Korean J Gastroenterol.  2011 Feb;57(2):82-99. 10.4166/kjg.2011.57.2.82.

Guidelines for the Treatment of Irritable Bowel Syndrome

• Kwon JG
• Park KS
• Park JH
• Park JM
• Park CH
• Lee KJ
• Park HJ
• Rhee JC
• The Korean Society of Neurogastroenterology and Motility

• KMID: 1775839
• DOI: http://doi.org/10.4166/kjg.2011.57.2.82

Abstract

Traditional symptom-based therapies of irritable bowel syndrome (IBS) are directed at the relief of individual IBS symptoms, but they are often of limited efficacy in addressing the entire symptom complex. Combinations of drugs to target bothersome symptoms are suggested as the first-line pharmacologic treatment. Increasing knowledge of the pathophysiology and molecular mechanisms of IBS has resulted in the development of several new therapeutic approaches. Thirteen consensus statements for the treatment of IBS were developed using the modified Delphi approach. Exclusion diets have modest efficacy in improving symptoms in some IBS patients. Symptom-based therapies with dietary fiber, bulking agents, laxatives, antispasmodics and laxatives are effective in the improvement of some individual symptoms, e.g. dietary fiber and bulking agents for constipation, laxatives for constipation, antispasmodics for abdominal pain and discomfort, antidiarrheals for diarrhea. 5HT3 receptor antagonists and 5HT4 receptor agonists are effective in the relief of global IBS symptoms and individual symptoms such as abdominal pain and abnormal bowel habits. A short term course of nonabsorbable antibiotics may improve global IBS symptoms, particularly in patients with diarrhea- predominant IBS. Some probiotics appear to have the potential benefit in improving global IBS symptoms. Selective C-2 chloride channel activator is more effective than placebo at relieving global IBS symptoms in patients with constipation-predominant IBS. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are equally effective in relieving global IBS symptoms, and have some benefits in treating abdominal pain. Certain types of psychologic therapy may be effective in improving global symptoms in some IBS patients. Further studies are strongly needed to develop better treatment strategies for Korean patients with IBS.

Keyword

Irritable bowel syndrome; Treatment; Guideline

MeSH Terms

Anti-Infective Agents/therapeutic use
Antidepressive Agents/therapeutic use
Antidiarrheals/therapeutic use
Dietary Fiber/therapeutic use
Humans
Irritable Bowel Syndrome/*therapy
Laxatives/therapeutic use
Parasympatholytics/therapeutic use
Probiotics/therapeutic use
Serotonin 5-HT4 Receptor Agonists/therapeutic use
Serotonin Antagonists/therapeutic use

Figure

• 

  Fig. 1. Flow chart for searching strategy.

Reference

References

1. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009; 104(Suppl 1):S1–S35.

2. Lee SY, Lee KJ, Kim SJ, Cho SW. Prevalence and risk factors for overlaps between gastroesophageal reflux disease, dyspepsia, and irritable bowel syndrome: a population-based study. Digestion. 2009; 79:196–201.

3. Park DW, Lee OY, Shim SG, et al. The Differences in Prevalence and Sociodemographic Characteristics of Irritable Bowel Syndrome According to Rome II and Rome III. J Neurogastroenterol Motil. 2010; 16:186–193.

4. Lu CL, Chang FY, Lang HC, Chen CY, Luo JC, Lee SD. Gender difference on the symptoms, health-seeking behaviour, social impact and sleep quality in irritable bowel syndrome: a Rome II-based survey in an apparent healthy adult Chinese population in Taiwan. Aliment Pharmacol Ther. 2005; 21:1497–1505.

5. Rey E, García-Alonso MO, Moreno-Ortega M, Alvarez-Sanchez A, Diaz-Rubio M. Determinants of quality of life in irritable bowel syndrome. J Clin Gastroenterol. 2008; 42:1003–1009.

6. El-Serag HB, Olden K, Bjorkman D. Health-related quality of life among persons with irritable bowel syndrome: a systematic review. Aliment Pharmacol Ther. 2002; 16:1171–1185.

7. Spiegel BM. The burden of IBS: looking at metrics. Curr Gastroenterol Rep. 2009; 11:265–269.

8. Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B, Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004; 20(Suppl 2):1–9.

9. Systematic review on the management of irritable bowel syndrome in the European Union. Eur J Gastroenterol Hepatol. 2007; 19(Suppl 1):S11–S37.

10. Gwee KA, Bak YT, Ghoshal UC, et al. Asian consensus on irritable bowel syndrome. J Gastroenterol Hepatol. 2010; 25:1189–1205.

11. Park HJ. Treatment guidelines of irritable bowel syndrome. Korean J Neurogastroenterol Motil. 2005; 11:36–43.

12. Park JH, Byeon JS, Shin WG, et al. Diagnosis of irritable bowel syndrome: a systematic review. Korean J Gastroenterol. 2010; 55:308–315.

13. Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J. 1978; 2:653–654.

14. Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schünemann HJ. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133(6 Suppl):123S–131S.

15. Monsbakken KW, Vandvik PO, Farup PG. Perceived food intolerance in subjects with irritable bowel syndrome–etiology, prevalence and consequences. Eur J Clin Nutr. 2006; 60:667–672.

16. Simrén M, Månsson A, Langkilde AM, et al. Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion. 2001; 63:108–115.

17. Nanda R, James R, Smith H, Dudley CR, Jewell DP. Food intolerance and the irritable bowel syndrome. Gut. 1989; 30:1099–1104.

18. Jones VA, McLaughlan P, Shorthouse M, Workman E, Hunter JO. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet. 1982; 2:1115–1117.

19. Bentley SJ, Pearson DJ, Rix KJ. Food hypersensitivity in irritable bowel syndrome. Lancet. 1983; 2:295–297.

20. Stefanini GF, Saggioro A, Alvisi V, et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol. 1995; 30:535–541.

21. Zwetchkenbaum J, Burakoff R. The irritable bowel syndrome and food hypersensitivity. Ann Allergy. 1988; 61:47–49.

22. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004; 53:1459–1464.

23. McKee AM, Prior A, Whorwell PJ. Exclusion diets in irritable bowel syndrome: are they worthwhile? J Clin Gastroenterol. 1987; 9:526–528.

24. Dainese R, Galliani EA, De Lazzari F, Di Leo V, Naccarato R. Discrepancies between reported food intolerance and sensitization test findings in irritable bowel syndrome patients. Am J Gastroenterol. 1999; 94:1892–1897.

25. Park MI, Camilleri M. Is there a role of food allergy in irritable bowel syndrome and functional dyspepsia? A systematic review. Neurogastroenterol Motil. 2006; 18:595–607.

26. Drisko J, Bischoff B, Hall M, McCallum R. Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. J Am Coll Nutr. 2006; 25:514–522.

27. Costabile A, Klinder A, Fava F, et al. Whole-grain wheat break-fast cereal has a prebiotic effect on the human gut microbiota: a double-blind, placebo-controlled, crossover study. Br J Nutr. 2008; 99:110–120.

28. Soltoft J, Krag B, Gudmand-Hoyer E, Kristensen E, Wulff HR. A double-blind trial of the effect of wheat bran on symptoms of irritable bowel syndrome. Lancet. 1976; 1:270–272.

29. Manning AP, Heaton KW, Harvey RF. Wheat fibre and irritable bowel syndrome. A controlled trial. Lancet. 1977; 2:417–418.

30. Ritchie JA, Truelove SC. Treatment of irritable bowel syndrome with lorazepam, hyoscine butylbromide, and ispaghula husk. Br Med J. 1979; 1:376–378.

31. Longstreth GF, Fox DD, Youkeles L, Forsythe AB, Wolochow DA. Psyllium therapy in the irritable bowel syndrome. A double-blind trial. Ann Intern Med. 1981; 95:53–56.

32. Arthurs Y, Fielding JF. Double blind trial of ispaghula/polox-amer in the irritable bowel syndrome. Ir Med J. 1983; 76:253.

33. Nigam P, Kapoor KK, Rastog CK, Kumar A, Gupta AK. Different therapeutic regimens in irritable bowel syndrome. J Assoc Physicians India. 1984; 32:1041–1044.

34. Kruis W, Weinzierl M, Schüssler P, Holl J. Comparison of the therapeutic effect of wheat bran, mebeverine and placebo in patients with the irritable bowel syndrome. Digestion. 1986; 34:196–201.

35. Lucey MR, Clark ML, Lowndes J, Dawson AM. Is bran efficacious in irritable bowel syndrome? A double blind placebo controlled crossover study. Gut. 1987; 28:221–225.

36. Prior A, Whorwell PJ. Double blind study of ispaghula in irritable bowel syndrome. Gut. 1987; 28:1510–1513.

37. Jalihal A, Kurian G. Ispaghula therapy in irritable bowel syndrome: improvement in overall well-being is related to reduction in bowel dissatisfaction. J Gastroenterol Hepatol. 1990; 5:507–513.

38. Fowlie S, Eastwood MA, Prescott R. Irritable bowel syndrome: assessment of psychological disturbance and its influence on the response to fibre supplementation. J Psychosom Res. 1992; 36:175–180.

39. Rees G, Davies J, Thompson R, Parker M, Liepins P. Randomised-controlled trial of a fibre supplement on the symptoms of irritable bowel syndrome. J R Soc Promot Health. 2005; 125:30–34.

40. Ford AC, Talley NJ, Spiegel BM, et al. Effect of fibre, anti-spasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and metaanalysis. BMJ. 2008; 337:a2313.

41. Bijkerk CJ, de Wit NJ, Muris JW, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ. 2009; 339:b3154.

42. Snook J, Shepherd HA. Bran supplementation in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 1994; 8:511–514.

43. Khoshoo V, Armstead C, Landry L. Effect of a laxative with and without tegaserod in adolescents with constipation predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006; 23:191–196.

44. Tack J, Fried M, Houghton LA, Spicak J, Fisher G. Systematic review: the efficacy of treatments for irritable bowel syndrome–a European perspective. Aliment Pharmacol Ther. 2006; 24:183–205.

45. Lüttecke K. A three-part controlled study of trimebutine in the treatment of irritable colon syndrome. Curr Med Res Opin. 1980; 6:437–443.

46. Centonze V, Imbimbo BP, Campanozzi F, Attolini E, Daniotti S, Albano O. Oral cimetropium bromide, a new antimuscarinic drug, for long-term treatment of irritable bowel syndrome. Am J Gastroenterol. 1988; 83:1262–1266.

47. Dobrilla G, Imbimbo BP, Piazzi L, Bensi G. Longterm treatment of irritable bowel syndrome with cimetropium bromide: a double blind placebo controlled clinical trial. Gut. 1990; 31:355–358.

48. Awad R, Dibildox M, Ortiz F. Irritable bowel syndrome treatment using pinaverium bromide as a calcium channel blocker. A randomized double-blind placebo-controlled trial. Acta Gastroenterol Latinoam. 1995; 25:137–144.

49. Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol. 1997; 32:765–768.

50. Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial. Dig Liver Dis. 2007; 39:530–536.

51. Baldi F, Longanesi A, Blasi A, et al. Clinical and functional evaluation of the efficacy of otilonium bromide: a multicenter study in Italy. Ital J Gastroenterol. 1991; 23(8 Suppl 1):60–63.

52. Battaglia G, Morselli-Labate AM, Camarri E, et al. Otilonium bromide in irritable bowel syndrome: a double-blind, placebo-controlled, 15-week study. Aliment Pharmacol Ther. 1998; 12:1003–1010.

53. Glende M, Morselli-Labate AM, Battaglia G, Evangelista S. Extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide in irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2002; 14:1331–1338.

54. Chey WY, Jin HO, Lee MH, Sun SW, Lee KY. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol. 2001; 96:1499–1506.

55. Lavö B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome–a double-blind placebo controlled study. Scand J Gastroenterol Suppl. 1987; 130:77–80.

56. Hovdenak N. Loperamide treatment of the irritable bowel syndrome. Scand J Gastroenterol Suppl. 1987; 130:81–84.

57. Efskind PS, Bernklev T, Vatn MH. A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol. 1996; 31:463–468.

58. Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig Dis Sci. 1984; 29:239–247.

59. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007; 132:397–414.

60. Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther. 2000; 14:775–782.

61. Delvaux M, Louvel D, Mamet JP, Campos-Oriola R, Frexinos J. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 1998; 12:849–855.

62. Bardhan KD, Bodemar G, Geldof H, et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2000; 14:23–34.

63. Camilleri M, Chey WY, Mayer EA, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med. 2001; 161:1733–1740.

64. Chey WD, Chey WY, Heath AT, et al. Longterm safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2004; 99:2195–2203.

65. Lembo AJ, Olden KW, Ameen VZ, Gordon SL, Heath AT, Carter EG. Effect of alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: analysis of two controlled trials. Clin Gastroenterol Hepatol. 2004; 2:675–682.

66. Camilleri M, Mayer EA, Drossman DA, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther. 1999; 13:1149–1159.

67. Chang L, Ameen VZ, Dukes GE, McSorley DJ, Carter EG, Mayer EA. A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS. Am J Gastroenterol. 2005; 100:115–123.

68. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet. 2000; 355:1035–1040.

69. Krause R, Ameen V, Gordon SH, et al. A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS. Am J Gastroenterol. 2007; 102:1709–1719.

70. Lembo T, Wright RA, Bagby B, et al. Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2001; 96:2662–2670.

71. Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and metaanalysis. Am J Gastroenterol. 2009; 104:1831–1843.

72. Chang L, Chey WD, Harris L, Olden K, Surawicz C, Schoenfeld P. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol. 2006; 101:1069–1079.

73. Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome. Digestion. 2008; 77:225–235.

74. Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol. 2008; 43:1202–1211.

75. Nyhlin H, Bang C, Elsborg L, et al. A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome. Scand J Gastroenterol. 2004; 39:119–126.

76. Müller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther. 2001; 15:1655–1666.

77. Novick J, Miner P, Krause R, et al. A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2002; 16:1877–1888.

78. Kellow J, Lee OY, Chang FY, et al. An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut. 2003; 52:671–676.

79. Tack J, Müller-Lissner S, Bytzer P, et al. A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation. Gut. 2005; 54:1707–1713.

80. Harish K, Hazeena K, Thomas V, Kumar S, Jose T, Narayanan P. Effect of tegaserod on colonic transit time in male patients with constipation-predominant irritable bowel syndrome. J Gastroenterol Hepatol. 2007; 22:1183–1189.

81. Chey WD, Paré P, Viegas A, Ligozio G, Shetzline MA. Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial. Am J Gastroenterol. 2008; 103:1217–1225.

82. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004; 2:895–904.

83. George AM, Meyers NL, Hickling RI. Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome–multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting. Aliment Pharmacol Ther. 2008; 27:830–837.

84. Lembo AJ, Cremonini F, Meyers N, Hickling R. Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation – a doubleblind, randomized, placebo-controlled, study. Aliment Pharmacol Ther. 2010; 31:979–990.

85. Spiller RC, Meyers NL, Hickling RI. Identification of patients with non-d, non-C irritable bowel syndrome and treatment with renzapride: an exploratory, multicenter, randomized, double-blind, placebo-controlled clinical trial. Dig Dis Sci. 2008; 53:3191–3200.

86. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006; 145:557–563.

87. Yang J, Lee HR, Low K, Chatterjee S, Pimentel M. Rifaximin versus other antibiotics in the primary treatment and retreatment of bacterial overgrowth in IBS. Dig Dis Sci. 2008; 53:169–174.

88. Pimentel M. An evidence-based treatment algorithm for IBS based on a bacterial/SIBO hypothesis: Part 2. Am J Gastroenterol. 2010; 105:1227–1230.

89. Pimentel M, Chatterjee S, Chow EJ, Park S, Kong Y. Neomycin improves constipation-predominant irritable bowel syndrome in a fashion that is dependent on the presence of methane gas: subanalysis of a double-blind randomized controlled study. Dig Dis Sci. 2006; 51:1297–1301.

90. Bittner AC, Croffut RM, Stranahan MC. Prescript-Assist pro-biotic-prebiotic treatment for irritable bowel syndrome: a methodologically oriented, 2-week, randomized, placebo-controlled, double-blind clinical study. Clin Ther. 2005; 27:755–761.

91. Bittner AC, Croffut RM, Stranahan MC, Yokelson TN. Prescript-assist probiotic-prebiotic treatment for irritable bowel syndrome: an open-label, partially controlled, 1-year extension of a previously published controlled clinical trial. Clin Ther. 2007; 29:1153–1160.

92. Drouault-Holowacz S, Bieuvelet S, Burckel A, Cazaubiel M, Dray X, Marteau P. A double blind randomized controlled trial of a probiotic combination in 100 patients with irritable bowel syndrome. Gastroenterol Clin Biol. 2008; 32:147–152.

93. Dughera L, Elia C, Navino M, Cisarò F. ARMONIA Study Group. Effects of symbiotic preparations on constipated irritable bowel syndrome symptoms. Acta Biomed. 2007; 78:111–116.

94. Enck P, Zimmermann K, Menke G, Müller-Lissner S, Martens U, Klosterhalfen S. A mixture of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel syndrome–a randomized controlled trial with primary care physicians. Neurogastroenterol Motil. 2008; 20:1103–1109.

95. Fanigliulo L, Comparato G, Aragona G, et al. Role of gut microflora and probiotic effects in the irritable bowel syndrome. Acta Biomed. 2006; 77:85–89.

96. Guyonnet D, Chassany O, Ducrotte P, et al. Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double-blind, controlled trial. Aliment Pharmacol Ther. 2007; 26:475–486.

97. Hong KS, Kang HW, Im JP, et al. Effect of probiotics on symptoms in korean adults with irritable bowel syndrome. Gut Liver. 2009; 3:101–107.

98. Kajander K, Hatakka K, Poussa T, Färkkilä M, Korpela R. A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther. 2005; 22:387–394.

99. Kajander K, Myllyluoma E, Rajilić-Stojanović M, et al. Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota. Aliment Pharmacol Ther. 2008; 27:48–57.

100. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil. 2005; 17:687–696.

101. Kim YG, Moon JT, Lee KM, Chon NR, Park H. The effects of probiotics on symptoms of irritable bowel syndrome. Korean J Gastroenterol. 2006; 47:413–419.

102. Ligaarden SC, Axelsson L, Naterstad K, Lydersen S, Farup PG. A candidate probiotic with unfavourable effects in subjects with irritable bowel syndrome: a randomised controlled trial. BMC Gastroenterol. 2010; 10:16.

103. Niv E, Naftali T, Hallak R, Vaisman N. The efficacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome–a double blind, placebo-controlled, randomized study. Clin Nutr. 2005; 24:925–931.

104. O'Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005; 128:541–551.

105. Simrén M, Ohman L, Olsson J, et al. Clinical trial: the effects of a fermented milk containing three probiotic bacteria in patients with irritable bowel syndrome – a randomized, double-blind, controlled study. Aliment Pharmacol Ther. 2010; 31:218–227.

106. Sinn DH, Song JH, Kim HJ, et al. Therapeutic effect of Lactobacillus acidophilus-SDC 2012, 2013 in patients with irritable bowel syndrome. Dig Dis Sci. 2008; 53:2714–2718.

107. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006; 101:1581–1590.

108. Zeng J, Li YQ, Zuo XL, Zhen YB, Yang J, Liu CH. Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2008; 28:994–1002.

109. Zifarelli G, Pusch M. CLC chloride channels and transporters: a biophysical and physiological perspective. Rev Physiol Biochem Pharmacol. 2007; 158:23–76.

110. Johanson JF, Drossman DA, Panas R, Wahle A, Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2008; 27:685–696.

111. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome–results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009; 29:329–341.

112. Talley NJ, Spiller R. Irritable bowel syndrome: a little under-stood organic bowel disease? Lancet. 2002; 360:555–564.

113. Clouse RE. Managing functional bowel disorders from the top down: lessons from a well-designed treatment trial. Gastroenterology. 2003; 125:249–253.

114. Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-be-havioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003; 125:19–31.

115. Kuiken SD, Tytgat GN, Boeckxstaens GE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study. Clin Gastroenterol Hepatol. 2003; 1:219–228.

116. Heefner JD, Wilder RM, Wilson ID. Irritable colon and depression. Psychosomatics. 1978; 19:540–547.

117. Myren J, Groth H, Larssen SE, Larsen S. The effect of trimipr-amine in patients with the irritable bowel syndrome. A double-blind study. Scand J Gastroenterol. 1982; 17:871–875.

118. Vahedi H, Merat S, Momtahen S, et al. Clinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2008; 27:678–684.

119. Vahedi H, Merat S, Rashidioon A, Ghoddoosi A, Malekzadeh R. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther. 2005; 22:381–385.

120. Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol. 2004; 99:914–920.

121. Tack J, Broekaert D, Fischler B, Van Oudenhove L, Gevers AM, Janssens J. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006; 55:1095–1103.

122. Talley NJ, Kellow JE, Boyce P, Tennant C, Huskic S, Jones M. Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial. Dig Dis Sci. 2008; 53:108–115.

123. Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and metaanalysis. Gut. 2009; 58:367–378.

124. Halpert A, Dalton CB, Diamant NE, et al. Clinical response to tricyclic antidepressants in functional bowel disorders is not related to dosage. Am J Gastroenterol. 2005; 100:664–671.

125. Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther. 1994; 8:159–166.

126. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007; (4):CD005454.

127. Greene B, Blanchard EB. Cognitive therapy for irritable bowel syndrome. J Consult Clin Psychol. 1994; 62:576–582.

128. Payne A, Blanchard EB. A controlled comparison of cognitive therapy and self-help support groups in the treatment of irritable bowel syndrome. J Consult Clin Psychol. 1995; 63:779–786.

129. Kennedy TM, Chalder T, McCrone P, et al. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial. Health Technol Assess. 2006; 10:iii–iv. ix-x, 1–67.

130. Heitkemper MM, Jarrett ME, Levy RL, et al. Self-management for women with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004; 2:585–596.

131. Guthrie E, Creed F, Dawson D, Tomenson B. A controlled trial of psychological treatment for the irritable bowel syndrome. Gastroenterology. 1991; 100:450–457.

132. Creed F, Fernandes L, Guthrie E, et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology. 2003; 124:303–317.

133. van der Veek PP, van Rood YR, Masclee AA. Clinical trial: short- and long-term benefit of relaxation training for irritable bowel syndrome. Aliment Pharmacol Ther. 2007; 26:943–952.

134. Keefer L, Blanchard EB. The effects of relaxation response meditation on the symptoms of irritable bowel syndrome: results of a controlled treatment study. Behav Res Ther. 2001; 39:801–811.

135. Blanchard EB, Schwarz SP, Suls JM, et al. Two controlled evaluations of multicomponent psychological treatment of irritable bowel syndrome. Behav Res Ther. 1992; 30:175–189.

136. Shaw G, Srivastava ED, Sadlier M, Swann P, James JY, Rhodes J. Stress management for irritable bowel syndrome: a controlled trial. Digestion. 1991; 50:36–42.

137. Galovski TE, Blanchard EB. The treatment of irritable bowel syndrome with hypnotherapy. Appl Psychophysiol Biofeedback. 1998; 23:219–232.

138. Simrén M, Ringström G, Björnsson ES, Abrahamsson H. Treatment with hypnotherapy reduces the sensory and motor component of the gastrocolonic response in irritable bowel syndrome. Psychosom Med. 2004; 66:233–238.

139. Boyce PM, Talley NJ, Balaam B, Koloski NA, Truman G. A randomized controlled trial of cognitive behavior therapy, relaxation training, and routine clinical care for the irritable bowel syndrome. Am J Gastroenterol. 2003; 98:2209–2218.

140. Sanders KA, Blanchard EB, Sykes MA. Preliminary study of a self-administered treatment for irritable bowel syndrome: comparison to a wait list control group. Appl Psychophysiol Biofeedback. 2007; 32:111–119.

141. Lackner JM, Mesmer C, Morley S, Dowzer C, Hamilton S. Psychological treatments for irritable bowel syndrome: a systematic review and metaanalysis. J Consult Clin Psychol. 2004; 72:1100–1113.

142. Kennedy T, Jones R, Darnley S, Seed P, Wessely S, Chalder T. Cognitive behaviour therapy in addition to antispasmodic treatment for irritable bowel syndrome in primary care: randomised controlled trial. BMJ. 2005; 331:435.

143. Horwitz BJ, Fisher RS. The irritable bowel syndrome. N Engl J Med. 2001; 344:1846–1850.