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Gastrointestinal pain

Abstract

Gastrointestinal (GI) pain — a form of visceral pain — is common in some disorders, such as irritable bowel syndrome, Crohn’s disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.

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Fig. 1: Pathways and mechanisms that contribute to GI pain.
Fig. 2: Peripheral nerve activation.
Fig. 3: Causes of pain in GI disorders.
Fig. 4: Pharmacological management of GI pain.

References

  1. 1.

    Gebhart, G. F. & Bielefeldt, K. Physiology of visceral pain. Compr. Physiol. 6, 1609–1633 (2016). This review provides an overview of the basic visceral pain mechanisms.

    CAS  Google Scholar 

  2. 2.

    Aziz, Q. et al. The IASP classification of chronic pain for ICD-11. Pain 160, 69–76 (2019).

    Google Scholar 

  3. 3.

    Treede, R.-D. et al. A classification of chronic pain for ICD-11. Pain 156, 1003–1007 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kosek, E. et al. Do we need a third mechanistic descriptor for chronic pain states? Pain 157, 1382–1386 (2016).

    Google Scholar 

  5. 5.

    Mayer, E. A., Gupta, A., Kilpatrick, L. A. & Hong, J.-Y. Imaging brain mechanisms in chronic visceral pain. Pain 156, S50–S63 (2015).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Meerveld, B. G.-V. & Johnson, A. C. Mechanisms of stress-induced visceral pain. J. Neurogastroenterol. Motil. 24, 7–18 (2018).

    Google Scholar 

  7. 7.

    Kloner, R. A. & Chaitman, B. Angina and its management. J. Cardiovasc. Pharmacol. Ther. 22, 199–209 (2017).

    Google Scholar 

  8. 8.

    Picard, F., Sayah, N., Spagnoli, V., Adjedj, J. & Varenne, O. Vasospastic angina: a literature review of current evidence. Arch. Cardiovasc. Dis. 112, 44–55 (2019).

    Google Scholar 

  9. 9.

    Stavropoulos, S. N., Friedel, D., Modayil, R. & Parkman, H. P. Diagnosis and management of esophageal achalasia. Br. Med. J. 354, i2785 (2016).

    Google Scholar 

  10. 10.

    Kavitt, R. T., Lipowska, A. M., Anyane-Yeboa, A. & Gralnek, I. M. Diagnosis and treatment of peptic ulcer disease. Am. J. Med. 132, 447–456 (2019).

    CAS  Google Scholar 

  11. 11.

    Drewes, A. M. et al. Guidelines for the understanding and management of pain in chronic pancreatitis. Pancreatology 17, 720–731 (2017).

    Google Scholar 

  12. 12.

    Wilkins, T., Agabin, E., Varghese, J. & Talukder, A. Gallbladder dysfunction: cholecystitis, choledocholithiasis, cholangitis, and biliary dyskinesia. Prim. Care Clin. Off. Pract. 44, 575–597 (2017).

    Google Scholar 

  13. 13.

    Mayans, L. Nephrolithiasis. Prim. Care Clin. Off. Pract. 46, 203–212 (2019).

    Google Scholar 

  14. 14.

    Zheng, P., Zhang, W., Leng, J. & Lang, J. Research on central sensitization of endometriosis-associated pain: a systematic review of the literature. J. Pain Res. 12, 1447–1456 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Zaidi, N., Thomas, D. & Chughtai, B. Management of chronic prostatitis (CP). Curr. Urol. Rep. 19, 88 (2018).

    Google Scholar 

  16. 16.

    Enck, P. et al. Irritable bowel syndrome. Nat. Rev. Dis. Primers 2, 16014 (2016). This review summarizes functional (primary) GI pain with IBS as an example.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Falcone, T. & Flyckt, R. Clinical management of endometriosis. Obstet. Gynecol. 131, 557–571 (2018).

    Google Scholar 

  18. 18.

    Pape, J., Falconi, G., De Mattos Lourenco, T. R., Doumouchtsis, S. K. & Betschart, C. Variations in bladder pain syndrome/interstitial cystitis (IC) definitions, pathogenesis, diagnostics and treatment: a systematic review and evaluation of national and international guidelines. Int. Urogynecol. J. 30, 1795–1805 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Passavanti, M. B. et al. Chronic pelvic pain: assessment, evaluation, and objectivation. Pain Res. Treat. 2017, 9472925 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Sorensen, J., Bautsita, K., Lamvu, G. & Feranec, J. Evaluation and treatment of female sexual pain: a clinical review. Cureus 10, e2379 (2018).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Sikandar, S. & Dickenson, A. H. Visceral pain: the ins and outs, the ups and downs. Curr. Opin. Support. Palliat. Care 6, 17–26 (2012).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kennedy, P. J., Cryan, J. F., Dinan, T. G. & Clarke, G. Irritable bowel syndrome: a microbiome-gut-brain axis disorder? World J. Gastroenterol. 20, 14105–14125 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Giamberardino, M. A. & Vecchiet, L. Visceral pain, referred hyperalgesia and outcome: new concepts. Eur. J. Anaesthesiol. Suppl. 10, 61–66 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Sandler, R. S., Stewart, W. F., Liberman, J. N., Ricci, J. A. & Zorich, N. L. Abdominal pain, bloating, and diarrhea in the United States: prevalence and impact. Dig. Dis. Sci. 45, 1166–1171 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Russo, M. W. et al. Digestive and liver diseases statistics, 2004. Gastroenterology 126, 1448–1453 (2004).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Hotopf, M., Carr, S., Mayou, R., Wadsworth, M. & Wessely, S. Why do children have chronic abdominal pain, and what happens to them when they grow up? Population based cohort study. Br. Med. J. 316, 1196–1200 (1998).

    CAS  Google Scholar 

  27. 27.

    Drossman, D. A. et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig. Dis. Sci. 38, 1569–1580 (1993).

    CAS  Google Scholar 

  28. 28.

    Bielefeldt, K., Davis, B. & Binion, D. G. Pain and inflammatory bowel disease. Inflamm. Bowel Dis. 15, 778–788 (2009).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Torres, J., Mehandru, S., Colombel, J.-F. & Peyrin-Biroulet, L. Crohn’s disease. Lancet 389, 1741–1755 (2017).

    Google Scholar 

  30. 30.

    Kleeff, J. et al. Chronic pancreatitis. Nat. Rev. Dis. Primer 3, 17060 (2017).

    Google Scholar 

  31. 31.

    Olesen, S. S. et al. Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment. Pain Rep. 2, e625 (2017). This review provides an overview of visceral pain mechanisms with chronic pancreatitis as an example.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Keane, M. G., Horsfall, L., Rait, G. & Pereira, S. P. A case-control study comparing the incidence of early symptoms in pancreatic and biliary tract cancer. BMJ Open 4, e005720 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Drewes, A. M. et al. Pain in pancreatic ductal adenocarcinoma: a multidisciplinary, international guideline for optimized management. Pancreatology 18, 446–457 (2018). This paper provides a framework for multidisciplinary cancer pain management.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Rome Foundation. Rome IV online collection https://romeonline.org/product/rome-iv-online-collection-all-six-rome-iv-books-online/ (2019).

  35. 35.

    Van den Houte, K. et al. Prevalence and impact of self-reported irritable bowel symptoms in the general population. United European Gastroenterol. J. 7, 307–315 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Lovell, R. M. & Ford, A. C. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin. Gastroenterol. Hepatol. 10, 712–721.e4 (2012).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Costa, M. & Brookes, S. J. The enteric nervous system. Am. J. Gastroenterol. 89, S129–S137 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Brierley, S. M. & Blackshaw, L. A. in Chronic Abdominal and Visceral Pain, Theory and Practice (eds Pasricha, P. J., Willis, W. D. & Gebhart, G. F.) 45–66 (Taylor & Francis, 2006).

  39. 39.

    Traub, R. J. in Chronic Abdominal and Visceral Pain, Theory and Practice (eds Pasricha, P. J., Willis, W. D. & Gebhart, G. F.) 85–106 (Taylor & Francis, 2006).

  40. 40.

    Al-Chaer, E. D. &Willis, W. D. in Chronic Abdominal and Visceral Pain, Theory and Practice (eds Pasricha, P. J., Willis, W. D. & Gebhart, G. F.) 33–44 (Taylor & Francis, 2006).

  41. 41.

    Scholz, J. & Woolf, C. J. Can we conquer pain? Nat. Neurosci. 5, 1062–1067 (2002).

    CAS  Google Scholar 

  42. 42.

    Drewes, A. M. et al. Pain in chronic pancreatitis: the role of neuropathic pain mechanisms. Gut 57, 1616–1627 (2008).

    CAS  Google Scholar 

  43. 43.

    Petersen, P., Gao, C., Arendt-Nielsen, L., Gregersen, H. & Drewes, A. M. Pain intensity and biomechanical responses during ramp-controlled distension of the human rectum. Dig. Dis. Sci. 48, 1310–1316 (2003).

    Google Scholar 

  44. 44.

    Greenwood-Van Meerveld, B., Prusator, D. K. & Johnson, A. C. Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges. Am. J. Physiol.Gastrointest. Liver Physiol. 308, G885–G903 (2015).

    Google Scholar 

  45. 45.

    Brierley, S. M. & Linden, D. R. Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat. Rev. Gastroenterol. Hepatol. 11, 611–627 (2014). This paper illustrates sensitization in GI diseases.

    Google Scholar 

  46. 46.

    Knowles, C. H. & Aziz, Q. Basic and clinical aspects of gastrointestinal pain. Pain 141, 191–209 (2009).

    Google Scholar 

  47. 47.

    Bielefeldt, K. in Chronic Abdominal and Visceral Pain, Theory and Practice (eds Pasricha, P. J., Willis, W. D. & Gebhart, G. F.) 67–84 (Taylor & Francis, 2006).

  48. 48.

    Mayer, E. A. et al. Brain imaging approaches to the study of functional GI disorders: a Rome working team report. Neurogastroenterol. Motil. 21, 579–596 (2009).

    CAS  Google Scholar 

  49. 49.

    Willis, W. D. & Westlund, K. N. Neuroanatomy of the pain system and of the pathways that modulate pain. J. Clin. Neurophysiol. 14, 2–31 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Drewes, A. M. et al. The “human visceral homunculus” to pain evoked in the oesophagus, stomach, duodenum and sigmoid colon. Exp. Brain Res. 174, 443–452 (2006).

    Google Scholar 

  51. 51.

    Bonaz, B., Sinniger, V. & Pellissier, S. Vagal tone: effects on sensitivity, motility, and inflammation. Neurogastroenterol. Motil. 28, 455–462 (2016). This review provides an overview of vagal function in GI disorders.

    CAS  Google Scholar 

  52. 52.

    Sengupta, J. N. & Gebhart, G. F. in Physiology of the Gastrointestinal Tract (eds Johnson, L. R., Alpers, D. H., Christensen, J., Jacobson, E. D. & Walsh, J. H.) 483–519 (Raven Press, 1994).

  53. 53.

    Ren, K., Randich, A. & Gebhart, G. F. Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat. Pain 44, 311–319 (1991).

    CAS  Google Scholar 

  54. 54.

    Heinricher, M. M., Tavares, I., Leith, J. L. & Lumb, B. M. Descending control of nociception: specificity, recruitment and plasticity. Brain Res. Rev. 60, 214–225 (2009).

    CAS  Google Scholar 

  55. 55.

    Vanegas, H. & Schaible, H.-G. Descending control of persistent pain: inhibitory or facilitatory? Brain Res. Brain Res. Rev. 46, 295–309 (2004).

    Google Scholar 

  56. 56.

    Arendt-Nielsen, L. et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur. J. Pain 22, 216–241 (2018). This paper explains central sensitization in chronic (including GI) pain.

    CAS  Google Scholar 

  57. 57.

    Wilder-Smith, C. H., Schindler, D., Lovblad, K., Redmond, S. M. & Nirkko, A. Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls. Gut 53, 1595–1601 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

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

    Google Scholar 

  59. 59.

    Kuhlmann, L. et al. Patient and disease characteristics associate with sensory testing results in chronic pancreatitis. Clin. J. Pain 35, 786–793 (2019).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

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

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Olesen, S. S., Frøkjær, J. B., Lelic, D., Valeriani, M. & Drewes, A. M. Pain-associated adaptive cortical reorganisation in chronic pancreatitis. Pancreatology 10, 742–751 (2010).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Lelic, D., Olesen, S. S., Hansen, T. M., Valeriani, M. & Drewes, A. M. Functional reorganization of brain networks in patients with painful chronic pancreatitis. Eur. J. Pain 18, 968–977 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

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

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Frøkjær, J. B. et al. Reduced cortical thickness of brain areas involved in pain processing in patients with chronic pancreatitis. Clin. Gastroenterol. Hepatol. 10, 434–438.e1 (2012).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Wells, C. I., O’Grady, G. & Bissett, I. P. Colonic electromechanical abnormalities underlying post-operative ileus: a systematic and critical review. J. Neurogastroenterol. Motil. 25, 36–47 (2019).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Wang, X., Gong, Z., Wu, K., Wang, B. & Yuang, Y. Gastrointestinal dysmotility in patients with acute pancreatitis. J. Gastroenterol. Hepatol. 18, 57–62 (2003).

    Google Scholar 

  67. 67.

    Morales-Soto, W. & Gulbransen, B. D. Enteric glia: a new player in abdominal pain. Cell. Mol. Gastroenterol. Hepatol. 7, 433–445 (2019).

    Google Scholar 

  68. 68.

    Pokusaeva, K. et al. GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. Neurogastroenterol. Motil. 29, e12904 (2017).

    Google Scholar 

  69. 69.

    Schemann, M., Frieling, T. & Enck, P. To learn, to remember, to forget—how smart is the gut? Acta Physiol. 7, e13296 (2019).

    Google Scholar 

  70. 70.

    Andrews, P. L. R. & Sanger, G. J. Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr. Opin. Pharmacol. 2, 650–656 (2002).

    CAS  Google Scholar 

  71. 71.

    Dinan, T. G. & Cryan, J. F. The microbiome-gut-brain axis in health and disease. Gastroenterol. Clin. North Am. 46, 77–89 (2017).

    Google Scholar 

  72. 72.

    Mayer, E. A., Tillisch, K. & Gupta, A. Gut/brain axis and the microbiota. J. Clin. Invest. 125, 926–938 (2015). This paper reviews the function of microbiota in the brain and pain processing.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Luczynski, P. et al. Microbiota regulates visceral pain in the mouse. eLife 6, e25887 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Kannampalli, P. et al. Probiotic Lactobacillus rhamnosus GG (LGG) and prebiotic prevent neonatal inflammation-induced visceral hypersensitivity in adult rats. Neurogastroenterol. Motil. 26, 1694–1704 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Heiss, C. N. & Olofsson, L. E. The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system. J. Neuroendocrinol. 31, e12684 (2019).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Cervero, F., Connell, L. A. & Lawson, S. N. Somatic and visceral primary afferents in the lower thoracic dorsal root ganglia of the cat. J. Comp. Neurol. 228, 422–431 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Jänig, W. Neurobiology of visceral afferent neurons: neuroanatomy, functions, organ regulations and sensations. Biol. Psychol. 42, 29–51 (1996).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Sugiura, Y., Terui, N. & Hosoya, Y. Difference in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers. J. Neurophysiol. 62, 834–840 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Arendt-Nielsen, L., Laursen, R. J. & Drewes, A. M. Referred pain as an indicator for neural plasticity. Prog. Brain Res. 129, 343–356 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Qin, C., Malykhina, A. P., Akbarali, H. I. & Foreman, R. D. Cross-organ sensitization of lumbosacral spinal neurons receiving urinary bladder input in rats with inflamed colon. Gastroenterology 129, 1967–1978 (2005).

    Google Scholar 

  81. 81.

    Grundy, L. & Brierley, S. M. Cross-organ sensitization between the colon and bladder: to pee or not to pee? Am. J. Physiol. Gastrointest. Liver Physiol. 314, G301–G308 (2018). This article describes the complex interactions in cross-organ sensitization.

    Google Scholar 

  82. 82.

    Garrison, D. W., Chandler, M. J. & Foreman, R. D. Viscerosomatic convergence onto feline spinal neurons from esophagus, heart and somatic fields: effects of inflammation. Pain 49, 373–382 (1992).

    CAS  Google Scholar 

  83. 83.

    Brock, C. et al. Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus. Eur. J. Pain 14, 273–281 (2010).

    CAS  Google Scholar 

  84. 84.

    Sami, S. A. K. et al. Cortical changes to experimental sensitization of the human esophagus. Neuroscience 140, 269–279 (2006).

    CAS  Google Scholar 

  85. 85.

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

    Google Scholar 

  86. 86.

    Olivar, T. & Laird, J. M. Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes. Pain 79, 67–73 (1999).

    CAS  Google Scholar 

  87. 87.

    Colloca, L. et al. Neuropathic pain. Nat. Rev. Dis. Primer 3, 17002 (2017).

    Google Scholar 

  88. 88.

    Drewes, A. in Pain from Unrelated Treatment (ed. Jarrell, J.) 55–69 (Wolters Kluwer, 2018).

  89. 89.

    Søfteland, E. et al. Association between visceral, cardiac and sensorimotor polyneuropathies in diabetes mellitus. J. Diabetes Complic. 28, 370–377 (2014).

    Google Scholar 

  90. 90.

    Frøkjaerl, J. B. et al. Gastrointestinal symptoms in type-1 diabetes: is it all about brain plasticity? Eur. J. Pain 15, 249–257 (2011).

    Google Scholar 

  91. 91.

    Treede, R.-D. et al. Chronic pain as a symptom or a disease. Pain 160, 19–27 (2019).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Mearin, F. et al. Bowel disorders. Gastroenterology 150, 1393–1407.e5 (2016).

    Google Scholar 

  93. 93.

    Chang, L. et al. Functional bowel disorders: a roadmap to guide the next generation of research. Gastroenterology 154, 723–735 (2018).

    Google Scholar 

  94. 94.

    Paice, J. A. et al. AAPT diagnostic criteria for chronic cancer pain conditions. J. Pain 18, 233–246 (2017).

    Google Scholar 

  95. 95.

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

    Google Scholar 

  96. 96.

    Sharma, M., Simpson, K., Bennett, M. & Gupta, S. (eds) Practical Management of Complex Cancer Pain (Oxford Univ. Press, 2014).

  97. 97.

    Brown, M. & Farquhar-Smith, P. Pain in cancer survivors; filling in the gaps. Br. J. Anaesth. 119, 723–736 (2017).

    CAS  Google Scholar 

  98. 98.

    Drewes, A. M. et al. Experimental pain in the stomach: a model based on electrical stimulation guided by gastroscopy. Gut 41, 753–757 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Graven-Nielsen, T. & Arendt-Nielsen, L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat. Rev. Rheumatol. 6, 599–606 (2010).

    Google Scholar 

  100. 100.

    Mertz, H., Fullerton, S., Naliboff, B. & Mayer, E. A. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 42, 814–822 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Stawowy, M., Funch-Jensen, P., Arendt-Nielsen, L. & Drewes, A. M. Somatosensory changes in the referred pain area in patients with cholecystolithiasis. Eur. J. Gastroenterol. Hepatol. 17, 865–870 (2005).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Bielefeldt, K., Christianson, J. A. & Davis, B. M. Basic and clinical aspects of visceral sensation: transmission in the CNS. Neurogastroenterol. Motil. 17, 488–499 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Talley, N. J., Zinsmeister, A. R. & Melton, L. J. Irritable bowel syndrome in a community: symptom subgroups, risk factors, and health care utilization. Am. J. Epidemiol. 142, 76–83 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Vardeh, D., Mannion, R. J. & Woolf, C. J. Toward a mechanism-based approach to pain diagnosis. J. Pain 17, T50–T69 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Mujagic, Z. et al. Systematic review: instruments to assess abdominal pain in irritable bowel syndrome. Aliment. Pharmacol. Ther. 42, 1064–1081 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Olesen, A. E., Farmer, A. D., Olesen, S. S., Aziz, Q. & Drewes, A. M. Management of chronic visceral pain. Pain Manag. 6, 469–486 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Farrar, J. T. Jr, Y., J. P., LaMoreaux, L., Werth, J. L. & Poole, R. M. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94, 149–158 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Akbar, A. et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut 59, 767–774 (2010).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Teo, K., Johnson, M. H., Drewes, A. M. & Windsor, J. A. A comprehensive pain assessment tool (COMPAT) for chronic pancreatitis: development, face validation and pilot evaluation. Pancreatology 17, 706–719 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Spiegel, B. et al. Measuring irritable bowel syndrome patient-reported outcomes with an abdominal pain numeric rating scale. Aliment. Pharmacol. Ther. 30, 1159–1170 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Spiegel, B. M. R. et al. Characterizing abdominal pain in IBS: guidance for study inclusion criteria, outcome measurement and clinical practice. Aliment. Pharmacol. Ther. 32, 1192–1202 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Olesen, S. S. et al. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLOS ONE 8, e57963 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Olesen, S. S., van Goor, H., Bouwense, S. A. W., Wilder-Smith, O. H. G. & Drewes, A. M. Reliability of static and dynamic quantitative sensory testing in patients with painful chronic pancreatitis. Reg. Anesth. Pain Med. 37, 530–536 (2012).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Bouin, M. et al. Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology 122, 1771–1777 (2002).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Bouwense, S. A. et al. Is altered central pain processing related to disease stage in chronic pancreatitis patients with pain? An exploratory study. PLOS ONE 8, e55460 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Kuhlmann, L., Olesen, S. S., Olesen, A. E., Arendt-Nielsen, L. & Drewes, A. M. Mechanism-based pain management in chronic pancreatitis – is it time for a paradigm shift? Expert Rev. Clin. Pharmacol. 12, 249–258 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Botha, C. et al. Preliminary report: modulation of parasympathetic nervous system tone influences oesophageal pain hypersensitivity. Gut 64, 611–617 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Fukudo, S. et al. Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention. Neuroimage 47, 946–951 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Tanaka, Y. et al. Differential activation in amygdala and plasma noradrenaline during colorectal distention by administration of corticotropin-releasing hormone between healthy individuals and patients with irritable bowel syndrome. PLOS ONE 11, e0157347 (2016).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Lee, I.-S., Wang, H., Chae, Y., Preissl, H. & Enck, P. Functional neuroimaging studies in functional dyspepsia patients: a systematic review. Neurogastroenterol. Motil. 28, 793–805 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Lelic, D. et al. Brain networks encoding rectal sensation in type 1 diabetes. Neuroscience 237, 96–105 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Farmer, A. D. & Aziz, Q. Mechanisms of visceral pain in health and functional gastrointestinal disorders. Scand. J. Pain 5, 51–60 (2014).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Srinath, A., Young, E. & Szigethy, E. Pain management in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 20, 2433–2449 (2014).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Beckers, A. B. et al. Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: a review for the gastroenterologist. Neurogastroenterol. Motil. 29, e13013 (2017).

    Google Scholar 

  126. 126.

    Sharpstone, D. & Colin-Jones, D. G. Chronic, non-visceral abdominal pain. Gut 35, 833–836 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    [No authors listed] Abdominal wall tenderness test: could Carnett cut costs? Lancet 337, 1134 (1991).

  128. 128.

    Drenth, J. P. & van der Meer, J. W. Hereditary periodic fever. N. Engl. J. Med. 345, 1748–1757 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Kim, E. N. et al. Median arcuate ligament syndrome — review of this rare disease. JAMA Surg. 151, 471–477 (2016).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Sato, Y. & Fukudo, S. Gastrointestinal symptoms and disorders in patients with eating disorders. Clin. J. Gastroenterol. 8, 255–263 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Longhurst, H. & Cicardi, M. Hereditary angio-oedema. Lancet 379, 474–481 (2012).

    Google Scholar 

  132. 132.

    Bissell, D. M., Anderson, K. E. & Bonkovsky, H. L. Porphyria. N. Engl. J. Med. 377, 862–872 (2017).

    CAS  Google Scholar 

  133. 133.

    McQuay, H. J., Derry, S., Eccleston, C., Wiffen, P. J. & Moore, A. R. Evidence for analgesic effect in acute pain—50 years on. Pain 153, 1364–1367 (2012).

    Google Scholar 

  134. 134.

    Hermanns, T. et al. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial. Eur. Urol. 56, 407–412 (2009).

    CAS  Google Scholar 

  135. 135.

    Ford, A. C. et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. Br. Med. J. 337, a2313 (2008).

    Google Scholar 

  136. 136.

    Schug, S. A. & Goddard, C. Recent advances in the pharmacological management of acute and chronic pain. Ann. Palliat. Med. 3, 263–275 (2014).

    Google Scholar 

  137. 137.

    O’Brien, T. et al. European Pain Federation position paper on appropriate opioid use in chronic pain management. Eur. J. Pain 21, 3–19 (2017).

    Google Scholar 

  138. 138.

    Szigethy, E., Knisely, M. & Drossman, D. Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nat. Rev. Gastroenterol. Hepatol. 15, 168–180 (2017).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Hacker, K. E., Reynolds, R. K. & Uppal, S. Ongoing strategies and updates on pain management in gynecologic oncology patients. Gynecol. Oncol. 149, 410–419 (2018).

    Google Scholar 

  140. 140.

    Portenoy, R. K. Treatment of cancer pain. Lancet 377, 2236–2247 (2011).

    CAS  Google Scholar 

  141. 141.

    Enck, P., Klosterhalfen, S. & Weimer, K. Unsolved, forgotten, and ignored features of the placebo response in medicine. Clin. Ther. 39, 458–468 (2017).

    Google Scholar 

  142. 142.

    Vase, L. & Wartolowska, K. Pain, placebo, and test of treatment efficacy: a narrative review. Br. J. Anaesth. 123, e254–e262 (2019).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Drewes, A. M. et al. Controversies on the endoscopic and surgical management of pain in patients with chronic pancreatitis: pros and cons! Gut 68, 1343–1351 (2019).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Johnson, A. C. & Greenwood-Van Meerveld, B. The pharmacology of visceral pain. Adv. Pharmacol. 75, 273–301 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Drossman, D. A. et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome Foundation Working Team report. Gastroenterology 154, 1140–1171.e1 (2018). This report reviews the pharmacological mechanisms when treating functional visceral pain.

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Colombel, J.-F., Shin, A. & Gibson, P. R. AGA clinical practice update on functional gastrointestinal symptoms in patients with inflammatory bowel disease: expert review. Clin. Gastroenterol. Hepatol. 17, 380–390.e1 (2019).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Edwards, R. R. et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain 157, 1851–1871 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Camilleri, M., Lembo, A. & Katzka, D. A. Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits. Clin. Gastroenterol. Hepatol. 15, 1338–1349 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Kilgallon, E. et al. Chronic continuous abdominal pain: evaluation of diagnostic features, iatrogenesis and drug treatments in a cohort of 103 patients. Aliment. Pharmacol. Ther. 49, 1282–1292 (2019).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Iskandar, H. N. et al. Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease. J. Clin. Gastroenterol. 48, 423–429 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Saito, Y. A. et al. Randomised clinical trial: pregabalin vs placebo for irritable bowel syndrome. Aliment. Pharmacol. Ther. 49, 389–397 (2019).

    CAS  Google Scholar 

  152. 152.

    Muthuraman, A., Singh, N., Jaggi, A. S. & Ramesh, M. Drug therapy of neuropathic pain: current developments and future perspectives. Curr. Drug Targets 15, 210–253 (2014).

    CAS  Google Scholar 

  153. 153.

    Obata, H. Analgesic mechanisms of antidepressants for neuropathic pain. Int. J. Mol. Sci. 18, 2483 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Tack, J. et al. Efficacy of mirtazapine in patients with functional dyspepsia and weight loss. Clin. Gastroenterol. Hepatol. 14, 385–392.e4 (2016).

    CAS  Google Scholar 

  155. 155.

    Camilleri, M. & Boeckxstaens, G. Dietary and pharmacological treatment of abdominal pain in IBS. Gut 66, 966–974 (2017).

    CAS  Google Scholar 

  156. 156.

    Han, S. et al. Discovery of APD371: identification of a highly potent and selective CB2 agonist for the treatment of chronic pain. ACS Med. Chem. Lett. 8, 1309–1313 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Ahmed, W. & Katz, S. Therapeutic use of cannabis in inflammatory bowel disease. Gastroenterol. Hepatol. 12, 668–679 (2016).

    Google Scholar 

  158. 158.

    Camilleri, M. Cannabinoids and gastrointestinal motility: pharmacology, clinical effects, and potential therapeutics in humans. Neurogastroenterol. Motil. 30, e13370 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Olesen, A. E. et al. The absorption profile of pregabalin in chronic pancreatitis. Basic Clin. Pharmacol. Toxicol. 111, 385–390 (2012).

    CAS  Google Scholar 

  160. 160.

    Aghazadeh-Habashi, A. & Jamali, F. Pharmacokinetics of meloxicam administered as regular and fast dissolving formulations to the rat: influence of gastrointestinal dysfunction on the relative bioavailability of two formulations. Eur. J. Pharm. Biopharm. 70, 889–894 (2008).

    CAS  Google Scholar 

  161. 161.

    Li, J. et al. Prediction of drug disposition in diabetic patients by means of a physiologically based pharmacokinetic model. Clin. Pharmacokinet. 54, 179–193 (2015).

    CAS  Google Scholar 

  162. 162.

    Smith, B. S., Yogaratnam, D., Levasseur-Franklin, K. E., Forni, A. & Fong, J. Introduction to drug pharmacokinetics in the critically ill patient. Chest 141, 1327–1336 (2012).

    CAS  Google Scholar 

  163. 163.

    Olesen, A. E., Brokjaer, A., Fisher, I. W. & Larsen, I. M. Pharmacological challenges in chronic pancreatitis. World J. Gastroenterol. 19, 7302–7307 (2013).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Olausson, E. A. et al. Postprandial plasma glucose response and gastrointestinal symptom severity in patients with diabetic gastroparesis. J. Diabetes Sci. Technol. 8, 881–888 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Farmer, A. D. et al. Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol. J. 7, 7–20 (2019).

    CAS  Google Scholar 

  166. 166.

    Hatton, G. B., Madla, C. M., Rabbie, S. C. & Basit, A. W. All disease begins in the gut: influence of gastrointestinal disorders and surgery on oral drug performance. Int. J. Pharm. 548, 408–422 (2018).

    CAS  Google Scholar 

  167. 167.

    Tennant, F. Why oral opioids may not be effective in a subset of chronic pain patients. Postgrad. Med. 128, 18–22 (2016).

    Google Scholar 

  168. 168.

    Leppert, W., Malec-Milewska, M., Zajaczkowska, R. & Wordliczek, J. Transdermal and topical drug administration in the treatment of pain. Molecules 23, 1–16 (2018).

    Google Scholar 

  169. 169.

    Brock, C. et al. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs 72, 1847–1865 (2012).

    CAS  Google Scholar 

  170. 170.

    Poulsen, J. L., Brock, C., Olesen, A. E., Nilsson, M. & Drewes, A. M. Evolving paradigms in the treatment of opioid-induced bowel dysfunction. Ther. Adv. Gastroenterol. 8, 360–372 (2015).

    CAS  Google Scholar 

  171. 171.

    Farmer, A. D. et al. Pathophysiology, diagnosis, and management of opioid-induced constipation. Lancet Gastroenterol. Hepatol. 3, 203–212 (2018).

    Google Scholar 

  172. 172.

    Dumonceau, J.-M. et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial. Gut 56, 545–552 (2007).

    Google Scholar 

  173. 173.

    Chandra, A. & Quinones-Baldrich, W. J. Chronic mesenteric ischemia: how to select patients for invasive treatment. Semin. Vasc. Surg. 23, 21–28 (2010).

    Google Scholar 

  174. 174.

    Uden, S. et al. Antioxidant therapy for recurrent pancreatitis: biochemical profiles in a placebo-controlled trial. Aliment. Pharmacol. Ther. 6, 229–240 (1992).

    CAS  Google Scholar 

  175. 175.

    Rustagi, T. & Njei, B. Antioxidant therapy for pain reduction in patients with chronic pancreatitis: a systematic review and meta-analysis. Pancreas 44, 812–818 (2015).

    CAS  Google Scholar 

  176. 176.

    Mitchell, H., Porter, J., Gibson, P. R., Barrett, J. & Garg, M. Review article: implementation of a diet low in FODMAPs for patients with irritable bowel syndrome-directions for future research. Aliment. Pharmacol. Ther. 49, 124–139 (2019).

    Google Scholar 

  177. 177.

    Mekhail, N. A. et al. Clinical applications of neurostimulation: forty years later. Pain Pract. 10, 103–112 (2010).

    Google Scholar 

  178. 178.

    Roy, H., Offiah, I. & Dua, A. Neuromodulation for pelvic and urogenital pain. Brain Sci. 8, 180 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. 179.

    Rombouts, S. J. E. et al. Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br. J. Surg. 102, 182–193 (2015).

    CAS  Google Scholar 

  180. 180.

    Apkarian, A. V., Baliki, M. N. & Geha, P. Y. Towards a theory of chronic pain. Prog. Neurobiol. 87, 81–97 (2009).

    Google Scholar 

  181. 181.

    Gallagher, R. M. Chronification to maldynia: biopsychosocial failure of pain homeostasis. Pain Med. 12, 993–995 (2011).

    Google Scholar 

  182. 182.

    Keefer, L. et al. Centrally mediated disorders of gastrointestinal pain. Gastroenterology 150, 1408–1419 (2016).

    Google Scholar 

  183. 183.

    Burns, J. W., Johnson, B. J., Mahoney, N., Devine, J. & Pawl, R. Cognitive and physical capacity process variables predict long-term outcome after treatment of chronic pain. J. Consult. Clin. Psychol. 66, 434–439 (1998).

    CAS  Google Scholar 

  184. 184.

    Peters, M. L. Emotional and cognitive influences on pain experience. Mod. Trends Pharmacopsychiatry 30, 138–152 (2015).

    Google Scholar 

  185. 185.

    Walk, D. & Poliak-Tunis, M. Chronic pain management: an overview of taxonomy, conditions commonly encountered, and assessment. Med. Clin. North Am. 100, 1–16 (2016).

    Google Scholar 

  186. 186.

    Palsson, O. S. & Whitehead, W. E. Psychological treatments in functional gastrointestinal disorders: a primer for the gastroenterologist. Clin. Gastroenterol. Hepatol. 11, 208–216 (2013).

    Google Scholar 

  187. 187.

    Berrill, J. W., Sadlier, M., Hood, K. & Green, J. T. Mindfulness-based therapy for inflammatory bowel disease patients with functional abdominal symptoms or high perceived stress levels. J. Crohns Colitis 8, 945–955 (2014).

    Google Scholar 

  188. 188.

    Ballou, S. & Keefer, L. Psychological interventions for irritable bowel syndrome and inflammatory bowel diseases. Clin. Transl. Gastroenterol. 8, e214 (2017).

    PubMed  PubMed Central  Google Scholar 

  189. 189.

    Regueiro, M., Greer, J. B. & Szigethy, E. Etiology and treatment of pain and psychosocial issues in patients with inflammatory bowel diseases. Gastroenterology 152, 430–439.e4 (2017).

    Google Scholar 

  190. 190.

    Kinsinger, S. W. Cognitive-behavioral therapy for patients with irritable bowel syndrome: current insights. Psychol. Res. Behav. Manag. 10, 231–237 (2017).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    Lee, H. H., Choi, Y. Y. & Choi, M.-G. The efficacy of hypnotherapy in the treatment of irritable bowel syndrome: a systematic review and meta-analysis. J. Neurogastroenterol. Motil. 20, 152–162 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Palsson, O. S. Hypnosis treatment of gastrointestinal disorders: a comprehensive review of the empirical evidence. Am. J. Clin. Hypn. 58, 134–158 (2015).

    Google Scholar 

  193. 193.

    Flik, C. E. et al. Efficacy of individual and group hypnotherapy in irritable bowel syndrome (IMAGINE): a multicentre randomised controlled trial. Lancet Gastroenterol. Hepatol. 4, 20–31 (2019).

    Google Scholar 

  194. 194.

    Aucoin, M., Lalonde-Parsi, M.-J. & Cooley, K. Mindfulness-based therapies in the treatment of functional gastrointestinal disorders: a meta-analysis. Evid. Based Complement. Altern. Med. 2014, 140724 (2014).

    Google Scholar 

  195. 195.

    Juel, J., Abrahamsen, R., Olesen, S. S. & Drewes, A. M. A pilot-study of hypnotherapy as complementary treatment for pain in chronic pancreatitis. J. Complement. Integr. Med. 15, 20170084 (2018).

    Google Scholar 

  196. 196.

    Dworkin, R. H. et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J. Pain 9, 105–121 (2008).

    Google Scholar 

  197. 197.

    Olesen, S. S. et al. Pain severity reduces life quality in chronic pancreatitis: implications for design of future outcome trials. Pancreatology 14, 497–502 (2014).

    Google Scholar 

  198. 198.

    McHorney, C. A., Ware, J. E. & Raczek, A. E. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med. Care 31, 247–263 (1993).

    CAS  Google Scholar 

  199. 199.

    Fitzsimmons, D. et al. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur. J. Cancer 35, 939–941 (1999).

    CAS  Google Scholar 

  200. 200.

    Wassef, W. et al. Pancreatitis quality of life instrument: a psychometric evaluation. Am. J. Gastroenterol. 111, 1177–1186 (2016).

    Google Scholar 

  201. 201.

    Eypasch, E. et al. Gastrointestinal Quality of Life Index: development, validation and application of a new instrument. Br. J. Surg. 82, 216–222 (1995).

    CAS  Google Scholar 

  202. 202.

    Stevens, T. et al. Adding triamcinolone to endoscopic ultrasound-guided celiac plexus blockade does not reduce pain in patients with chronic pancreatitis. Clin. Gastroenterol. Hepatol. 10, 186–191.e1 (2012).

    CAS  Google Scholar 

  203. 203.

    Baghdadi, S., Abbas, M. H., Albouz, F. & Ammori, B. J. Systematic review of the role of thoracoscopic splanchnicectomy in palliating the pain of patients with chronic pancreatitis. Surg. Endosc. 22, 580–588 (2008).

    Google Scholar 

  204. 204.

    Gewandter, J. S. et al. Research design characteristics of published pharmacologic randomized clinical trials for irritable bowel syndrome and chronic pelvic pain conditions: an ACTTION systematic review. J. Pain 19, 717–726 (2018).

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    Giannetti, E. et al. A mixture of 3 bifidobacteria decreases abdominal pain and improves the quality of life in children with irritable bowel syndrome: a multicenter, randomized, double-blind, placebo-controlled, crossover trial. J. Clin. Gastroenterol. 51, e5–e10 (2017).

    Google Scholar 

  206. 206.

    Guy, W. ECDEU Assessment Manual for Psychopharmacology. (U.S. Department of Health, Education, and Welfare, 1976).

  207. 207.

    Boom, M. et al. Fentanyl utility function: a risk-benefit composite of pain relief and breathing responses. Anesthesiology 119, 663–674 (2013).

    Google Scholar 

  208. 208.

    Roozekrans, M. et al. Benefit versus severe side effects of opioid analgesia. Anesthesiology 128, 932–942 (2018).

    CAS  Google Scholar 

  209. 209.

    Olesen, A. E. et al. A pragmatic utility function to describe the risk-benefit composite of opioid and nonopioid analgesic medication. J. Pharmacol. Exp. Ther. 371, 1–6 (2018).

    Google Scholar 

  210. 210.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Tack, J. et al. The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS. Gut 66, 1403–1413 (2017).

    CAS  Google Scholar 

  212. 212.

    Wouters, M. M. et al. Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology 150, 875–887.e9 (2016).

    CAS  Google Scholar 

  213. 213.

    Kovacic, K. et al. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol. Hepatol. 2, 727–737 (2017).

    Google Scholar 

  214. 214.

    Aroniadis, O. C., Drossman, D. A. & Simrén, M. A perspective on brain–gut communication: the American Gastroenterology Association and American Psychosomatic Society Joint Symposium on Brain–Gut Interactions and the Intestinal Microenvironment. Psychosom. Med. 79, 847–856 (2017).

    Google Scholar 

  215. 215.

    Pusceddu, M. M. & Gareau, M. G. Visceral pain: gut microbiota, a new hope? J. Biomed. Sci. 25, 73 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216.

    Oʼ Mahony, S. M., Dinan, T. G. & Cryan, J. F. The gut microbiota as a key regulator of visceral pain. Pain 158, S19–S28 (2017).

    Google Scholar 

  217. 217.

    Crouzet, L. et al. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol. Motil. 25, e272–e282 (2013).

    CAS  Google Scholar 

  218. 218.

    Ringel, Y. The gut microbiome in irritable bowel syndrome and other functional bowel disorders. Gastroenterol. Clin. North Am. 46, 91–101 (2017).

    Google Scholar 

  219. 219.

    Hungin, A. P. S. et al. Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice—an evidence-based international guide. Aliment. Pharmacol. Ther. 38, 864–886 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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Introduction (A.M.D. and E.S.); Epidemiology (S.S.O. and A.D.F.); Mechanisms/pathophysiology (A.M.D. and V.R.); Diagnosis, screening and prevention (A.M.D., S.S.O. and A.D.F.); Management (A.E.O., E.S., V.R., S.S.O. and A.M.D.); Quality of life (E.S. and S.S.O.); Outlook (S.S.O., A.M.D. and A.E.O.); Overview of Primer (A.M.D.).

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Drewes, A.M., Olesen, A.E., Farmer, A.D. et al. Gastrointestinal pain. Nat Rev Dis Primers 6, 1 (2020). https://doi.org/10.1038/s41572-019-0135-7

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