Skip to main content

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

  • Review Article
  • Published:

Unraveling the mystery of pain in chronic pancreatitis

Nature Reviews Gastroenterology & Hepatology volume 9, pages 140–151 (2012)Cite this article

Subjects

Abstract

Chronic pancreatitis is typically a painful condition and it can be associated with a severe burden of disease. The pathogenesis of pain in this disorder is poorly understood and its treatment has been largely empirical, often consisting of surgical or other invasive methods, with an outcome that is variable and frequently unsatisfactory. Human and experimental studies have indicated a critical role for neuronal mechanisms that result in peripheral and central sensitization. The pancreatic nociceptor seems to be significantly affected in this condition, with increased excitability associated with downregulation of potassium currents. Some of the specific molecules implicated in this process include the vanilloid receptor, TRPV1, nerve growth factor, the protease activated receptor 2 and a variety of others that are discussed in this Review. Studies have also indicated novel therapeutic targets for this condition.

Key Points

  • Managing the pain of pancreatitis is an important unmet medical need

  • Current theories about its pathogenesis have shifted towards a neurobiological rather than a purely mechanical basis, with a major emphasis on sensitization of peripheral and central pathways involved in nociception

  • Pancreatic inflammation, neural remodeling and injury, and changes in the central nervous system contribute to ongoing pain in this condition

  • Studies implicate several targets for novel therapies, including TRPV1, trypsin, tryptase and protease activated receptor 2 signaling, as well as nerve growth factor

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

Access options

Buy this article

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

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

Figure 1: The nociceptor and its three major functions.
Figure 2: A hypothetical stimulus response curve illustrating the concept of sensitization.
Figure 3: A rat model of chronic pancreatitis illustrates changes in nociceptive sensitivity, neuronal excitability and ion currents.
Figure 4: NGF and chronic pancreatitis.
Figure 5: Effects of anti-NGF treatment on chronic pancreatitis.
Figure 6: Studies in humans with chronic pancreatitis.
Figure 7: Peripheral mechanisms of pain in chronic pancreatitis.

Similar content being viewed by others

References

  1. American Gastroenterological Association. The Burden of Gastrointestinal Diseases. AGA Publications. http://www.lewin.com/content/publications/2695.pdf (2001).

  2. Everhart, J. E. The Burden of Digestive Diseases in the United States. (US Department of Health and Human Services, NIH Publication No. 09–6443) (US Government Printing Office, Washington D.C. 2008).

    Google Scholar 

  3. Mullady, D. K. et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut 60, 77–84 (2011).

    Article  PubMed  Google Scholar 

  4. Williams, J. G. et al. Gastroenterology services in the UK. The burden of disease, and the organisation and delivery of services for gastrointestinal and liver disorders: a review of the evidence. Gut 56 (Suppl. 1), 1–113 (2007).

    Article  PubMed  Google Scholar 

  5. Rerknimitr, R. Asian chronic pancreatitis: the common and the unique. J. Gastroenterol. Hepatol. 26 (Suppl. 2), 6–11 (2011).

    Article  PubMed  Google Scholar 

  6. Ammann, R. W., Akovbiantz, A., Largiader, F. & Schueler, G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 86, 820–828 (1984).

    CAS  PubMed  Google Scholar 

  7. Thuluvath, P. J., Imperio, D., Nair, S. & Cameron, J. L. Chronic pancreatitis. Long-term pain relief with or without surgery, cancer risk, and mortality. J. Clin. Gastroenterol. 36, 159–165 (2003).

    Article  PubMed  Google Scholar 

  8. Jupp, J., Fine, D. & Johnson, C. D. The epidemiology and socioeconomic impact of chronic pancreatitis. Best Pract. Res. Clin. Gastroenterol. 24, 219–231 (2010).

    Article  PubMed  Google Scholar 

  9. DiMagno, E. P. Toward understanding (and management) of painful chronic pancreatitis. Gastroenterology 116, 1252–1257 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Warshaw, A. L., Banks, P. A. & Fernandez-Del Castillo, C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 115, 765–776 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Strate, T. et al. Resection vs drainage in treatment of chronic pancreatitis: long-term results of a randomized trial. Gastroenterology 134, 1406–1411 (2008).

    Article  PubMed  Google Scholar 

  12. Dite, P., Ruzicka, M., Zboril, V. & Novotny, I. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 35, 553–558 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Mullhaupt, B. & Ammann, R. W. Total pancreatectomy for intractable pain in chronic pancreatitis? Pancreas 39, 111–112 (2010).

    Article  PubMed  Google Scholar 

  14. Ebbehoj, N., Borly, L., Madsen, P. & Svendsen, L. B. Pancreatic tissue pressure and pain in chronic pancreatitis. Pancreas 1, 556–558 (1986).

    Article  CAS  PubMed  Google Scholar 

  15. Ebbehoj, N., Christensen, E. & Madsen, P. Prediction of outcome of pancreaticogastrostomy for pain in chronic pancreatitis. Scand. J. Gastroenterol. 22, 337–342 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Ebbehoj, N., Klaaborg, K. E., Kronborg, O. & Madsen, P. Pancreaticogastrostomy for chronic pancreatitis. Am. J. Surg. 157, 315–317 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Ebbehoj, N., Borly, L., Bulow, J., Rasmussen, S. G. & Madsen, P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. A longitudinal study. Scand. J. Gastroenterol. 25, 462–466 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Ebbehoj, N. et al. Pancreatic tissue fluid pressure in chronic pancreatitis. Relation to pain, morphology, and function. Scand. J. Gastroenterol. 25, 1046–1051 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Ebbehoj, N., Borly, L., Madsen, P. & Matzen, P. Pancreatic tissue fluid pressure during drainage operations for chronic pancreatitis. Scand. J. Gastroenterol. 25, 1041–1045 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Ebbehoj, N. Pancreatic tissue fluid pressure and pain in chronic pancreatitis. Dan. Med. Bull. 39, 128–133 (1992).

    CAS  PubMed  Google Scholar 

  21. Karanjia, N. D. & Reber, H. A. The cause and management of the pain of chronic pancreatitis. Gastroenterol. Clin. North Am. 19, 895–904 (1990).

    CAS  PubMed  Google Scholar 

  22. Karanjia, N. D. et al. Compartment syndrome in experimental chronic obstructive pancreatitis: effect of decompressing the main pancreatic duct. Br. J. Surg. 81, 259–264 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Manes, G., Buchler, M., Pieramico, O., Di Sebastiano, P. & Malfertheiner, P. Is increased pancreatic pressure related to pain in chronic pancreatitis? Int. J. Pancreatol. 15, 113–117 (1994).

    CAS  PubMed  Google Scholar 

  24. Renou, C., Grandval, P., Ville, E. & Laugier, R. Endoscopic treatment of the main pancreatic duct: correlations among morphology, manometry, and clinical follow-up. Int. J. Pancreatol. 27, 143–149 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Bornman, P. C. et al. Pathogenesis of pain in chronic pancreatitis: ongoing enigma. World J. Surg. 27, 1175–1182 (2003).

    Article  PubMed  Google Scholar 

  26. Anaparthy, R. & Pasricha, P. J. Pain and chronic pancreatitis: is it the plumbing or the wiring? Curr. Gastroenterol. Rep. 10, 101–106 (2008).

    Article  PubMed  Google Scholar 

  27. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dubin, A. E. & Patapoutian, A. Nociceptors: the sensors of the pain pathway. J. Clin. Invest. 120, 3760–3772 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pasricha, P. J. Approach to the patient with abdominal pain in Principles of Clinical Gastroenterology (eds Yamada, T. et al.) 228–254 (Wiley Blackwell, Chichester, 2008).

    Chapter  Google Scholar 

  30. Sandkuhler, J. Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev. 89, 707–758 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  33. Woolf, C. J. & Costigan, M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc. Natl Acad. Sci. USA 96, 7723–7730 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Winston, J. H. et al. Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a. J. Pain 4, 329–337 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Smiley, M. M., Lu, Y., Vera-Portocarrero, L. P., Zidan, A. & Westlund, K. N. Intrathecal gabapentin enhances the analgesic effects of subtherapeutic dose morphine in a rat experimental pancreatitis model. Anesthesiology 101, 759–765 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Lu, Y., Vera-Portocarrero, L. P. & Westlund, K. N. Intrathecal coadministration of D-APV and morphine is maximally effective in a rat experimental pancreatitis model. Anesthesiology 98, 734–740 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Houghton, A. K., Kadura, S. & Westlund, K. N. Dorsal column lesions reverse the reduction of homecage activity in rats with pancreatitis. Neuroreport 8, 3795–3800 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Kim, E. H. et al. Activation of nociceptive neurons in T9 and T10 in cerulein pancreatitis. J. Surg. Res. 117, 195–201 (2004).

    Article  PubMed  Google Scholar 

  39. Vera-Portocarrero, L. P. & Westlund, K. N. Attenuation of nociception in a model of acute pancreatitis by an NK-1 antagonist. Pharmacol. Biochem. Behav. 77, 631–640 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, L., Zhang, X. & Westlund, K. N. Restoration of spontaneous exploratory behaviors with an intrathecal NMDA receptor antagonist or a PKC inhibitor in rats with acute pancreatitis. Pharmacol. Biochem. Behav. 77, 145–153 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Winston, J. H., He, Z. J., Shenoy, M., Xiao, S. Y. & Pasricha, P. J. Molecular and behavioral changes in nociception in a novel rat model of chronic pancreatitis for the study of pain. Pain 117, 214–222 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Vera-Portocarrero, L. P., Lu, Y. & Westlund, K. N. Nociception in persistent pancreatitis in rats: effects of morphine and neuropeptide alterations. Anesthesiology 98, 474–484 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Unno, T., Inaba, Y., Ohashi, H. & Komori, S. Inhibitory effects of organotin compounds on voltage-dependent, tetrodotoxin-resistant Na+ channel current in guinea pig dorsal root ganglion cells. Toxicol. In Vitro 16, 141–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Jenkins, S. M., Ehman, K. & Barone, S. Jr. Structure-activity comparison of organotin species: dibutyltin is a developmental neurotoxicant in vitro and in vivo. Brain Res. Dev. Brain Res. 151, 1–12 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Khaliq, M. A., Husain, R., Seth, P. K. & Srivastava, S. P. Effect of dibutyltin dilaurate on regional brain polyamines in rats. Toxicol. Lett. 55, 179–183 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Kobayashi, H. et al. Effects of tri-, di- and monobutyltin on synaptic parameters of the cholinergic system in the cerebral cortex of mice. Jpn J. Pharmacol. 72, 317–324 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Liddle, R. A. The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis. Biochim. Biophys. Acta 1772, 869–878 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nishimura, S. et al. Hydrogen sulfide as a novel mediator for pancreatic pain in rodents. Gut 58, 762–770 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Xu, G. Y. et al. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology 133, 1282–1292 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Ceppa, E. et al. Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G556–G571 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schwartz, E. S. et al. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140, 1283–1291.e1–2 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Hoogerwerf, W. A. et al. The proteinase-activated receptor 2 is involved in nociception. J. Neurosci. 21, 9036–9042 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Amadesi, S. et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J. Physiol. 575, 555–571 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hoogerwerf, W. A. et al. Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain. Gastroenterology 127, 883–891 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Xu, G. Y., Winston, J. H., Shenoy, M., Yin, H. & Pasricha, P. J. Enhanced excitability and suppression of A-type K+ current of pancreas-specific afferent neurons in a rat model of chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G424–G431 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stewart, T., Beyak, M. J. & Vanner, S. Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons. J. Physiol. 552, 797–807 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dang, K., Bielefeldt, K. & Gebhart, G. F. Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G573–G579 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Qian, A. H. et al. Voltage-gated potassium channels in IB4-positive colonic sensory neurons mediate visceral hypersensitivity in the rat. Am. J. Gastroenterol. 104, 2014–2027 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Black, J. A., Liu, S., Tanaka, M., Cummins, T. R. & Waxman, S. G. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108, 237–247 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Hughes, M. S. et al. Brain-derived neurotrophic factor is upregulated in rats with chronic pancreatitis and mediates pain behavior. Pancreas 40, 551–556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu, L., Shenoy, M. & Pasricha, P. J. Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. JOP 12, 389–394 (2011).

    PubMed  Google Scholar 

  63. Woolf, C. J., Safieh-Garabedian, B., Ma, Q. P., Crilly, P. & Winter, J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 62, 327–331 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Toma, H., Winston, J., Micci, M. A., Shenoy, M. & Pasricha, P. J. Nerve growth factor expression is up-regulated in the rat model of L-arginine-induced acute pancreatitis. Gastroenterology 119, 1373–1381 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Zhu, Y. et al. Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. http://dx.doi.org/10.1152/ajpgi.00053.2011.

  66. Zhu, Y. et al. Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology 141, 370–377 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Hoogerwerf, W. A. et al. The role of mast cells in the pathogenesis of pain in chronic pancreatitis. BMC Gastroenterol. 5, 8 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Vardanyan, M. et al. Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist. Pain 151, 257–265 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Feng, Q. X. et al. Astrocytic activation in thoracic spinal cord contributes to persistent pain in rat model of chronic pancreatitis. Neuroscience 167, 501–509 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Liu, P. Y. et al. Spinal microglia initiate and maintain hyperalgesia in a rat model of chronic pancreatitis. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2011.09.041.

  71. Vera-Portocarrero, L. P. et al. Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis. Gastroenterology 130, 2155–2164 (2006).

    Article  PubMed  Google Scholar 

  72. Ceyhan, G. O. et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology 136, 177–186 e1 (2009).

    Article  PubMed  Google Scholar 

  73. Woolf, C. J. What is this thing called pain? J. Clin. Invest. 120, 3742–3744 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ceyhan, G. O., Michalski, C. W., Demir, I. E., Muller, M. W. & Friess, H. Pancreatic pain. Best Pract. Res. Clin. Gastroenterol. 22, 31–44 (2008).

    Article  PubMed  Google Scholar 

  75. Friess, H. et al. Nerve growth factor and its high-affinity receptor in chronic pancreatitis. Ann. Surg. 230, 615–624 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Di Sebastiano, P. et al. Expression of interleukin 8 (IL-8) and substance P in human chronic pancreatitis. Gut 47, 423–428 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Hartel, M. et al. Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut 55, 519–528 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Buchler, M. Changes in peptidergic innervation in chronic pancreatitis. Pancreas 7, 183–192 (1992).

    Article  CAS  PubMed  Google Scholar 

  79. Shrikhande, S. V. et al. NK-1 receptor gene expression is related to pain in chronic pancreatitis. Pain 91, 209–217 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Zhu, Z. W., Friess, H., Wang, L., Zimmermann, A. & Buchler, M. W. Brain-derived neurotrophic factor (BDNF) is upregulated and associated with pain in chronic pancreatitis. Dig. Dis. Sci. 46, 1633–1639 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Ceyhan, G. O. et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 56, 534–544 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Di Sebastiano, P. et al. Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis. Gastroenterology 112, 1648–1655 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Ceyhan, G. O. et al. Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis. Lab. Invest. 89, 347–361 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Braganza, J. M. Towards a novel treatment strategy for acute pancreatitis. 1. Reappraisal of the evidence on aetiogenesis. Digestion 63, 69–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Esposito, I. Mast cell distribution and activation in chronic pancreatitis. Hum. Pathol. 32, 1174–1183 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Friess, H. et al. Identification of disease-specific genes in chronic pancreatitis using DNA array technology. Ann. Surg. 234, 769–778 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Buscher, H. C., Wilder-Smith, O. H. & van Goor, H. Chronic pancreatitis patients show hyperalgesia of central origin: a pilot study. Eur. J. Pain 10, 363–370 (2006).

    Article  PubMed  Google Scholar 

  88. Dimcevski, G. et al. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology 132, 1546–1556 (2007).

    Article  PubMed  Google Scholar 

  89. Olesen, S. S., Frokjaer, J. B., Lelic, D., Valeriani, M. & Drewes, A. M. Pain-associated adaptive cortical reorganisation in chronic pancreatitis. Pancreatology 10, 742–751 (2011).

    Article  Google Scholar 

  90. Olesen, S. S. et al. Slowed EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal cerebral pain processing? Eur. J. Gastroenterol. Hepatol. 23, 418–424 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Frokjaer, J. B. et al. Altered brain microstructure assessed by diffusion tensor imaging in patients with chronic pancreatitis. Gut 60, 1554–1562 (2011).

    Article  PubMed  Google Scholar 

  92. Dimcevski, G. et al. Hypoalgesia to experimental visceral and somatic stimulation in painful chronic pancreatitis. Eur. J. Gastroenterol. Hepatol. 18, 755–764 (2006).

    Article  PubMed  Google Scholar 

  93. Dimcevski, G. et al. Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis. Pancreas 35, 22–29 (2007).

    Article  PubMed  Google Scholar 

  94. Olesen, S. S. et al. Descending inhibitory pain modulation is impaired in patients with chronic pancreatitis. Clin. Gastroenterol. Hepatol. 8, 724–730 (2010).

    Article  PubMed  Google Scholar 

  95. Gebhart, G. F. It's chickens and eggs all over again: is central reorganization the result or cause of persistent visceral pain? Gastroenterology 132, 1618–1620 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Bouwense, S. A., Buscher, H. C., van Goor, H. & Wilder-Smith, O. H. Has central sensitization become independent of nociceptive input in chronic pancreatitis patients who fail thoracoscopic splanchnicectomy? Reg. Anesth. Pain Med. 36, 531–536 (2011).

    Article  PubMed  Google Scholar 

  97. Buscher, H. C., van Goor, H. & Wilder-Smith, O. H. Effect of thoracoscopic splanchnic denervation on pain processing in chronic pancreatitis patients. Eur. J. Pain 11, 437–443 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Eisenach, J. C., Carpenter, R. & Curry, R. Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis. Pain 101, 89–95 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Bradbury, E. J., McMahon, S. B. & Ramer, M. S. Keeping in touch: sensory neurone regeneration in the CNS. Trends Pharmacol. Sci. 21, 389–394 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Lee, M., Silverman, S. M., Hansen, H., Patel, V. B. & Manchikanti, L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 14, 145–161 (2011).

    PubMed  Google Scholar 

  101. Olesen, S. S. et al. Randomised clinical trial: pregabalin attenuates experimental visceral pain through sub-cortical mechanisms in patients with painful chronic pancreatitis. Aliment. Pharmacol. Ther. 34, 878–887 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Olesen, S. S., Bouwense, S. A., Wilder-Smith, O. H., van Goor, H. & Drewes, A. M. Pregabalin reduces pain in patients with chronic pancreatitis in a randomized, controlled trial. Gastroenterology 141, 536–543 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Katz, N. et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain 152, 2248–2258 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Te, A. E. A study to investigate tanezumab in patients with interstitial cystitis/painful bladder syndrome. Curr. Urol. Rep. 12, 245–246 (2011).

    Article  PubMed  Google Scholar 

  105. Evans, R. J. et al. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J. Urol. 185, 1716–1721 (2010).

    Article  CAS  Google Scholar 

  106. Schnitzer, T. J. et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage 19, 639–646 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wong, G. Y. & Gavva, N. R. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res. Rev. 60, 267–277 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Sprenger, T. et al. Imaging pain modulation by subanesthetic S-(+)-ketamine. Anesth. Analg. 103, 729–737 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Ilkjaer, S., Dirks, J., Brennum, J., Wernberg, M. & Dahl, J. B. Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans. Br. J. Anaesth. 79, 600–605 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Bouwense, S. A., Buscher, H. C., van Goor, H. & Wilder-Smith, O. H. S-ketamine modulates hyperalgesia in patients with chronic pancreatitis pain. Reg. Anesth. Pain Med. 36, 303–307 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stanford University School of Medicine, 300 Pasteur Drive, M211 Alway Building, Stanford, 94305, CA, USA

    Pankaj Jay Pasricha

Authors
  1. Pankaj Jay Pasricha
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pasricha, P. Unraveling the mystery of pain in chronic pancreatitis. Nat Rev Gastroenterol Hepatol 9, 140–151 (2012). https://doi.org/10.1038/nrgastro.2011.274

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2011.274

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

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

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