Current Gastroenterology Reports

, Volume 12, Issue 5, pp 417–426 | Cite as

The Hypersensitive Esophagus: Pathophysiology, Evaluation, and Treatment Options

  • Jose M. Remes-TrocheEmail author


Visceral hypersensitivity plays a key role in the pathogenesis of esophageal functional disorders such as functional heartburn and chest pain of presumed esophageal origin (noncardiac chest pain). About 80% of patients with unexplained noncardiac chest pain exhibit lower esophageal sensory thresholds when compared to controls during esophageal sensory testing (ie, esophageal barostat, impedance planimetry). Such information has led to prescription of peripherally and/or centrally acting therapies for the management of these patients. This review summarizes and highlights recent and significant findings regarding the pathophysiology, evaluation, and treatment of the hypersensitive esophagus, a central factor in functional esophageal disorders.


Esophagus Hypersensitivity Functional chest pain Heartburn Balloon distension Impedance planimetry Barostat Nonerosive gastroesophageal reflux disease 



I sincerely acknowledge the technical support provided by Mr. Eli de la Cruz Patino and manuscript preparation by Maria Medellin.


Dr. Remes-Troche was supported by grant M0034-FOMIX VERACRUZ 68427 from the National Science and Technology Council (CONACYT). No potential conflict of interest relevant to this article was reported.


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

  1. 1.
    Katz PO, Codario R, Castell DO: Approach to the patient with unexplained chest pain. Compr Ther 1997, 23:249–253.PubMedGoogle Scholar
  2. 2.
    Achem S, DeVault K: Recent developments in chest pain of undetermined origin. Curr Gastroenterol Rep 2000, 2:201–209.CrossRefPubMedGoogle Scholar
  3. 3.
    •• Galmiche JP, Clouse RE, Bálint A, et al.: Functional esophageal disorders. In The Functional Gastrointestinal Disorders, edn 3. Edited by Drosssman DA, Corazziari E, Spiller RC, et al. Lawrence KS: Allen Press; 2006:369–418. This chapter provides a comprehensive review addressing all the information regarding functional esophageal disorders, from epidemiologic data to new therapeutic options.Google Scholar
  4. 4.
    Faybush EM, Fass R: Gastroesophageal reflux disease in noncardiac chest pain. Gastroenterol Clin North Am 2004, 33:41–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Van Handel D, Fass R: The pathophysiology of non-cardiac chest pain. J Gastroenterol Hepatol 2005, 20:S6–S13.CrossRefPubMedGoogle Scholar
  6. 6.
    Mujica V, Mudipalli R, Rao S: Pathophysiology of chest pain in patients with nutcracker esophagus. Am J Gastroenterol 2001, 96:1371–1377.CrossRefPubMedGoogle Scholar
  7. 7.
    Clouse RE, Lustman PJ: Psychiatric illness and contraction abnormalities of the esophagus. N Engl J Med 1983, 309:1337–1342.CrossRefPubMedGoogle Scholar
  8. 8.
    Cannon RO 3 rd, Benjamin SB: Chest pain as a consequence of abnormal visceral nociception. Dig Dis Sci 1993, 38:193–196.CrossRefPubMedGoogle Scholar
  9. 9.
    Olden KW: The psychological aspects of noncardiac chest pain. Gastroenterol Clin North Am 2004, 33:61–67.CrossRefPubMedGoogle Scholar
  10. 10.
    Rao SS, Gregersen H, Hayek B, et al.: Unexplained chest pain: the hypersensitive, hyperreactive, and poorly compliant esophagus. Ann Intern Med 1996, 124:950–958.PubMedGoogle Scholar
  11. 11.
    Rao SS, Hayek B, Summers RW: Functional chest pain of esophageal origin: hyperalgesia or motor dysfunction. Am J Gastroenterol 2001, 96:2584–2589.CrossRefPubMedGoogle Scholar
  12. 12.
    Sarkar S, Aziz Q, Woolf CJ, et al.: Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet 2000, 356:1154–1159.CrossRefPubMedGoogle Scholar
  13. 13.
    Lembo AJ: Visceral hypersensitivity in noncardiac chest pain. Gastroenterol Clin North Am 2004, 33:55–60.CrossRefPubMedGoogle Scholar
  14. 14.
    • Nasr I, Attaluri A, Hashmi S, et al.: S Investigation of esophageal sensation and biomechanical properties in functional chest pain. Neurogastroenterol Motil 2010, 22:520–526, e116. This article describes a recent study in a large cohort of patients with functional chest pain (N = 189) that shows 75% of patients had esophageal hypersensitivity during esophageal balloon distension test.Google Scholar
  15. 15.
    •• Fass R, Gasiorowska A: Refractory GERD: what is it? Curr Gastroenterol Rep 2008, 10:252–257. This article provides an excellent review of the most important findings regarding the mechanisms involved in refractory GERD, and noting the importance of esophageal hypersensitivity in this special group of patients.CrossRefPubMedGoogle Scholar
  16. 16.
    Zerbib F, Roman S, Ropert A, et al.: Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006, 101:1956–1963.CrossRefPubMedGoogle Scholar
  17. 17.
    Chahal PS, Rao SS: Functional chest pain: nociception and visceral hyperalgesia. J Clin Gastroenterol 2005, 39(Suppl 3):S204–S209.CrossRefPubMedGoogle Scholar
  18. 18.
    Patel RS, Rao SSC: Biomechanical and sensory parameters of the human esophagus at four levels. Am J Physiol 1998, 275:G187–G191.PubMedGoogle Scholar
  19. 19.
    Rao SSC, Mudipalli RS, Mujica VR, et al.: Effects of gender and age on esophageal biomechanical properties and sensation. Am J Gastroenterol 2003, 98:1688–1695.CrossRefPubMedGoogle Scholar
  20. 20.
    Sengupta JN: An overview of esophageal sensory receptors. Am J Med 2000, 108(Suppl 4a):87 S–89 S.Google Scholar
  21. 21.
    • Fass R: Sensory testing of the esophagus. J Clin Gastroenterol 2004, 38:628–641. This review provides useful information regarding all the sensory tests used to evaluate sensorimotor properties of the esophagus. Although considered as research tools, these tests help address which pathophysiologic mechanism is involved before deciding a symptom-based therapy.CrossRefPubMedGoogle Scholar
  22. 22.
    Page AJ, Blackshaw LA: An in vitro study of the properties of vagal afferent fibres innervating the ferret oesophagus and stomach. J Physiol (Lond) 1998, 512:907–916.CrossRefGoogle Scholar
  23. 23.
    Beattie DT, Smith JA, Marquess D, et al.: The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol 2004, 143:549–560.CrossRefPubMedGoogle Scholar
  24. 24.
    Willert RP, Woolf CJ, Hobson AR, et al.: The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology 2004, 126:683–692.CrossRefPubMedGoogle Scholar
  25. 25.
    Bertrand C, Nadel JA, Yamawaki I, et al.: Role of kinins in the vascular extravasation evoked by antigen and mediated by tachykinins in guinea pig trachea. J Immunol 1993, 151:4902–4907.PubMedGoogle Scholar
  26. 26.
    Page AJ, Blackshaw LA: GABA B receptors inhibit mechanosensitivity of primary afferent endings. J Neurosci 1999, 19:8597–8602.PubMedGoogle Scholar
  27. 27.
    Petrocellis DL, Chu CJ, Moriello AS, et al.: Actions of two naturally occurring saturated N-acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels. Br J Pharmacol 2004, 143:251–256.CrossRefPubMedGoogle Scholar
  28. 28.
    Kollarik M, Ru F: Adenosine activates a subset of nociceptive vagal sensory nerves in esophagus. Gastroenterology 2006, 130(Suppl 2):A-252.Google Scholar
  29. 29.
    Fass R, Naliboff B, Higa L, et al.: Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology. 1998, 115:1363–1373.CrossRefPubMedGoogle Scholar
  30. 30.
    Cervero F, Laird J: From acute to chronic pain: mechanisms and hypothesis. In Progress in Brain Research. Edited by Zimmerman GCM. Elsevier, Amsterdam; 1996:3–16.Google Scholar
  31. 31.
    Cervero F, Laird J, Garcia-Nicas E: Secondary hyperalgesia and presynaptic inhibition: an update. Eur J Pain 2003, 7:345–351.CrossRefPubMedGoogle Scholar
  32. 32.
    Tack J: Is there a unifying role for visceral hypersensitivity and irritable bowel syndrome in non-erosive reflux disease? Digestion 2008, 78(Suppl 1):42–45.CrossRefPubMedGoogle Scholar
  33. 33.
    Trimble KC, Pryde A, Heading RC: Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut 1995, 37:7–12CrossRefPubMedGoogle Scholar
  34. 34.
    Drewes AM, Arendt-Nielsen L, Funch-Jensen P, Gregersen H: Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain. World J Gastroenterol 2006, 12:2806–2817.PubMedGoogle Scholar
  35. 35.
    Matthews PJ, Aziz Q, Facer P, et al.: Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 2004, 16:897–902.CrossRefPubMedGoogle Scholar
  36. 36.
    Remes-Troche JM, Chahal P, Mudipalli R, Rao SS: Adenosine modulates oesophageal sensorimotor function in humans. Gut 2009, 58:1049–1055.CrossRefPubMedGoogle Scholar
  37. 37.
    Remes-Troche JM, Attaluri A, Hashmi S, et al.: The role of adenosine in esophageal nociception in patients with functional chest pain. Gastroenterology 2009, 136(Suppl 1):A93.Google Scholar
  38. 38.
    Caviglia R, Ribolsi M, Maggiano N, et al.: Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol 2005, 100:543–548.CrossRefPubMedGoogle Scholar
  39. 39.
    Vela MF, Craft BM, Sharma N, et al.: Intercellular space distance is increased in refractory heartburn patients with positive symptom index regardless of whether symptoms are caused by acid or nonacid reflux: a study using impedance-pH and electron microscopy. Gastroenterology 2009, 136(Suppl 1):A426.Google Scholar
  40. 40.
    • Vela MF, Craft BM, Sharma N, et al.: Intercellular space distance is increased in refractory heartburn patients with GERD but not those with functional heartburn (FH): a study using impedance-pH and electron microscopy. Gastroenterology 2009, 136(Suppl 1):A63. This article describes a very important study evaluating the relationship between DIS and esophageal acid exposure in subjects with GERD and functional heartburn. The authors report that DIS may be a helpful tool to discriminate GERD from functional heartburn. Implications for therapy may be that those with increased DIS need improved reflux control, whereas those with functional symptoms may benefit from non-GERD treatments (eg, visceral analgesia).Google Scholar
  41. 41.
    Aziz Q, Andersson J, Valind S, Thompson D: Identification of human brain loci processing esophageal sensation using positron emission tomography. Gastroenterology 1997, 113:50–97.CrossRefPubMedGoogle Scholar
  42. 42.
    Shaker R, Kern M, Arndorfer R, et al.: Cerebral cortical fMRI responses to esophageal acid exposure and distention: a comparative study. Gastroenterology 1996, 130(Suppl 2):A395.Google Scholar
  43. 43.
    Hobson AR, Khan RW, Sarkar S, et al.: Development of esophageal hypersensitivity following experimental duodenal acidification. Am J Gastroenterol 2004, 99:813–820.CrossRefPubMedGoogle Scholar
  44. 44.
    Penagini R, Hebbard G, Horowitz M, et al.: Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease. Gut 1998, 42:251–257.CrossRefPubMedGoogle Scholar
  45. 45.
    Sarkar S, Hobson AR, Furlong PL, et al.: Central neural mechanisms mediating human visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol 2001, 281:G1196–G1202.PubMedGoogle Scholar
  46. 46.
    Balaban DH, Yamamoto Y, Liu J, et al.: Sustained esophageal contraction: a marker of esophageal chest pain identified by intraluminal ultrasonography. Gastroenterology 1999, 116:29–37.CrossRefPubMedGoogle Scholar
  47. 47.
    Pehlivanov N, Liu J, Mittal R: Sustained esophageal contraction: a motor correlate of heartburn symptom. Am J Physiol Gastrointest Liver Physiol 2001, 281:G743–G751.PubMedGoogle Scholar
  48. 48.
    Johnston BT, Lewis SA, Collins JS, et al.: Acid perception in gastro-oesophageal reflux disease is dependent on psychosocial factors. Scand J Gastroenterol 1995, 30:1–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Rubenstein JH, Nojkov B, Korsnes S, et al.: Oesophageal hypersensitivity is associated with features of psychiatric disorders and the irritable bowel syndrome. Aliment Pharmacol Ther 2007, 26:443–452.CrossRefPubMedGoogle Scholar
  50. 50.
    Richter JF, Barish CF, Castell DO: Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 1986, 91:845–852.PubMedGoogle Scholar
  51. 51.
    Shapiro M, Green C, Bautista JM, et al.: Functional heartburn patients demonstrate traits of functional bowel disorder but lack a uniform increase of chemoreceptor sensitivity to acid. Am J Gastroenterol 2006, 101:1084–1091.CrossRefPubMedGoogle Scholar
  52. 52.
    Remes-Troche JM, Maher J, Mudipalli R, Rao SS: Altered esophageal sensory-motor function in patients with persistent symptoms after Nissen fundoplication. Am J Surg 2007, 193:200–205.CrossRefPubMedGoogle Scholar
  53. 53.
    Chen CL, Szczesniak MM, Cook IJ: Evidence for oesophageal visceral hypersensitivity and aberrant symptom referral in patients with globus. Neurogastroenterol Motil 2009, 21:1142–e96.CrossRefPubMedGoogle Scholar
  54. 54.
    Remes-Troche JM, Chahal P, Schulze K, Rao SC: Esophageal barostat or impedance planimetry: which is best suited for esophageal sensory testing? Neurogastroenterol Motil 2006, 18:713–714.Google Scholar
  55. 55.
    Drewes AM, Schipper KP,Dimcevksi C, et al.: Multimodal assessment of pain in the esophagus: a new experimental model. Am J Physiol Gastrointest Liver Physiol 2002, 283:G95–G103.PubMedGoogle Scholar
  56. 56.
    Dickman R, Emmons S, Cui H, et al.: The effect of a therapeutic trial of high-dose rabeprazole on symptom response of patients with non-cardiac chest pain: a randomized, double-blind, placebo-controlled, crossover trial. Aliment Pharmacol Ther 2005, 22:547–555.CrossRefPubMedGoogle Scholar
  57. 57.
    Varaia I, Logue E, O’Connor C, et al.: Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J 2000, 140:367–372.CrossRefGoogle Scholar
  58. 58.
    Broekaert D, Fischler B, Sifrim D, et al.: Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study. Aliment Pharmacol Ther 2006, 23:365–370.CrossRefPubMedGoogle Scholar
  59. 59.
    Rodriguez-Stanley S, Zubaidi S, Proskin HM, et al.: Effect of tegaserod on esophageal pain threshold, regurgitation and symptom relief in patients with functional heartburn and mechanical sensitivity. Clin Gastroenterol Hepatol 2006, 4:442–450.CrossRefPubMedGoogle Scholar
  60. 60.
    Peghini PL, Katz PO, Castell DO: Imipramine decreases oesophageal pain perception in human male volunteers. Gut 1998, 42:807–813.CrossRefPubMedGoogle Scholar
  61. 61.
    Prakash C, Clouse RE: Long term outcome of tricyclic antidepressant treatment of functional chest pain. Dig Dis Sci 1999, 44:81–90.Google Scholar
  62. 62.
    Clouse RE, Lustman PJ, Eckert TC, et al.: Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities. A double-blind, placebo-controlled trial. Gastroenterology 1987, 92:1027–1036.PubMedGoogle Scholar
  63. 63.
    Rao SS, Mudipalli RS, Remes-Troche JM, et al.: Theophylline improves esophageal chest pain—a randomized, placebo-controlled study. Am J Gastroenterol 2007, 102:930–938.CrossRefPubMedGoogle Scholar
  64. 64.
    Jones H, Cooper P, Miller V, et al.: Treatment of non-cardiac chest pain: a controlled trial of hypnotherapy. Gut 2006, 55:1403–1408.CrossRefPubMedGoogle Scholar
  65. 65.
    Rao SS, Mudipalli RS, Mujica V, et al.: An open-label trial of theophylline for functional chest pain. Dig Dis Sci 2002, 12:2763–2768.CrossRefGoogle Scholar
  66. 66.
    Cannon RO, Quyyumi AA, Mincemoyer R, et al.: Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med 1994, 330:1411–1417.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratorio de Fisiologia Digestiva y Motilidad GastrointestinalInstituto de Investigaciones Medico BiologicasVeracruzMexico

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