Top

Published in:

01-07-2011 | Review Article

The Risk of Ischaemic Colitis in Irritable Bowel Syndrome Patients Treated with Serotonergic Therapies

Author: Professor James H. Lewis

Published in: Drug Safety | Issue 7/2011

Abstract

Ischaemic colitis (IC) is the most common form of ischaemic injury to the gastrointestinal (GI) tract. IC typically presents with the sudden onset of lower abdominal pain, cramping and rectal bleeding, and is usually self-limited with low morbidity, although it may cause gangrenous or fulminant colitis, especially when the right colon is involved. Multiple medical conditions, as well as several pharmacological agents, are associated with IC, including irritable bowel syndrome (IBS) and drugs used for its treatment that act on gut serotonin 5-HT receptors. These include the selective 5-HT₃ receptor antagonist alosetron, currently approved for the treatment of severe diarrhoea-predominant IBS in women who fail to respond to conventional treatment, and cilansetron, another 5-HT₃ receptor antagonist that is no longer in clinical development. In addition, the 5-HT₄ receptor partial agonist tegaserod, which was approved for the treatment of constipation-predominant IBS in women, was associated with IC in the postmarketing setting, as was renzapride, a 5-HT₄ agonist/5-HT₃ antagonist.

Although several hypotheses have been proposed, the pathophysiological basis for development of IC with 5-HT₃receptor antagonists or 5-HT₄ receptor agonists remains unknown. Of interest, several population-based studies demonstrated that a diagnosis of IBS (independent of serotonergic therapies) increases the risk of developing IC 2- to 4-fold. As a result, IBS patients with the acute onset of abdominal pain, tenderness, diarrhoea or lower intestinal bleeding, especially those with predisposing conditions or medications, should be evaluated promptly for IC. The management of IC remains supportive; most cases of non-gangrenous IC, as seen in the alosetron and tegaserod databases, have been transient and have resolved spontaneously without complications or death.

Despite the small number of deaths associated with alosetron in patients with complications of constipation and because of the ongoing requirement to prescribe alosetron under a risk management plan, misconceptions persist regarding the definition, incidence, severity and outcome of IC in clinical trials and the postmarketing setting. In this article, the frequency and clinical characteristics of IC associated with the use of alosetron and other serotonergic agents are examined, evidence of an association between IC and IBS is reviewed, and a scoring system to aid in the diagnosis of IC in any clinical situation is proposed.

Brandt LJ, Boley SJ. Colonic ischemia. Surg Clin North Am 1992 Feb; 72(1): 203–29PubMed

Higgins PD, Davis KJ, Laine L. Systematic review: the epidemiology of ischaemic colitis. Aliment Pharmacol Ther 2004 Apr 1; 19(7): 729–38PubMedCrossRef

Suh DC, Kahler KH, Choi IS, et al. Patients with irritable bowel syndrome or constipation have an increased risk for ischaemic colitis. Aliment Pharmacol Ther 2007 Mar 15; 25(6): 681–92PubMedCrossRef

Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia. American Gastrointestinal Association. Gastroenterology 2000 May; 118(5): 954–68PubMedCrossRef

Brandt LJ, Feuerstadt P, Blaszka MC. Anatomic patterns, patient characteristics, and clinical outcomes in ischemic colitis: a study of 313 cases supported by histology. Am J Gastroenterol 2010 Oct; 105(10): 2245–52PubMedCrossRef

Gandhi SK, Hanson MM, Vernava AM, et al. Ischemic colitis. Dis Colon Rectum 1996 Jan; 39(1): 88–100PubMedCrossRef

American Gastroenterological Association medical position statement: guidelines on intestinal ischemia. Gastroenterology 2000 May; 118(5): 951–3CrossRef

Longstreth GF, Yao JF. Diseases and drugs that increase risk of acute large bowel ischemia. Clin Gastroenterol Hepatol 2010 Jan; 8(1): 49–54PubMedCrossRef

Longstreth GF, Yao JF. Epidemiology, clinical features, high-risk factors, and outcome of acute large bowel ischemia. Clin Gastroenterol Hepatol 2009 Oct; 7(10): 1075–80PubMedCrossRef

10.

Gallo-Torres H, Brinker A, Avigan M. Alosetron: ischemic colitis and serious complications of constipation. Am J Gastroenterol 2006 May; 101(5): 1080–3PubMedCrossRef

11.

Chang L, Tong K, Ameen V. Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinical characteristics, outcomes, and incidences. Am J Gastroenterol 2010 Apr; 105(4): 866–75PubMedCrossRef

12.

Chang L, Chey WD, Harris L, et al. 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 May; 101(5): 1069–79PubMedCrossRef

13.

Elder K, Lashner BA, Al SF. Clinical approach to colonic ischemia. Cleve Clin J Med 2009 July; 76(7): 401–9PubMedCrossRef

14.

Stamatakos M, Douzinas E, Stefanaki C, et al. Ischemic colitis: surging waves of update. Tohoku J Exp Med 2009; 218(2): 83–92PubMedCrossRef

15.

Boley SJ, Schwartz S, Lash J, et al. Reversible vascular occlusion of the colon. Surg Gynecol Obstet 1963 Jan; 116: 53–60PubMed

16.

Marston A, Pheils MT, Thomas ML, et al. Ischaemic colitis. Gut 1966 Feb; 7(1): 1–15PubMedCrossRef

17.

Boley SJ. 1989 David H. Sun lecture. Colonic ischemia: 25 years later. Am J Gastroenterol 1990 Aug; 85(8): 931–4PubMed

18.

Sotiriadis J, Brandt LJ, Behin DS, et al. Ischemic colitis has a worse prognosis when isolated to the right side of the colon. Am J Gastroenterol 2007 Oct; 102(10): 2247–52PubMedCrossRef

19.

Theodoropoulou A, Sfiridaki A, Oustamanolakis P, et al. Genetic risk factors in young patients with ischemic colitis. Clin Gastroenterol Hepatol 2008 Aug; 6(8): 907–11PubMedCrossRef

20.

Cohen DC, Winstanley A, Engledow A, et al. Marathoninduced ischemic colitis: why running is not always good for you. Am J Emerg Med 2009 Feb; 27(2): 255–7PubMedCrossRef

21.

Sanchez LD, Tracy JA, Berkoff D, et al. Ischemic colitis in marathon runners: a case-based review. J Emerg Med 2006 Apr; 30(3): 321–6PubMedCrossRef

22.

Lucas W, Schroy III PC. Reversible ischemic colitis in a high endurance athlete. Am J Gastroenterol 1998 Nov; 93(11): 2231–4PubMedCrossRef

23.

Cappell MS. Colonic toxicity of administered drugs and chemicals. Am J Gastroenterol 2004 Jun; 99(6): 1175–90PubMedCrossRef

24.

Hass DJ, Kozuch P, Brandt LJ. Pharmacologically mediated colon ischemia. Am J Gastroenterol 2007 Aug; 102(8): 1765–80PubMedCrossRef

25.

Green BT, Tendler DA. Ischemic colitis: a clinical review. South Med J 2005 Feb; 98(2): 217–22PubMedCrossRef

26.

Heer M, Repond F, Hany A, et al. Acute ischaemic colitis in a female long distance runner. Gut 1987 July; 28(7): 896–9PubMedCrossRef

27.

Chang L, Kahler KH, Sarawate C, et al. Assessment of potential risk factors associated with ischaemic colitis. Neurogastroenterol Motil 2008 Jan; 20(1): 36–42PubMed

28.

Walker AM, Bohn RL, Cali C, et al. Risk factors for colon ischemia. Am J Gastroenterol 2004 July; 99(7): 1333–7PubMedCrossRef

29.

Lewis JH. Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol 2010 Feb; 4(1): 13–29PubMedCrossRef

30.

Briefing document for the Joint Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Subcommittee. Lotronex® (alosetron hydrochloride tablets) [online]. Available from URL: http://www.fda.gov/ohrms/dockets/AC/02/briefing/3848B1_01_GSK%20Briefing%20Pkg.pdf [Accessed 2010 Nov 23]

31.

Hervé S, Beaugerie L, Bouhnik Y, et al. Irritable bowel syndrome is more frequent in patients hospitalized for ischaemic colitis: results of a case-control study. Neurogastroenterol Motil 2009 Nov; 21(11): 1170–6PubMedCrossRef

32.

Cole JA, Cook SF, Sands BE, et al. Occurrence of colon ischemia in relation to irritable bowel syndrome. Am J Gastroenterol 2004 Mar; 99(3): 486–91PubMedCrossRef

33.

Brinker A, Avigan M. Epidemiology of ischaemic colitis. Aliment Pharmacol Ther 2004 Sept. 15; 20(6): 697–8PubMedCrossRef

34.

Brinker A, Senior J, Beitz J. Misdiagnosis of ischemic colitis as irritable bowel syndrome [abstract no. PII-16]. Clin Pharmacol Ther 2003; 73(2): 33CrossRef

35.

Singh G, Mithal A, Triadafilopoulos G. Patients with irritable bowel syndrome have a high-risk of developing ischemic colitis [abstract no. 349]. Gastroenterology 2004; 126 (4 Suppl. 2): A41

36.

Zou X, Cao J, Yao Y, et al. Endoscopic findings and clinicopathologic characteristics of ischemic colitis: a report of 85 cases. Dig Dis Sci 2009 Sep; 54(9): 2009–15PubMedCrossRef

37.

Delvaux M, Louvel D, Mamet JP, et al. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1998 Sep; 12(9): 849–55PubMedCrossRef

38.

Clayton NM, Sargent R, Butler A, et al. The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat. Neurogastroenterol Motil 1999 Jun; 11(3): 207–17PubMedCrossRef

39.

Lotronex® (alosetron hydrochloride) tablets [package insert]. San Diego (CA): Prometheus Laboratories Inc., 2010

40.

Prometheus Laboratories, Inc., San Diego (CA). (Data on file)

41.

Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroenterology 2001 Feb; 120(2): 557–60PubMedCrossRef

42.

Chey WD, Cash BD. Cilansetron: a new serotonergic agent for the irritable bowel syndrome with diarrhoea. Expert Opin Investig Drugs 2005 Feb; 14(2): 185–93PubMedCrossRef

43.

Cilansetron: Solvay Pharmaceuticals suspends registration activities in the U.S., while discussions in Europe continue [press release]. 2005 Nov 29 [online]. Available from URL: http://global.abbottgrowth.com/services/news/newsreleases/0,,36458-2-0,00.htm [Accessed 2010 Jul 28]

44.

Pfannkuche JJ, Buhl T, Games R, et al. The properties of a new prokinetically-active drug, SDZ HTF 919 [abstract no.]. Neurogastroenterol Motil 1995; 7: 280

45.

FDA patient safety news. New drug for women with constipation-predominant IBS [online]. Available from URL: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/transcript.cfm?show=10 [Accessed 2011 Jan 27]

46.

Joelsson BE, Shetzline MA, Cunningham S. Tegaserod and ischemic colitis [letter]. N Engl J Med 2004 Sep 23; 350(13): 1363–4CrossRef

47.

Muller-Lissner S, Kamm MA, Musoglu A, et al. Safety, tolerability, and efficacy of tegaserod over 13 months in patients with chronic constipation. Am J Gastroenterol 2006 Nov; 101(11): 2558–69PubMedCrossRef

48.

Brinker AD, Mackey AC, Prizont R. Tegaserod and ischemic colitis. N Engl J Med 2004 Sep 23; 351(13): 1361–4PubMed

49.

DiBaise JK. Tegaserod-associated ischemic colitis. Pharmacotherapy 2005 Apr; 25(4): 620–5PubMedCrossRef

50.

FDA briefing document. Gastrointestinal Drugs Advisory Committee. Zelnorm® for treatment of chronic constipation [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4056B1_02_A-FDA-Zelnorm.pdf [Accessed 2011 Jan 27]

51.

Heading R, Bardhan K, Hollerbach S, et al. Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome: a European perspective. Aliment Pharmacol Ther 2006 Jul 15; 24(2): 207–36PubMedCrossRef

52.

Shetzline MA, Cohard-Radice M, Joelsson B. Ischemic colitis, irritable bowel syndrome, and tegaserod: an alternative viewpoint. Pharmacotherapy 2005 Nov; 25(11): 1684–5PubMedCrossRef

53.

US Food and Drug Administration. Public Health Advisory. Tegaserod maleate (marketed as Zelnorm) [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm078972.htm [Accessed 2010 Mar 8]

54.

US Food and Drug Administration. Zelnorm (tagaserod maleate) information [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103223.htm [Accessed 2010 Mar 8]

55.

Lembo AJ, Cremonini F, Meyers N, et al. Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation-a double-blind, randomized, placebo-controlled, study. Aliment Pharmacol Ther 2010 May; 31(9): 979–90PubMed

56.

Lotronex® risk management program [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4040B1_17_FDA-Tab-2.pdf [Accessed 2009 Jul 13]

57.

Zelnorm® [package insert]. East Hanover (NJ): Novartis Pharmaceuticals, 2006

58.

Camilleri M. Is there an experimental basis for the development of ischaemic colitis as a result of 5-HT₃ antagonist treatment? Neurogastroenterol Motil 2007 Feb; 19(2): 77–84PubMedCrossRef

59.

Deana DG, Dean PJ. Reversible ischemic colitis in young women: association with oral contraceptive use. Am J Surg Pathol 1995 Apr; 19(4): 454–62PubMedCrossRef

60.

Koch K, Campanella C, Baidoo CA, et al. Pharmacodynamics and pharmacokinetics of oral contraceptives coadministered with alosetron (Lotronex). Dig Dis Sci 2004 Aug; 49(7–8): 1244–9PubMedCrossRef

61.

Millson D, Sohail S, Lettis S, et al. Duration of inhibition of the flare response to intradermal 5-hydroxytryptamine in man by GR68755, an novel specific 5-HT3 receptor antagonist. Br J Clin Pharmacol 1992; 33: 546–7CrossRef

62.

Painsipp E, Shahbazian A, Holzer P. Alosetron, cilansetron and tegaserod modify mesenteric but not colonic blood flow in rats. Br J Pharmacol 2009 Nov; 158(5): 1210–26PubMedCrossRef

63.

Grundy D, McLean P, Stead R. Impact of 5-HT3 receptor blockade on colonic haemodynamic responses to ischaemia and reperfusion in the rat. Neurogastroenterol Motil 2007 July; 19(7): 607–16PubMedCrossRef

64.

Reed DE, Vanner SJ. Long vasodilator reflexes projecting through the myenteric plexus in guinea-pig ileum. J Physiol (Lond) 2003 Dec 15; 553 (Pt 3): 911–24PubMedCrossRef

65.

Barbara G, Wang B, Stanghellini V, et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007 Jan; 132(1): 26–37PubMedCrossRef

66.

Buhner S, Li Q, Vignali S, et al. Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 2009 Oct; 137(4): 1425–34PubMedCrossRef

67.

Sand E, Themner-Persson A, Ekblad E. Infiltration of mast cells in rat colon is a consequence of ischemia/reperfusion. Dig Dis Sci 2008 Dec; 53(12): 3158–69PubMedCrossRef

68.

Ravnefjord A, Pettersson M, Rehnstrom E, et al. Acute colonic ischaemia in rats results in long-term structural changes without alterations of colonic sensitivity. Int J Exp Pathol 2008 Dec; 89(6): 476–89PubMedCrossRef

69.

Nakade Y, Fukuda H, Iwa M, et al. Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats. Am J Physiol Gastrointest Liver Physiol 2007 Apr; 292(4): G1037–44PubMedCrossRef

70.

Emmanuel AV, Kamm MA. Laser Doppler flowmetry as a measure of extrinsic colonic innervation in functional bowel disease. Gut 2000 Feb; 46(2): 212–7PubMedCrossRef

71.

Kvietys PR, Miller T, Granger DN. Intrinsic control of colonic blood flow and oxygenation. Am J Physiol 1980 Jun; 238(6): G478–84PubMed

72.

Kvietys PR, Barrowman JA, Harper SL, et al. Relations among canine intestinal motility, blood flow, and oxygenation. Am J Physiol 1986 July; 251 (1 Pt 1): G25–33PubMed

73.

von der Ohe MR, Hanson RB, Camilleri M. Serotonergic mediation of postprandial colonic tonic and phasic responses in humans. Gut 1994 Apr; 35(4): 536–41PubMedCrossRef

74.

Hammer J, Phillips SF, Talley NJ, et al. Effect of a 5HT₃-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome. Aliment Pharmacol Ther 1993 Oct; 7(5): 543–51PubMedCrossRef

75.

von der Ohe MR, Camilleri M, Kvols LK. A 5HT₃ antagonist corrects the postprandial colonic hypertonic response in carcinoid diarrhea. Gastroenterology 1994 May; 106(5): 1184–9PubMed

76.

Boley SJ, Agrawal GP, Warren AR, et al. Pathophysiologic effects of bowel distention on intestinal blood flow. Am J Surg 1969 Feb; 117(2): 228–34PubMedCrossRef

77.

Theodoropoulou A, Koutroubakis IE. Ischemic colitis: clinical practice in diagnosis and treatment. World J Gastroenterol 2008 Dec 28; 14(48): 7302–8PubMedCrossRef

78.

Ardigo GJ, Longstreth GF, Weston LA, et al. Passage of a large bowel cast caused by acute ischemia: report of two cases. Dis Colon Rectum 1998 Jun; 41(6): 793–6PubMedCrossRef

79.

GlaxoSmithKline. Lotronex® (alosetron hydrochloride) tablets briefing document for the Joint Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Subcommittee. Vol. 1 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3848B1_01_GSK%20Briefing%20Pkg.pdf [Accessed 2010 Jul 20]

80.

Ringel Y, Wilson J, D’Agostino R, et al. Development and validation of an ischemic colitis clinical diagnostic assessment instrument [abstract no. 1152]. Gastroenterology 2005; 128 (4 Suppl. 2): A467

81.

Wooltorton E. Tegaserod (Zelnorm) for irritable bowel syndrome: reports of serious diarrhea and intestinal ischemia. CMAJ 2004 June 22; 170(13): 1908PubMedCrossRef

82.

Bess AL, Cunningham SR. Dear Health Care Professional letter: important drug warning and prescribing information for Zelnorm [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4056B1_02_C-FDA-Appendix-1.pdf [Accessed 2011 Jan 25]

83.

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 Jan; 104 Suppl. 1: S1–35CrossRef

Title: The Risk of Ischaemic Colitis in Irritable Bowel Syndrome Patients Treated with Serotonergic Therapies
Author: Professor James H. Lewis
Publication date: 01-07-2011
Publisher: Springer International Publishing
Published in: Drug Safety / Issue 7/2011
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.2165/11590690-000000000-00000

At a glance: The STEP trials

Springer Medicine

The Risk of Ischaemic Colitis in Irritable Bowel Syndrome Patients Treated with Serotonergic Therapies

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2011

Electronic Drug Interaction Alerts in Ambulatory Care

Risk of Hospitalization for Hip Fracture and Pneumonia Associated with Antipsychotic Prescribing in the Elderly

Sources of Information on Lymphoma Associated with Anti-Tumour Necrosis Factor Agents

Adherence to Biochemical Monitoring Recommendations in Patients Starting with Renin Angiotensin System Inhibitors

Drug Prescribing Before and During Pregnancy in South West France

Association between Leukotriene-Modifying Agents and Suicide