. 77, 510–515 (2014).

    PubMed  Google Scholar 

  29. Homma, Y. Hypersensitive bladder: towards clear taxonomy surrounding interstitial cystitis. Int. J. Urol. 20, 742–743 (2013).

    PubMed  Google Scholar 

  30. Clemens, J. Q. Afferent neurourology: an epidemiological perspective. J. Urol. 184, 432–439 (2010).

    PubMed  Google Scholar 

  31. Lai, H. H., Vetter, J., Jain, S., Gereau, R. W. 4th & Andriole, G. L. The overlap and distinction of self-reported symptoms between interstitial cystitis/bladder pain syndrome and overactive bladder: a questionnaire based analysis. J. Urol. 192, 1679–1685 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. Schur, E. A. et al. Feeling bad in more ways than one: comorbidity patterns of medically unexplained and psychiatric conditions. J. Gen. Intern. Med. 22, 818–821 (2007).

    PubMed  PubMed Central  Google Scholar 

  33. Warren, J. W., Langenberg, P. & Clauw, D. J. The number of existing functional somatic syndromes (FSSs) is an important risk factor for new, different FSSs. J. Psychosom. Res. 74, 12–17 (2013).

    PubMed  Google Scholar 

  34. Lackner, J. M. et al. Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 11, 1147–1157 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. Le, H. et al. Co-morbidity of migraine with somatic disease in a large population-based study. Cephalalgia 31, 43–64 (2011).

    PubMed  Google Scholar 

  36. Bullones Rodriguez, M. A. et al. Evidence for overlap between urological and nonurological unexplained clinical conditions. J. Urol. 189, S66–74 (2013).

    PubMed  Google Scholar 

  37. Kim, S. E. & Chang, L. Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms? Neurogastroenterol. Motil. 24, 895–913 (2012).

    CAS  PubMed  Google Scholar 

  38. Gwilym, S. E. et al. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum. 61, 1226–1234 (2009).

    PubMed  Google Scholar 

  39. Van Houdenhove, B. & Luyten, P. Central sensitivity syndromes: stress system failure may explain the whole picture. Semin. Arthritis Rheum. 39, 218–219 (2009).

    PubMed  Google Scholar 

  40. Arendt-Nielsen, L. Central sensitization in humans: assessment and pharmacology. Handb. Exp. Pharmacol. 227, 79–102 (2015).

    CAS  PubMed  Google Scholar 

  41. Cruz-Almeida, Y. & Fillingim, R. B. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med. 15, 61–72 (2014).

    PubMed  Google Scholar 

  42. Geber, C. et al. Test-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): a multi-centre study. Pain 152, 548–556 (2011).

    PubMed  Google Scholar 

  43. Li, J., Simone, D. A. & Larson, A. A. Windup leads to characteristics of central sensitization. Pain 79, 75–82 (1999).

    CAS  PubMed  Google Scholar 

  44. Chung, O. Y., Bruehl, S., Diedrich, L. & Diedrich, A. The impact of blood pressure and baroreflex sensitivity on wind-up. Anesth. Analg. 107, 1018–1025 (2008).

    PubMed  Google Scholar 

  45. Walker, L. S., Sherman, A. L., Bruehl, S., Garber, J. & Smith, C. A. Functional abdominal pain patient subtypes in childhood predict functional gastrointestinal disorders with chronic pain and psychiatric comorbidities in adolescence and adulthood. Pain 153, 1798–1806 (2012).

    PubMed  PubMed Central  Google Scholar 

  46. Dengler-Crish, C. M., Bruehl, S. & Walker, L. S. Increased wind-up to heat pain in women with a childhood history of functional abdominal pain. Pain 152, 802–808 (2011).

    PubMed  PubMed Central  Google Scholar 

  47. Arebi, N. et al. Distinct neurophysiological profiles in irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G1086–G1093 (2011).

    CAS  PubMed  Google Scholar 

  48. Pfau, D. B., Rolke, R., Nickel, R., Treede, R. D. & Daublaender, M. Somatosensory profiles in subgroups of patients with myogenic temporomandibular disorders and fibromyalgia syndrome. Pain 147, 72–83 (2009).

    PubMed  Google Scholar 

  49. Blumenstiel, K. et al. Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia. Clin. J. Pain 27, 682–690 (2011).

    PubMed  Google Scholar 

  50. Smith, B. W. et al. Habituation and sensitization to heat and cold pain in women with fibromyalgia and healthy controls. Pain 140, 420–428 (2008).

    PubMed  Google Scholar 

  51. Lai, H. H., Gardner, V., Ness, T. J. & Gereau, R. W. 4th Segmental hyperalgesia to mechanical stimulus in interstitial cystitis/bladder pain syndrome: evidence of central sensitization. J. Urol. 191, 1294–1299 (2014).

    PubMed  Google Scholar 

  52. Larsson, M. B. et al. Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome. Gastroenterology 142, 463–472 (2012).

    PubMed  Google Scholar 

  53. Cagnie, B. et al. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin. Arthritis Rheum. 44, 68–75 (2014).

    PubMed  Google Scholar 

  54. Mayer, T. G. et al. The development and psychometric validation of the central sensitization inventory. Pain Pract. 12, 276–285 (2012).

    PubMed  Google Scholar 

  55. Neblett, R. et al. The Central Sensitization Inventory (CSI): establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample. J. Pain 14, 438–445 (2013).

    PubMed  PubMed Central  Google Scholar 

  56. Neblett, R. et al. Ability of the central sensitization inventory to identify central sensitivity syndromes in an outpatient chronic pain sample. Clin. J. Pain 31, 323–332 (2015).

    PubMed  Google Scholar 

  57. Gierk, B. et al. The somatic symptom scale-8 (SSS-8): a brief measure of somatic symptom burden. JAMA Intern. Med. 174, 399–407 (2014).

    PubMed  Google Scholar 

  58. Kroenke, K., Spitzer, R. L. & Williams, J. B. The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms. Psychosom. Med. 64, 258–266 (2002).

    PubMed  Google Scholar 

  59. Hauser, W., Brahler, E., Wolfe, F. & Henningsen, P. Patient Health Questionnaire 15 as a generic measure of severity in fibromyalgia syndrome: surveys with patients of three different settings. J. Psychosom. Res. 76, 307–311 (2014).

    PubMed  Google Scholar 

  60. Spiller, R. C. et al. The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease. Aliment. Pharmacol. Ther. 32, 811–820 (2010).

    CAS  PubMed  Google Scholar 

  61. Koh, J. S. et al. Depression and somatic symptoms may influence on chronic prostatitis/chronic pelvic pain syndrome: a preliminary study. Psychiatry Investig. 11, 495–498 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. Kanai, A. & Andersson, K. E. Bladder afferent signaling: recent findings. J. Urol. 183, 1288–1295 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Birder, L. et al. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol. Urodynam. 29, 128–139 (2010).

    CAS  Google Scholar 

  64. Kanai, A. in Handbook of experimental pharmacology (eds Andersson, K. E. & Michel, M. C.) 171–206 (Springer, 2011).

    Google Scholar 

  65. Chapple, C. Chapter 2: pathophysiology of neurogenic detrusor overactivity and the symptom complex of 'overactive bladder'. Neurourol. Urodynam. 33, S6–S13 (2014).

    Google Scholar 

  66. Yoshimura, N. & de Groat, W. C. Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation. J. Neurosci. 19, 4644–4653 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Habler, H. J., Janig, W. & Koltzenburg, M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J. Physiol. 425, 545–562 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Mazieres, L., Jiang, C. & Lindstrom, S. The C fibre reflex of the cat urinary bladder. J. Physiol. 513, 531–541 (1998).

    PubMed  PubMed Central  Google Scholar 

  69. Xiao, Z. et al. Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats. Am. J. Physiol. Renal Physiol. 307, F673–F679 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gillespie, J. I., van Koeveringe, G. A., de Wachter, S. G. & de Vente, J. On the origins of the sensory output from the bladder: the concept of afferent noise. BJU Int. 103, 1324–1333 (2009).

    PubMed  Google Scholar 

  71. Keay, S. K., Birder, L. A. & Chai, T. C. Evidence for bladder urothelial pathophysiology in functional bladder disorders. BioMed Res. Int. 2014, 865463 (2014).

    PubMed  PubMed Central  Google Scholar 

  72. Chacko, S., Cortes, E., Drake, M. J. & Fry, C. H. Does altered myogenic activity contribute to OAB symptoms from detrusor overactivity? ICI-RS 2013. Neurourol. Urodynam. 33, 577–580 (2014).

    CAS  Google Scholar 

  73. Ustinova, E. E., Fraser, M. O. & Pezzone, M. A. Cross-talk and sensitization of bladder afferent nerves. Neurourol. Urodynam. 29, 77–81 (2010).

    Google Scholar 

  74. Malykhina, A. P. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience 149, 660–672 (2007).

    CAS  PubMed  Google Scholar 

  75. Giamberardino, M. A. et al. Viscero-visceral hyperalgesia: characterization in different clinical models. Pain 151, 307–322 (2010).

    PubMed  Google Scholar 

  76. Brumovsky, P. R. & Gebhart, G. F. Visceral organ cross-sensitization — an integrated perspective. Auton. Neurosci. 153, 106–115 (2010).

    CAS  PubMed  Google Scholar 

  77. Malykhina, A. P., Wyndaele, J. J., Andersson, K. E., De Wachter, S. & Dmochowski, R. R. Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011. Neurourol. Urodynam. 31, 352–358 (2012).

    Google Scholar 

  78. Minagawa, T., Wyndaele, M., Aizawa, N., Igawa, Y. & Wyndaele, J. J. Mechanisms of pelvic organ cross-talk: 2. Impact of colorectal distention on afferent nerve activity of the rat bladder. J. Urol. 190, 1123–1130 (2013).

    PubMed  Google Scholar 

  79. Wyndaele, M. et al. Mechanisms of pelvic organ crosstalk: 1. Peripheral modulation of bladder inhibition by colorectal distention in rats. J. Urol. 190, 765–771 (2013).

    PubMed  Google Scholar 

  80. Malykhina, A. P. et al. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol. Motil. 18, 936–948 (2006).

    CAS  PubMed  Google Scholar 

  81. Rudick, C. N., Chen, M. C., Mongiu, A. K. & Klumpp, D. J. Organ cross talk modulates pelvic pain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1191–R1198 (2007).

    CAS  PubMed  Google Scholar 

  82. Guo, Y. J. et al. Lower urinary tract symptoms in women with irritable bowel syndrome. Int. J. Urol. 17, 175–181 (2010).

    PubMed  Google Scholar 

  83. Monga, A. K., Marrero, J. M., Stanton, S. L., Lemieux, M. C. & Maxwell, J. D. Is there an irritable bladder in the irritable bowel syndrome? Br. J. Obstet. Gynaecol. 104, 1409–1412 (1997).

    CAS  PubMed  Google Scholar 

  84. Wyndaele, M., De Winter, B. Y., Pelckmans, P. & Wyndaele, J. J. Lower bowel function in urinary incontinent women, urinary continent women and in controls. Neurourol. Urodynam. 30, 138–143 (2011).

    Google Scholar 

  85. Wyndaele, M. et al. Exploring associations between lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems in women: a study in women with urological and GI problems versus a control population. BJU Int. 115, 958–967 (2015).

    PubMed  Google Scholar 

  86. Burgers, R. et al. Functional defecation disorders in children with lower urinary tract symptoms. J. Urol. 189, 1886–1891 (2013).

    PubMed  Google Scholar 

  87. De Wachter, S. & Wyndaele, J. J. Impact of rectal distention on the results of evaluations of lower urinary tract sensation. J. Urol. 169, 1392–1394 (2003).

    PubMed  Google Scholar 

  88. Cardozo, L. & Robinson, D. Special considerations in premenopausal and postmenopausal women with symptoms of overactive bladder. Urology 60, 64–71; discussion 71 (2002).

    PubMed  Google Scholar 

  89. Alling Moller, L., Lose, G. & Jorgensen, T. Risk factors for lower urinary tract symptoms in women 40 to 60 years of age. Obstet. Gynecol. 96, 446–451 (2000).

    CAS  PubMed  Google Scholar 

  90. Klingele, C. J., Lightner, D. J., Fletcher, J. G., Gebhart, J. B. & Bharucha, A. E. Dysfunctional urinary voiding in women with functional defecatory disorders. Neurogastroenterol. Motil. 22, e1094–e1284 (2010).

    Google Scholar 

  91. Carter, D. & Beer-Gabel, M. Lower urinary tract symptoms in chronically constipated women. Int. Urogynecol. J. 23, 1785–1789 (2012).

    PubMed  Google Scholar 

  92. Coyne, K. S. et al. The prevalence of chronic constipation and faecal incontinence among men and women with symptoms of overactive bladder. BJU Int. 107, 254–261 (2011).

    PubMed  Google Scholar 

  93. Yamaguchi, O. et al. Defining overactive bladder as hypersensitivity. Neurourol. Urodynam. 26, 904–907 (2007).

    Google Scholar 

  94. Daly, D. & Chapple, C. Relationship between overactive bladder (OAB) and irritable bowel syndrome (IBS): concurrent disorders with a common pathophysiology? BJU Int. 111, 530–531 (2013).

    PubMed  Google Scholar 

  95. Fitzgerald, M. P. et al. Childhood urinary symptoms predict adult overactive bladder symptoms. J. Urol. 175, 989–993 (2006).

    PubMed  PubMed Central  Google Scholar 

  96. Rodrigues, P., Hering, F. & Campagnari, J. C. Involuntary detrusor contraction is a frequent finding in patients with recurrent urinary tract infections. Urol. Intern. 93, 67–73 (2014).

    Google Scholar 

  97. Saito, M. et al. Bladder dysfunction after acute urinary retention in the rats: a novel over active bladder model. Mol. Cell. Biochem. 333, 109–114 (2010).

    CAS  PubMed  Google Scholar 

  98. Parsons, B. A. & Drake, M. J. Animal models in overactive bladder research. Handb. Exp. Pharmacol. 2011, 15–43 (2011).

    Google Scholar 

  99. Fitzgerald, M. P., Koch, D. & Senka, J. Visceral and cutaneous sensory testing in patients with painful bladder syndrome. Neurourol. Urodynam. 24, 627–632 (2005).

    Google Scholar 

  100. Giamberardino, M. A., Tana, C. & Costantini, R. Pain thresholds in women with chronic pelvic pain. Curr. Opin. Obstet. Gynecol. 26, 253–259 (2014).

    PubMed  Google Scholar 

  101. Ness, T. J., Powell-Boone, T., Cannon, R., Lloyd, L. K. & Fillingim, R. B. Psychophysical evidence of hypersensitivity in subjects with interstitial cystitis. J. Urol. 173, 1983–1987 (2005).

    PubMed  Google Scholar 

  102. Ness, T. J., Lloyd, L. K. & Fillingim, R. B. An endogenous pain control system is altered in subjects with interstitial cystitis. J. Urol. 191, 364–370 (2014).

    PubMed  Google Scholar 

  103. Fujihara, A., Ukimura, O., Iwata, T. & Miki, T. Neuroselective measure of the current perception threshold of A-delta and C-fiber afferents in the lower urinary tract. Int. J. Urol. 18, 341–349 (2011).

    PubMed  Google Scholar 

  104. Wenzler, D. L., Burks, F. N., Cooney, M. & Peters, K. M. Proof of concept trial on changes in current perception threshold after sacral neuromodulation. Neuromodulation 18, 228–231 (2015).

    PubMed  Google Scholar 

  105. Gleason, J. L. et al. Sacral neuromodulation effects on periurethral sensation and urethral sphincter activity. Neurourol. Urodynam. 32, 476–479 (2013).

    Google Scholar 

  106. Vijaya, G. et al. Antimuscarinic effects on current perception threshold: a prospective placebo control study. Neurourol. Urodynam. 31, 75–79 (2012).

    CAS  Google Scholar 

  107. Kenton, K., Lowenstein, L. & Brubaker, L. Tolterodine causes measurable restoration of urethral sensation in women with urge urinary incontinence. Neurourol. Urodynam. 29, 555–557 (2010).

    Google Scholar 

  108. Song, Q. X., Chermansky, C. J., Birder, L. A., Li, L. & Damaser, M. S. Brain-derived neurotrophic factor in urinary continence and incontinence. Nat. Rev. Urol. 11, 579–588 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bhide, A. A., Cartwright, R., Khullar, V. & Digesu, G. A. Biomarkers in overactive bladder. Int. Urogynecol. J. 24, 1065–1072 (2013).

    PubMed  Google Scholar 

  110. Kim, J. C., Park, E. Y., Seo, S. I., Park, Y. H. & Hwang, T. K. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J. Urol. 175, 1773–1776; discussion 1776 (2006).

    CAS  PubMed  Google Scholar 

  111. Liu, H. T., Chancellor, M. B. & Kuo, H. C. Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int. 103, 1668–1672 (2009).

    CAS  PubMed  Google Scholar 

  112. Liu, H. T., Chancellor, M. B. & Kuo, H. C. Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur. Urol. 56, 700–706 (2009).

    CAS  PubMed  Google Scholar 

  113. Liu, H. T., Lin, H. & Kuo, H. C. Increased serum nerve growth factor levels in patients with overactive bladder syndrome refractory to antimuscarinic therapy. Neurourol. Urodynam. 30, 1525–1529 (2011).

    Google Scholar 

  114. Wang, L. W., Han, X. M., Chen, C. H., Ma, Y. & Hai, B. Urinary brain-derived neurotrophic factor: a potential biomarker for objective diagnosis of overactive bladder. Int. Urol. Nephrol. 46, 341–347 (2014).

    CAS  PubMed  Google Scholar 

  115. Antunes-Lopes, T., Pinto, R., Carvalho-Barros, S., Diniz, P. & Martins-Silva, C. Urinary levels of brain derived neurotrophic factor (BDNF) in women with overactive bladder (OAB) syndrome correlate with the severity of symptoms. Eur. Urol. Suppl. 10, 277–278 (2012).

    Google Scholar 

  116. Pinto, R. et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur. Urol. 58, 360–365 (2010).

    CAS  PubMed  Google Scholar 

  117. Griffiths, D., Tadic, S. D., Schaefer, W. & Resnick, N. M. Cerebral control of the bladder in normal and urge-incontinent women. NeuroImage 37, 1–7 (2007).

    PubMed  Google Scholar 

  118. Komesu, Y. M., Ketai, L. H., Mayer, A. R., Teshiba, T. M. & Rogers, R. G. Functional MRI of the brain in women with overactive bladder: brain activation during urinary urgency. Female Pelvic Med. Reconstr. Surg. 17, 50–54 (2011).

    PubMed  PubMed Central  Google Scholar 

  119. Griffiths, D. J. Use of functional imaging to monitor central control of voiding in humans. Handb. Exp. Pharmacol. 2011, 81–97 (2011).

    Google Scholar 

  120. Coyne, K. S. et al. Risk factors and comorbid conditions associated with lower urinary tract symptoms: EpiLUTS. BJU Int. 103 (Suppl. 3), 24–32 (2009).

    PubMed  Google Scholar 

  121. Kaplan, S. A. et al. Systematic review of the relationship between bladder and bowel function: implications for patient management. Int. J. Clin. Pract. 67, 205–216 (2013).

    CAS  PubMed  Google Scholar 

  122. de Araujo, M. P. et al. Urodynamic study and quality of life in patients with fibromyalgia and lower urinary tract symptoms. Int. Urogynecol. J. Pelvic Floor Dysfunct. 19, 1103–1107 (2008).

    PubMed  Google Scholar 

  123. Chung, J. H. et al. The association between overactive bladder and fibromyalgia syndrome: a community survey. Neurourol. Urodynam. 32, 66–69 (2013).

    Google Scholar 

  124. Brand, K., Littlejohn, G., Kristjanson, L., Wisniewski, S. & Hassard, T. The fibromyalgia bladder index. Clin. Rheumatol. 26, 2097–2103 (2007).

    PubMed  Google Scholar 

  125. Wassem, R., McDonald, M. & Racine, J. Fibromyalgia: patient perspectives on symptoms, symptom management, and provider utilization. Clin. Nurse Spec. 16, 24–28; discussion 29–30 (2002).

    PubMed  Google Scholar 

  126. White, K. P., Speechley, M., Harth, M. & Ostbye, T. The London Fibromyalgia Epidemiology Study: comparing the demographic and clinical characteristics in 100 random community cases of fibromyalgia versus controls. J. Rheumatol. 26, 1577–1585 (1999).

    CAS  PubMed  Google Scholar 

  127. Eliasson, K., Elfving, B., Nordgren, B. & Mattsson, E. Urinary incontinence in women with low back pain. Man. Ther. 13, 206–212 (2008).

    PubMed  Google Scholar 

  128. Matsumoto, S. et al. Relationship between overactive bladder and irritable bowel syndrome: a large-scale internet survey in Japan using the overactive bladder symptom score and Rome III criteria. BJU Int. 111, 647–652 (2013).

    PubMed  Google Scholar 

  129. Smith, M. D., Russell, A. & Hodges, P. W. Do incontinence, breathing difficulties, and gastrointestinal symptoms increase the risk of future back pain? J. Pain 10, 876–886 (2009).

    PubMed  Google Scholar 

  130. Smith, M. D., Russell, A. & Hodges, P. W. Is there a relationship between parity, pregnancy, back pain and incontinence? Int. Urogynecol. J. Pelvic Floor Dysfunct. 19, 205–211 (2008).

    PubMed  Google Scholar 

  131. Tincello, D. G. & Walker, A. C. Interstitial cystitis in the UK: results of a questionnaire survey of members of the Interstitial Cystitis Support Group. Eur. J. Obstet. Gynecol. Reprod. Biol. 118, 91–95 (2005).

    PubMed  Google Scholar 

  132. Clemens, J. Q. et al. Perceptions of 'urgency' in women with interstitial cystitis/bladder pain syndrome or overactive bladder. Neurourol. Urodynam. 30, 402–405 (2011).

    Google Scholar 

  133. Abrams, P., Hanno, P. & Wein, A. Overactive bladder and painful bladder syndrome: there need not be confusion. Neurourol. Urodynam. 24, 149–150 (2005).

    Google Scholar 

  134. Castro-Diaz, D. et al. Urgency and pain in patients with overactive bladder and bladder pain syndrome. What are the differences? Int. J. Clin. Pract. 68, 356–362 (2014).

    CAS  PubMed  Google Scholar 

  135. Klumpp, D. J. & Rudick, C. N. Summation model of pelvic pain in interstitial cystitis. Nat. Clin. Pract. Urol. 5, 494–500 (2008).

    PubMed  Google Scholar 

  136. Kilpatrick, L. A. et al. Gating of sensory information differs in patients with interstitial cystitis/painful bladder syndrome. J. Urol. 184, 958–963 (2010).

    PubMed  PubMed Central  Google Scholar 

  137. Twiss, C. et al. Increased startle responses in interstitial cystitis: evidence for central hyperresponsiveness to visceral related threat. J. Urol. 181, 2127–2133 (2009).

    PubMed  Google Scholar 

  138. Farmer, M. A. et al. Brain white matter abnormalities in female interstitial cystitis/bladder pain syndrome: A MAPP Network Neuroimaging Study. J. Urol. 194, 118–126 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. Clemens, J. Q., Elliott, M. N., Suttorp, M. & Berry, S. H. Temporal ordering of interstitial cystitis/bladder pain syndrome and non-bladder conditions. Urology 80, 1227–1231 (2012).

    PubMed  Google Scholar 

  140. Nickel, J. C. et al. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J. Urol. 184, 1358–1363 (2010).

    PubMed  Google Scholar 

  141. Clauw, D. J. et al. The relationship between fibromyalgia and interstitial cystitis. J. Psychiatr. Res. 31, 125–131 (1997).

    CAS  PubMed  Google Scholar 

  142. Warren, J. W., Wesselmann, U., Greenberg, P. & Clauw, D. J. Urinary symptoms as a prodrome of bladder pain syndrome/interstitial cystitis. Urology 83, 1035–1040 (2014).

    PubMed  Google Scholar 

  143. Clemens, J. Q., Meenan, R. T., O'Keeffe Rosetti, M. C., Kimes, T. A. & Calhoun, E. A. Case–control study of medical comorbidities in women with interstitial cystitis. J. Urol. 179, 2222–2225 (2008).

    PubMed  Google Scholar 

  144. Warren, J. W. et al. Antecedent nonbladder syndromes in case-control study of interstitial cystitis/painful bladder syndrome. Urology 73, 52–57 (2009).

    PubMed  Google Scholar 

  145. Wu, E. Q. et al. Interstitial cystitis: cost, treatment and co-morbidities in an employed population. PharmacoEconomics 24, 55–65 (2006).

    PubMed  Google Scholar 

  146. Langenberg, P. W. et al. Pelvic pain and surgeries in women before interstitial cystitis/painful bladder syndrome. Am. J. Obstet. Gynecol. 202, 286.e1–286.e6 (2010).

    Google Scholar 

  147. Warren, J. W., van de Merwe, J. P. & Nickel, J. C. Interstitial cystitis/bladder pain syndrome and nonbladder syndromes: facts and hypotheses. Urology 78, 727–732 (2011).

    PubMed  Google Scholar 

  148. Wu, E. Q. et al. A retrospective claims database analysis to assess patterns of interstitial cystitis diagnosis. Curr. Med. Res. Opin. 22, 495–500 (2006).

    PubMed  Google Scholar 

  149. Kato, K., Sullivan, P. F. & Pedersen, N. L. Latent class analysis of functional somatic symptoms in a population-based sample of twins. J. Psychosom. Res. 68, 447–453 (2010).

    PubMed  PubMed Central  Google Scholar 

  150. Arendt-Nielsen, L. et al. The effect of N-methyl-D-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study. Anesth. Analg. 81, 63–68 (1995).

    CAS  PubMed  Google Scholar 

  151. Koppert, W. et al. A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S+-ketamine, and lidocaine. Anesthesiology 95, 395–402 (2001).

    CAS  PubMed  Google Scholar 

  152. Gottrup, H. et al. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 101, 1400–1408 (2004).

    CAS  PubMed  Google Scholar 

  153. Iannetti, G. D. et al. Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans. Proc. Natl Acad. Sci. USA 102, 18195–18200 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Tuchman, M., Barrett, J. A., Donevan, S., Hedberg, T. G. & Taylor, C. P. Central sensitization and CaVα2δ ligands in chronic pain syndromes: pathologic processes and pharmacologic effect. J. Pain 11, 1241–1249 (2010).

    CAS  PubMed  Google Scholar 

  155. Wang, H. et al. Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects. J. Pain 9, 1088–1095 (2008).

    CAS  PubMed  Google Scholar 

  156. Iyengar, S., Webster, A. A., Hemrick-Luecke, S. K., Xu, J. Y. & Simmons, R. M. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J. Pharmacol. Exp. Ther. 311, 576–584 (2004).

    CAS  PubMed  Google Scholar 

  157. Harding, L. M., Kristensen, J. D. & Baranowski, A. P. Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers. Clin. J. Pain 21, 127–132 (2005).

    PubMed  Google Scholar 

  158. Kim, Y. T. et al. Gabapentin for overactive bladder and nocturia after anticholinergic failure. Int. Braz. J. Urol. 30, 275–278 (2004).

    PubMed  Google Scholar 

  159. Marencak, J., Cossons, N. H., Darekar, A. & Mills, I. W. Investigation of the clinical efficacy and safety of pregabalin alone or combined with tolterodine in female subjects with idiopathic overactive bladder. Neurourol. Urodynam. 30, 75–82 (2011).

    Google Scholar 

  160. Steers, W. D. et al. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int. 100, 337–345 (2007).

    CAS  PubMed  Google Scholar 

  161. Di Rezze, S. et al. Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study. Clin. Neuropharmacol. 35, 231–234 (2012).

    CAS  PubMed  Google Scholar 

  162. Hanna-Mitchell, A. T., Kashyap, M., Chan, W. V., Andersson, K. E. & Tannenbaum, C. Pathophysiology of idiopathic overactive bladder and the success of treatment: a systematic review from ICI-RS 2013. Neurourol. Urodynam. 33, 611–617 (2014).

    CAS  Google Scholar 

  163. Nitti, V. W. et al. Can we predict which patient will fail drug treatment for overactive bladder? A think tank discussion. Neurourol. Urodynam. 29, 652–657 (2010).

    Google Scholar 

  164. Riedl, A. et al. Somatic comorbidities of irritable bowel syndrome: a systematic analysis. J. Psychosom. Res. 64, 573–582 (2008).

    PubMed  Google Scholar 

  165. Gormley, E. A. et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J. Urol. 188, 2455–2463 (2012).

    PubMed  Google Scholar 

  166. Newman, D. K. & Wein, A. J. Office-based behavioral therapy for management of incontinence and other pelvic disorders. Urol. Clin. North Am. 40, 613–635 (2013).

    PubMed  Google Scholar 

  167. Marti, B. G., Valentini, F. A. & Robain, G. Contribution of behavioral and cognitive therapy to managing overactive bladder syndrome in women in the absence of contributive urodynamic diagnosis. Int. Urogynecol. J. 26, 169–173 (2015).

    PubMed  Google Scholar 

  168. Ford, A. C. et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1350–1365; quiz 1366 (2014).

    CAS  PubMed  Google Scholar 

  169. Andersson, K. E. in Bladder Dysfunction in the Adult: The Basis for Clinical Management Current Clinical Urology (eds Wein, A. et al.) 121–220 (Springer, 2014).

    Google Scholar 

  170. Lunn, M. P., Hughes, R. A. & Wiffen, P. J. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst. Rev. 1, CD007115 (2014).

    Google Scholar 

  171. Thin, N. N. et al. Systematic review of the clinical effectiveness of neuromodulation in the treatment of faecal incontinence. Br. J. Surg. 100, 1430–1447 (2013).

    CAS  PubMed  Google Scholar 

  172. Chodez, M. et al. Results of sacral nerve neuromodulation for double incontinence in adults. Tech. Coloproctol. 18, 1147–1151 (2014).

    CAS  PubMed  Google Scholar 

  173. Thomas, G. P., Dudding, T. C., Rahbour, G., Nicholls, R. J. & Vaizey, C. J. Sacral nerve stimulation for constipation. Br. J. Surg. 100, 174–181 (2013).

    CAS  PubMed  Google Scholar 

  174. Govaert, B., Melenhorst, J., van Kleef, M., van Gemert, W. G. & Baeten, C. G. Sacral neuromodulation for the treatment of chronic functional anorectal pain: a single center experience. Pain Pract. 10, 49–53 (2010).

    PubMed  Google Scholar 

  175. Jadav, A. M. et al. Does sacral nerve stimulation improve global pelvic function in women? Colorectal Dis. 15, 848–857 (2013).

    CAS  PubMed  Google Scholar 

  176. Peters, K. M. Sacral neuromodulation is an effective treatment for interstitial cystitis/bladder pain syndrome: pro. J. Urol. 188, 2043–2044 (2012).

    PubMed  Google Scholar 

  177. Powell, C. R. & Kreder, K. J. Long-term outcomes of urgency-frequency syndrome due to painful bladder syndrome treated with sacral neuromodulation and analysis of failures. J. Urol. 183, 173–176 (2010).

    PubMed  Google Scholar 

  178. Tirlapur, S. A., Vlismas, A., Ball, E. & Khan, K. S. Nerve stimulation for chronic pelvic pain and bladder pain syndrome: a systematic review. Acta Obstet. Gynecol. Scand. 92, 881–887 (2013).

    PubMed  Google Scholar 

Download references

Acknowledgements

W.S.R. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K23DK103910. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Urologic Surgery, Vanderbilt University Medical Center, A1302 Medical Center North, Nashville, 37232, Tennessee, USA

    W. Stuart Reynolds & Roger Dmochowski

  2. Division of Urology, University of Pennsylvania Health System, 34th & Civic Center Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Alan Wein

  3. Department of Anesthesiology, Vanderbilt University Medical Center, 701 Medical Arts Building, Nashville, 37232, Tennessee, USA

    Stephen Bruehl

Authors
  1. W. Stuart Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger Dmochowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan Wein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen Bruehl
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.S.R. and S.B. researched data for this article, all authors made a substantial contribution to discussions of content. W.S.R. wrote the manuscript and all authors reviewed and/or edited the manuscript prior to submission.

Corresponding author

Correspondence to W. Stuart Reynolds.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reynolds, W., Dmochowski, R., Wein, A. et al. Does central sensitization help explain idiopathic overactive bladder?. Nat Rev Urol 13, 481–491 (2016). https://doi.org/10.1038/nrurol.2016.95

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2016.95

  • Springer Nature Limited

This article is cited by

Search

Navigation