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Medscape Clinical Insights in IBS-C and Chronic Constipation: An Expert Interview With Philip S. Schoenfeld, MD, MSEd, MSc

Posted 11/08/2005

Editor's Note:
Irritable bowel syndrome (IBS), a functional gastrointestinal disorder characterized by the interplay of altered motility, abnormal visceral sensation, and psychosocial factors, is one of the most common reasons for referral to a gastroenterologist. Chronic constipation is one of the most frequent gastrointestinal symptoms in the United States, accounting for nearly 2.5-2.7 million physician visits and 39,000-90,000 hospitalizations per year in the United States.

Constipation may be stratified, with considerable overlap, into issues of stool consistency vs defecatory behavior. A fundamental challenge to the treating physician derives from the fact that the term "constipation" has different meanings for different individuals and is therefore often subjectively defined, depending largely on a patient's perception of alterations in his or her bowel function. Thus, it is essential that the clinician understand not only the symptom-based criteria for chronic constipation but also the myriad other complaints and descriptors that patients may use to define their problem.

Indeed, it is the overlap in symptoms reported by patients with IBS with a predominant bowel complaint of constipation (IBS-C) and chronic constipation that poses a challenge in differential diagnosis.

Medscape spoke with Philip S. Schoenfeld, MD, MSEd, MSc, Assistant Professor of Medicine, University of Michigan School of Medicine, Ann Arbor; Chief, Division of Gastroenterology, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan, to explore the impact of these clinically important gastrointestinal conditions on both the healthcare industry and patient alike, as well as to discuss the current state of the field regarding the management of IBS-C and chronic constipation, as framed by data presented during the 2005 annual meeting of the American College of Gastroenterology.

Medscape: Given the variety of descriptors that patients with chronic constipation may use to define their problem, and the varied clinical presentations of IBS, what should be the clinician's approach to working up the patient with the symptom of chronic constipation and to differentiating between IBS-C and chronic constipation, defining each as "real medical conditions" warranting treatment?

Dr. Schoenfeld: In the absence of alarm symptoms (eg, hematochezia, weight loss ≥ 10 pounds, family history of colon cancer/inflammatory bowel disease), patients with symptoms of chronic constipation or IBS do not require invasive diagnostic testing before initiating therapy. Primary care physicians may obtain a complete blood cell count and a fecal occult blood test because these basic tests identify other alarm signs (eg, iron-deficiency anemia or occult gastrointestinal bleeding). However, patients with chronic constipation/IBS symptoms and healthy controls have a similar probability of having clinically important disorders (eg, hypothyroidism, colon cancer). There is one possible exception: celiac sprue may present with IBS symptoms (ie, abdominal discomfort associated with altered bowel habits). Depending on the prevalence of celiac sprue in the geographic area, primary care physicians and gastroenterologists may consider obtaining serologic tests for celiac sprue (ie, endomysial antibody and/or tissue transglutaminase antibody testing) in patients with IBS symptoms. Finally, all individuals 50 years of age and older should be offered a colonoscopy as part of routine colorectal cancer screening.

Chronic constipation and IBS-C are 2 syndromes that share many symptoms. Both conditions are characterized by infrequent bowel movements; a sense of incomplete evacuation; straining to pass stool; and passage of hard, pellet-like stools. However, the severity of bloating and abdominal discomfort differentiates IBS-C from chronic constipation. If a patient describes considerable abdominal discomfort or bloating with their constipation symptoms, then this patient should be diagnosed with IBS-C. Therefore, physicians should ensure that they specifically ask constipated patients about abdominal discomfort in order to differentiate IBS-C from chronic constipation. This is important because only tegaserod has demonstrated improvement in the multiple symptoms of IBS-C, whereas several therapies, including lactulose and psyllium, are effective at improving stool frequency and consistency in patients with constipation.[1]

Medscape: Given the uncertainty over what constitutes effective management for chronic constipation and the challenges in diagnosing and treating IBS-C, our therapeutic arsenal has continued to evolve, with the goal of providing alternative treatment options to help meet these growing needs. In this setting, 5-HT4 agonist therapy may offer an effective therapeutic alternative for these patients. What is the pathophysiologic rationale for targeting the serotonergic system in patients with chronic constipation and IBS-C?

Dr. Schoenfeld: IBS is an organic disorder, characterized by identifiable pathophysiologic changes, including alterations in interleukin (IL)-10/IL-12 ratios consistent with a proinflammatory state, defects in serotonin receptors, and abnormalities in visceral hypersensitivity.[1-3] In other words, IBS is not a "functional" disorder that can only be diagnosed after other organic disorders are ruled out with diagnostic tests. Although IBS is an organic disorder, we do not have a simple blood test or tissue test to make the diagnosis. Therefore, we must rely on symptom-based diagnoses as discussed previously.

Research regarding the pathophysiologic basis of IBS is a rapidly advancing field. Patients with IBS and patients with ulcerative colitis demonstrate defective serotonin receptors in enterochromaffin cells. This defect results in a decrease in the activity of serotonin, which is the primary neurotransmitter in the enteric nervous system. Thus, IBS patients suffer from a decreased level of activity in the enteric nervous system, which produces decreased smooth muscle motility and an increased sensitivity to mild distention in the colon (ie, visceral hypersensitivity). 5-HT4 receptor agonists, such as tegaserod, stimulate serotonin receptors in the enteric nervous system that are downstream from the enterochromaffin cell. In other words, these agents bypass the defective serotonin receptors and stimulate downstream receptors to "normalize" enteric nervous system activity. This stimulation increases colonic motility, which can provide relief of chronic constipation symptoms and IBS symptoms.[2,3]

Medscape: A study presented during the 70th Annual Meeting of the American College of Gastroenterology (ACG) looked at the long-term efficacy of the 5-HT4 receptor agonist tegaserod in maintaining symptom improvement in patients with chronic constipation. What can you tell us about this study and what were the key findings?

Dr. Schoenfeld: In this 13-month extension study, Shetzline and colleagues[4] followed chronic constipation patients who initially participated in a 12-week, placebo-controlled, double-blind randomized controlled trial (RCT) comparing tegaserod vs placebo. Abdominal distention, bloating, and bowel habits were assessed monthly. Those patients who responded to tegaserod in the initial RCT continued to demonstrate significant improvement compared with baseline for abdominal distention, bothersomeness of constipation, satisfaction with bowel habits, and global relief of constipation. All of these improvements were statistically significant. These data constitute the longest duration data on improvement in constipation symptoms with any therapy.

Medscape: During this year's meeting proceedings, Reilly and colleagues[5] presented the results of a trial conducted in women with IBS-C evaluating patients' overall satisfaction with initial and repeated use of tegaserod. What were the clinically important findings of this study, and what, in your opinion, are the implications for clinical practice?

Dr. Schoenfeld: Women with IBS-C were randomized to tegaserod 6 mg twice daily vs placebo in this double-blind randomized controlled trial. This was a unique trial because patients were asked whether the study medication was better than previously used medications and whether they would use the study medication in the future for treatment of their IBS symptoms. These questions were asked in addition to standard questions about satisfactory relief of abdominal discomfort, altered bowel habits, and global IBS symptoms. The authors demonstrated that patients using tegaserod experienced greater relief of abdominal discomfort, constipation, and global IBS symptoms compared with placebo. Furthermore, the patients (up to 76%) were significantly more likely to report that tegaserod was more effective than medications previously used (the authors did not provide a detailed list of "other medications" used by patients) for their IBS, and up to 85% stated that they would continue to use this agent for treatment of their IBS and/or recommend this treatment to fellow patients with IBS.

Medscape: Were there any other data presented during this year's meeting that would help put this information into clinical context? What's new on the therapeutic landscape?

Dr. Schoenfeld: Several new treatments for chronic constipation and IBS were discussed during this year's ACG meeting. Lubiprostone, which activates a chloride channel in the gastrointestinal tract, was examined in a double-blind, randomized placebo-controlled trial conducted in patients with chronic constipation.[6] In this 4-week trial, lubiprostone was found to be superior to placebo in terms of decreasing time to onset of first bowel movement and in increasing spontaneous bowel movement frequency. Patients treated with lubiprostone passed approximately 6 spontaneous bowel movements per week compared with placebo-treated patients who passed approximately 4 spontaneous bowel movements per week.

Additionally, in a double-blind randomized controlled trial involving female IBS patients, Quigley and colleagues[7] assessed the impact of a novel probiotic strain, Bifidobacteria infantis 35624, on bowel movement frequency. They found that the probiotic B infantis improved altered bowel habits in these patients with IBS. This is a particularly interesting avenue for further research because previous work reported by the same group of investigators demonstrated improvement in bloating in IBS patients using this probiotic.

References
American College of Gastroenterology Functional GI Disorder Task Force. An Evidence Based Approach to the Management of Irritable Bowel Syndrome in North America. Am J Gastroenterol. 2002;98:S1-S26.
Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology. 2004;126:1657-1664.
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.
Shetzline M, Dolker M, Bottoli I, et al. Patients with chronic constipation who respond to tegaserod after 4 weeks maintain symptom improvement for over 13 months. Am J Gastroenterol. 2005;100:S-339. [Abstract #927]
Reilly MC, Bracco A, McBurney CR, et al. IBS-C patients have greater treatment satisfaction with initial and repeated use of tegaserod. Am J Gastroenterol. 2005;100:S-339. [Abstract #926]
Johanson JF, Gargano MA, Holland PC, et al. Phase III study of lubiprostone, a chloride channel-2 (ClC2) activator for the treatment of constipation: safety and primary efficacy. Am J Gastroenterol. 2005;100:S-328. [Abstract #896]
Quigley EM, Whorwell PJ, Altringer J, et al. Probiotic use results in normalization of bowel movement frequency in IBS. Results froma clinical trial with the novel probiotic Bifidobacteria infantis 35624. Am J. Gastroenterol. 2005;100:S-326. [Abstract #888]

Funding Information

Supported by an independent educational grant from Novartis.

Philip S. Schoenfeld, MD, MSEd, MSc, Assistant Professor of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; Chief, Division of Gastroenterology, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan

Philip S. Schoenfeld, MD, MSEd, MSc, has disclosed that he serves as a consultant to Novartis and GlaxoSmithKline. Dr. Schoenfeld has also disclosed that he serves on the speaker's bureau of Novartis.

Medscape Gastroenterology. 2005;7(2) �2005 Medscape

http://www.medscape.com/viewarticle/515591

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