Diagnosis, Pathophysiology, and Treatment of Irritable Bowel Syndrome CME

Author: Kevin W. Olden, MD


Introduction

Definition

Irritable bowel syndrome (IBS), in its essence, can be defined as a combination of abdominal pain or discomfort and altered bowel habit. The alteration in bowel habit can take the form of altered stool frequency (ie, diarrhea or constipation) or altered stool form in terms of thin, overly hard and firm, or soft (and even liquid) stools. Symptoms that are commonly associated with IBS include passage of clear or white mucus with a bowel movement, sensation of incomplete evacuation after having a bowel movement, and relief of abdominal pain or discomfort transiently after defecation and abdominal bloating. Patients with IBS have traditionally been described as being "constipation predominant," "diarrhea predominant," or as having an alternating pattern of constipation and diarrhea (ie, so-called "alternators)". Although the research on the exact epidemiology of these 3 variants of IBS is incomplete, our best understanding is that each type is represented approximately equally in the overall IBS population. Abdominal pain or discomfort is a sine qua non for the diagnosis of IBS. The pain or discomfort most commonly occurs in the left lower quadrant, but can be found anywhere in the abdomen; however, isolated pain or discomfort above the level of the umbilicus is uncommon in patients with pure IBS. This combination of altered bowel habits with abdominal pain or discomfort separates IBS from other functional bowel disorders, such as functional dyspepsia, functional constipation, functional diarrhea, or functional abdominal bloating, to name a few.

In addition to gastrointestinal symptoms, IBS has been associated with a number of extraintestinal conditions, such as fibromyalgia, sexual dysfunction, urinary symptoms, and certain psychiatric disorders in excess of non-IBS controls. These latter findings have implications both for further supporting the diagnosis of IBS, as well as for helping to define the level of disability of the patient who presents with IBS with extraintestinal manifestations.

Prevalence

A number of prevalence studies using standardized diagnostic criteria have been performed in the last 10 years to help determine the true prevalence of IBS. The overall prevalence of IBS is estimated to be approximately between 10% and 20% of the population.[1] Its prevalence varies by age -- it is higher in individuals in the second to fifth decades of life and declines considerably thereafter. Prevalence in individuals younger than 50 years of age has been determined to be somewhere between 15% and 20%, and in individuals older than 50 years of age, prevalence is approximately 10% to 12%.[2] This latter finding is important because IBS is generally considered a condition of "younger people." Its prevalence, although lower in elderly individuals, is not inconsiderable, however. An increasing number of transcultural and transracial population studies have been performed documenting a fairly constant prevalence across national boundaries and ethnic and racial lines for IBS. No particular country or geographic area seems to definitively stand out as having a higher or lower prevalence of IBS.

IBS does seem to be more prevalent in women. The sex ratio for individuals with IBS who chose not to seek care is 2:1 (female to male). Of interest, when individuals are studied who chose to seek care for IBS, the ratio jumps to 4:1 (female to male).[3] This may in part reflect the general tendency of females to seek medical care. However, it is reasonable to assume that most patients seen in clinical practice with IBS will be women.

Impact on Patients

IBS is not associated with excess mortality. A number of large retrospective studies have shown that patients diagnosed with IBS do not go on to develop inflammatory bowel disease, colorectal or other gastrointestinal cancers, or any other significant disorders of the cardiovascular or neurologic systems in excess of non-IBS controls. Overall life expectancy for individuals with IBS is as good as (or somewhat better than) that of the population at large. However, these favorable findings should not confuse the reader into thinking that IBS is not associated with significant morbidity. Patients with IBS have been shown to have rates of absenteeism from work that are almost 3 times that of non-IBS controls. Likewise, studies have shown that absence from school, as well as from work; inability to participate in activities of daily living; and the need to modify one's work setting, either in terms of working fewer hours per week, shifting the work setting to home, or in some cases, actually giving up one's occupation because of IBS, are all too common. In this respect, patients with IBS differ significantly from patients with most other chronic medical illness, and they differ dramatically from normal controls. In addition to income and productivity losses associated with IBS, a number of studies also have shown that the health-related quality of life (HRQOL) of patients with IBS is significantly lower than that of population-based controls and individuals with other chronic medical conditions. Two recent medical studies used the standard QOL instrument (ie, standard form-36 [SF-36]) to measure QOL in patients with IBS and then compared them to individuals with other chronic medical conditions, as well as to historic controls. In these 2 studies, patients with IBS were found to have dramatically lower QOL than did normal controls, which seems somewhat intuitive. However, these studies also showed that compared with individuals with rheumatoid arthritis, asthma, diabetes, as well as gastroesophageal reflux disease, IBS patients showed significantly lower levels of QOL, as measured by SF-36.[4,5] It is this profound impact on QOL that makes IBS a medical condition worthy of our attention. The essentially zero mortality rate associated with IBS is more than offset by its somewhat unique ability to induce morbidity as it impairs an individual's ability to participate effectively in society.[6]

Impact on Physicians

IBS has traditionally been viewed as a somewhat frustrating condition by physicians. The reasons for this are multifactorial. First, the lack of precise diagnostic criteria for IBS has led many patients with a variety of chronic abdominal pain syndromes to be seen as having "IBS" by physicians. These challenging patients have often made the physician-patient encounter a "painful" experience for the treating physician. The second frustration for physicians who treat IBS is the fact that disorder-specific treatments for IBS did not exist. This was further complicated by the fact that many of the proposed treatments for IBS had little evidence to support their usefulness in IBS. The final stress confronting physicians dealing with the IBS patient was how to properly diagnose the syndrome. Because IBS was considered a diagnosis of "exclusion," it was difficult for the treating physician to determine which tests should be routinely included in the evaluation of the IBS patient. Likewise, when to cease increasingly complicated and esoteric testing before finally arriving at a diagnosis of IBS has traditionally been an unclear area in the medical literature.

Fortunately for physicians, this somewhat dismal situation is rapidly evolving for the better. The development of validated diagnostic criteria for IBS has come into being (see detailed discussion below). Use of these criteria allows physicians to separate patients with IBS from patients with structural disorders of the gastrointestinal tract. The evaluation of the IBS patient is becoming increasingly rationalized. We have moved away from the concept of "diagnosis of exclusion" toward a so-called "positive approach" to diagnosis. This means that patients who fit the epidemiologic profile for IBS and have IBS-like symptoms that meet the Rome II diagnostic criteria for IBS are considered to have IBS, unless so-called "alarm factors" are present. The presence of alarm factors in turn would suggest that a disorder other than IBS was causing the patient's symptoms. Alarm factors, if present, require diagnostic evaluation on their own merit. If a patient meets Rome II criteria for IBS and does not have alarm factors, treatment for IBS should be initiated.

Subsequent failure to improve on a reasonable IBS treatment regimen or the development of other signs and symptoms inconsistent with IBS then prompt exploration of other diagnostic possibilities. This "positive diagnostic approach" has the potential of dramatically curtailing the use of scarce medical resources. Finally, the last 5 years have brought dramatic improvements in the care of IBS, from both pharmacologic and behavioral perspectives. The ability to offer patients proven treatments that offer real hope of improving IBS symptoms has greatly enhanced the role of the physician to effectively ameliorate the suffering of the IBS patient.

Economic Impact

Capturing the true cost of IBS to society is a difficult endeavor. It involves both the direct costs of medical care (ie, medications, hospitalizations, and emergency room and office visits); indirect costs, which represent considerable cost to society from lost productivity because of absence from work, school, and other activities; and intangible costs, which reflect the human suffering and inability to contribute completely to one's family and social circle because of IBS-related symptoms. It has been estimated that the annual direct medical charges generated by patients with IBS in the United States are in excess of $8 billion, compared to non-IBS controls.[1] If one adds the cost of absence from work, school, and other productive activities, indirect costs have been estimated to be about $20 billion. Thus, the direct financial cost of IBS to American society, as best we can estimate, is somewhere in the neighborhood of $20 billion to $30 billion dollars per year.[1] Again, this does not include the significant negative impact on QOL that is induced by IBS. The significant drain on the American economy makes IBS a condition worthy of treatment and focus in medical practice.

 

Diagnosis of IBS

Symptoms of IBS can be common to any number of gastrointestinal disorders. Abdominal pain, bloating, and diarrhea or constipation can easily generate an extensive list of potential diagnostic possibilities. To adopt an open-ended approach to diagnosis and to value all diagnostic possibilities equally has never been an effective approach in the diagnosis of IBS. However, with the development and validation of the Rome II criteria for the diagnosis of IBS, our approach to the diagnosis of this traditionally perplexing disorder is rapidly changing.

Diagnosing the patient with IBS should include 3 steps. First, determine whether the patient at first encounter meets the Rome diagnostic criteria for IBS. Second, conduct a history and physical examination looking for so-called "alarm factors." Third, perform diagnostic testing.

Diagnostic Criteria

The latest version of the Rome diagnostic criteria (Rome II) for IBS were first published in abbreviated form in 1999[7] and in full form in 2000.[8] See the Table below. The Rome criteria have been shown to be both sensitive and specific for the diagnosis of IBS[9] and can be used advantageously in clinical practice. If a patient presents with symptoms suggestive of IBS and epidemiologically fits the profile of a patient most likely to have IBS (ie, younger than 40 years of age and with typical symptoms), the Rome criteria can be used to validate the physician's initial impression. Starting with a "positive approach" to diagnosing IBS, as opposed to adopting a diagnosis of exclusion, sets the entire physician-patient encounter off in a positive and thoughtful direction. Providing the diagnostic framework presented by the Rome criteria gives the physician an intellectual basis for making an IBS diagnosis with confidence.[10]

History-Taking

The key to history-taking in a patient with suspected IBS is first and foremost to look for the presence of so-called "alarm factors." It is clear that the symptoms of IBS can be typical of many other structural disorders of the gastrointestinal tract. Diarrhea, abdominal bloating, and constipation can all represent an extraordinarily wide spectrum of gastrointestinal pathology. The challenge using the framework provided by the Rome II diagnostic criteria is to rapidly exclude the possibility of other disorders. The key is to look for symptoms in the history that are atypical of IBS and suggestive of other disorders. The list of so-called "alarm factors" can certainly be open to debate and discussion.

Physical Examination

After a patient history has been completed and the absence of "alarm factors" documented, a physical examination should always be performed. The physical examination should focus specifically on ruling out inflammatory bowel disease, colorectal or other gastrointestinal cancers, and malabsorption caused by luminal or pancreatic causes. Look for extraintestinal manifestations of inflammatory bowel disease, such as ophthalmic changes, Sicca syndrome, intraoral lesions (eg, aphthous ulcers), and skin or arthritic changes suggestive of inflammatory bowel disease. Likewise, signs of malabsorption, such as muscle wasting, nail or perioral changes, and weight loss should all be ruled out. Finally, the issue of colorectal cancer must be addressed. There is agreement in the functional bowel community that the best guide to help clarify this situation is to follow the colorectal cancer screening guidelines of the American Cancer Society. It is therefore recommended that patients 50 years of age or older who have never had a screening colonoscopy should have one performed as part of an IBS evaluation. Likewise, individuals 40 years of age or older who have a family history of colorectal cancer in a first-rank relative should also have a screening colonoscopy.[11] Finally, the use of sigmoidoscopy in individuals younger than 50 years old who have no family history is open to some discussion.[12]

Small bowel (to rule out Giardia or small bowel malabsorption) or colonic (to rule out microscopic colitis) biopsies may be indicated, particularly for patients with loose or watery stools.[13] These studies, although they include some diagnostic testing, may be considered part of the "physical examination" and initial evaluation of the patient with suspected IBS.

Diagnostic Testing

The use of diagnostic testing in IBS has become an increasingly controversial topic. Traditionally, the "diagnosis of exclusion" approach encouraged extensive diagnostic testing to evaluate patients with suspected IBS to rule out other possible causes of the disorder. Given the high prevalence of IBS , this approach has been subject to considerable scrutiny over the last 5 years.[10] Numerous studies have shown that the use of routine lactase hydrogen breath-testing for sugar malabsorption,[14] abdominal ultrasound,[15] routine computed tomography scanning, particularly in younger patients, and more esoteric tests, such as screening for acute intermittent porphyria[16] or thyroid testing for hyper- or hypothyroidism,[17] rarely yield data that change the diagnosis of IBS. Testing for bacterial overgrowth has been recently proposed by 1 group as a possible cause of IBS-like symptoms.[18] However, the article supporting the reasonableness of this approach studied a cohort of patients who were specifically referred by their treating physician to a tertiary center specializing in bacterial overgrowth. These patients were specifically referred to the tertiary center to rule out the possibility of bacterial overgrowth. However, given the selection bias in this study, the applicability of these data to the universe of IBS patients is open to some question. Based on the available literature, routine testing for bacterial overgrowth in patients with suspected IBS cannot be routinely recommended at this time.

One additional issue that is rapidly evolving in the area of IBS diagnosis is the issue of celiac disease. A number of studies have recently demonstrated a higher prevalence of celiac disease in the North American population than was previously thought, as well as a possible higher prevalence among patients with IBS-like symptoms.[19] This issue is yet to be completely resolved. It would therefore seem prudent for physicians who have patients with suspected IBS who have subtle signs or symptoms of celiac disease, such as osteoporosis in a premenopausal female or male, infertility, mild anemia, or weight loss, to evaluate the patient by obtaining celiac disease markers. Endoscopy with small bowel biopsy can confirm any equivocal serologic results.

Given these data, it would seem reasonable for the patient with IBS who presents absent alarm factors and who has a normal physical examination to have a complete blood count and chemistry panel and perhaps erythrocyte sedimentation rate measurement and thyroid function testing in the form of thyroid-stimulating hormone (TSH) levels. As noted above, in patients with diarrhea, additional initial investigation may be warranted, particularly investigation for the possibility of microscopic colitis and perhaps celiac disease.[17] For the majority of patients, this should end the initial evaluation. It is at this point that the physician should begin treatment and follow the patient prospectively. Failure to respond to reasonable treatment for IBS after a period of 2-4 weeks should certainly invite the physician to question the validity of IBS diagnosis and to consider additional evaluation as indicated. See the Figure below for a schematic that outlines this approach.

fig

Figure. Diagnostic approach.

 

Pathophysiology of IBS

The pathophysiology of IBS is a work in progress. Roughly 200 years after its initial description by the English physician William Powell, our understanding of what causes IBS symptoms remains incompletely understood. For most of the second half of the 20th century, tremendous attention was paid to the concept of altered gut motility as a cause of IBS symptoms.[20] However, several difficulties are apparent in this approach. First, although altered motility of the colon and small bowel can be demonstrated in patients with IBS, there is a very poor correlation between IBS symptomatology and the presence of alterations in gastrointestinal motility.[21] Likewise, drugs that alter gastrointestinal motility alone, such as antispasmodic[22,23] and prokinetic drugs like metoclopramide and cisapride,[24,25] have not been shown to be of any significant benefit in relieving IBS symptoms.

The third dilemma facing investigators in this area is that no pathognomonic pattern of gut dysmotility can be identified specifically with IBS, as opposed to other functional or organic disorders of the gut.[20] Altered motility, as occurs in IBS, is currently seen as one of many epiphenomena associated with the disorder, as opposed to being a cause of the disorder itself.

In the early 1980s, it was discovered that upon balloon distention in the rectum, individuals suffering from IBS were more sensitive to distention than were individuals who did not suffer from IBS.[26] This means that IBS patients feel discomfort at lower levels of balloon inflation in the rectum and lower bowel than do normal controls. This finding has been replicated in numerous studies, and the concept of "visceral" hypersensitivity has been established.[27] A second level of investigation in this area is the fascinating finding that individuals with IBS not only have a unique local response (in the rectum) to visceral stimulation, but they also tend to process signals in the brain differently from non-IBS controls. Mertz and others[27] have shown that IBS patients have differential responses in the anterior cingulate cortex and other areas of the brain when stimulated with rectal or sigmoid colon distention, compared with controls. These findings have been replicated by other investigators.[28] These data certainly suggest the possibility of a "brain-gut axis" where peripheral symptoms are processed in the end organ (ie, the colon), and then neural signals are carried via visceral afferents to the spinal cord, and then to the brain, where they are subject to additional processing.[29] It is this brain-gut axis that has received considerable attention recently in IBS research. The findings of enhanced visceral sensitivity in the colon and rectum, as well as altered processing of signals in the brain, have provided new insight. Regarding the pathophysiology of IBS, the altered processing of neural sensation in IBS patients logically raises the question as to which neurotransmitters play a role in this abnormal signal transmission.

A large number of neuropeptides are involved in the regulation of both gastrointestinal motility and sensation in the gut. These include motolin, gastrin, peptide Y, cholecystokinin, serotonin, and others.

Serotonin has received the most interest for a number of reasons. The first reason is the dramatic impact that modulation of serotonin has had on psychiatric disorders. The development of selective serotonin reuptake inhibitor (SSRI) medications in the late 1980s revolutionized the practice of psychiatry. The ability to treat depression with far fewer side effects than seen with earlier drugs made depression treatment more acceptable both to patients and physicians. The success of these medications led to increased interest in the role of serotonin in the nervous system. The second reason is that almost all (ie, more than 90%) of the serotonin contained in the body is found in the gut and not in the central nervous system.[29] This fact raises the reasonable question of whether modulation of serotonin action in the gut could influence IBS and other functional bowel symptoms.

Serotonin (5-HT) is an interesting molecule. There are at least 15 subtypes of the 5-HT molecule. 5-HT1 and 5-HT2 are contained almost exclusively in the central nervous system. These are the target neurotransmitters for the SSRIs. The subtypes of serotonin contained in the gut consist mainly of 5-HT3 and 5-HT4, which has led to the development of drugs designed specifically to act on these serotonin subtypes (see detailed discussion in the Management section below). Identifying the role of serotonin in the pathophysiology of IBS symptomatology has led to the investigation of other neurotransmitters. Cholecystokinin antagonist and various neurokinin antagonists are all actively being investigated for their potential to influence IBS symptomatology.[30] This has led to a whole new era of gastrointestinal pharmacology based on a brain-gut axis. The opportunity to develop interventions at the level of the bowel, spinal cord, and brain based on this pathophysiologic conceptual model is considerable.

 

Treatment of IBS

Diet and Lifestyle Modification

IBS is not caused by stress. Likewise it is not caused by any particular dietary indiscretion. However, stress can clearly influence outcomes and severity of IBS, as it can in many other diseases.[31] Identifying stressors in a patient's life and urging the patient to develop coping strategies can be key in helping improve overall symptomatology and sense of well being. The patient who is working 60 hours per week in a job that he or she truly does not enjoy needs to have the courage to look at the situation and consider it as part of the overall clinical "problem." Likewise, pressure points in one's family relations, economic situation, or other psychosocial variables need to be evaluated as part of the overall treatment of IBS. Most patients can accomplish this simply by recognizing these stressors and promoting positive life changes. Some patients may benefit from counseling or psychotherapy to help them work through this process.[32] Likewise, patients who have significant severe psychosocial issues, such as a history of being physically or sexually abused, or patients with diagnosable psychiatric disorders accompanying their IBS, such as depression or severe anxiety disorders like panic disorder may benefit from psychotherapy.[33] The literature supporting the efficacy of behavioral approaches in this setting is quite positive.[34] Cognitive behavioral therapy, hypnosis, and relaxation therapy have all been effectively applied to the treatment of IBS, particularly in patients with severe symptomatology.[35,36,37]

The issue of diet is more convoluted. Recent studies suggest that although individual patients may have "food triggers," there is no definitive evidence that suggests that food allergies or food intolerance to large food groups, such as meats or grains, are associated with either the development or the exacerbation of IBS symptoms. Patients should be encouraged to eat a healthy diet and to avoid only foods that they know specifically can trigger symptoms. Extensive testing, such as radioallergosorbent (RAST) or immunoglobulin E (IgE) or IgA testing, for gut-based food allergies is usually nonproductive in IBS patients.

Symptom-Targeted Treatment

In treating IBS, it is important for physicians to remember that IBS represents a spectrum of symptoms, including pain or discomfort, altered bowel habit, as well as additional symptoms, such as bloating, rectal urgency, or painful bowel movement. These symptoms tend to fluctuate over time in the patient who is suffering from IBS. This makes symptom-directed treatment, such as treatment for diarrhea or constipation, somewhat less than optimal. A patient with an alternating pattern of constipation and diarrhea with IBS may be treated for diarrhea only to have the symptom pattern shift to constipation, making the antidiarrheal treatment particularly unhelpful for the patient's condition. Recently, a number of reviews have been conducted to evaluate the efficacy of various treatments of IBS.[38] The most recent of these is a systematic review using evidenced-based medicine guidelines published by the American College of Gastroenterology (ACG).[39] In reviewing the available literature, the ACG task force concluded that clinical trials of antispasmodic agents were thought to have significant methodological deficiencies, such as short trial duration, small study numbers, and results that demonstrated inconsistent effectiveness.[39] The task force also noted that adverse events, particularly sedation and constipation, limited the dose range of these agents. This same task force reviewed the available evidence for bulking agents, such as wheat bran, corn fiber, and psyllium, and found that bulking agents were no more effective than placebo at relieving overall IBS symptoms. However, they also concluded that bulking agents could be helpful for IBS-related constipation. The antidiarrheal agent loperamide, the only antidiarrheal agent that has been systematically studied in IBS, was found to be helpful in terms of relieving IBS-related diarrhea, but no better than placebo at relieving the global symptoms of IBS, such as abdominal pain or discomfort, bloating, rectal urgency, and cramping.[40]

The use of antidepressants is a particularly interesting topic in the treatment of IBS. Given their demonstrated effectiveness in the treatment of neuropathic pain, such as peripheral neuropathy or migraine headaches, antidepressants naturally have stimulated interest for having a possible role in the treatment of IBS. In addition, the ability of antidepressants to affect gastrointestinal motility because of their impact on anticholinergic, serotonergic, and noradrenergic receptors, makes these drugs a particularly interesting possibility for the treatment of IBS.[41] However, the ACG systematic review concluded that the evidence was inadequate to support the effectiveness of tricyclic antidepressants for improvement of global IBS symptoms, but that there was some evidence to suggest that tricyclic antidepressants may indeed be effective for the treatment of IBS-related abdominal pain or discomfort.[39] Evidence published after publication of the review suggests that both desipramine[42] and paroxetine[43] may indeed be efficacious in the treatment of IBS, compared to standard medical treatment. Clearly, the role of antidepressants in the treatment of IBS needs to be further defined.

5-HT3 Antagonists

The presence of significant numbers of 5 -HT3 receptors in the gut has led to the development of a number of agents specific to this receptor site. Antagonism of the 5-HT3 receptor causes significant slowing in colonic transit and a decrease in visceral sensation. The first agent to be developed in this class was alosetron. A number of trials have confirmed the efficacy of alosetron at improving abdominal pain or discomfort, rectal urgency, stool consistency, and reduction of stool frequency in patients with IBS.[44] In addition, many of these trials included a global severity index (GSI) that measured a patient's self-report of overall well-being as it related to IBS symptomatology. The efficacy of alosetron in improving global well-being and global symptoms of IBS has been well established. However, alosetron unfortunately tends to produce severe constipation in a small number of patients and ischemic colitis in a smaller number of patients. The exact reason as to why alosetron causes ischemic colitis is yet to be elucidated. Because of these safety issues, the drug was withdrawn from the market in November 2000. However, because of the extraordinary efficacy of alosetron in relieving severe refractory symptoms of diarrhea-predominant IBS, the drug was rereleased by the FDA under a restricted prescribing program for women with severe diarrhea-predominant IBS who failed to respond to conventional IBS therapy. Under the restricted prescribing program, the recommended starting dose of this drug is 1.0 mg per day. This is noteworthy because when the drug was first released, the starting dose was 1.0 mg twice a day.

Alosetron is an extremely effective drug for the treatment of IBS with diarrhea in women. The incidence of ischemic colitis is somewhere in the neighborhood of 1 in 350 cases. However, this risk, in combination with the more common risk of severe constipation, needs to be remembered when treating patients with alosetron. Careful patient education, which currently includes the patient signing an informed consent form after reading a patient information form regarding the drug, in combination with careful postprescribing monitoring can do much to reduce adverse events associated with this otherwise highly efficacious agent.[46]

Cilansetron, another 5-HT3 antagonist, is currently in development to specifically treat IBS with diarrhea. This drug is in phase 3 trials and detailed data regarding its efficacy and safety are being evaluated. Its role in the clinical treatment of IBS remains to be determined.[46]

Management of IBS: 5-HT4 Agonists

Stimulation of the 5-HT4 receptor in the gut is associated with intestinal peristaltic reflexes, intestinal rates of colonic transit, and decrease in the activity of visceral afferent neurons. Stimulation of this receptor site should increase the rate of intestinal colonic transit, reduce the firing rate of colonic visceral afferent nerves, and in turn, reduce visceral sensitivity. The 5-HT4 partial agonist tegaserod is the only drug in this class approved by the US Food and Drug Administration (FDA). Currently approved for the treatment of IBS with constipation in women, this drug has been shown in a number of trials to increase the number of bowel movements, decrease bloating, reduce abdominal pain or discomfort, and improve stool frequency and consistency, compared with placebo, in a number of clinical trials.[47] To date, tegaserod has had an excellent safety profile. The major side effect associated with use of this drug is diarrhea, which is usually mild and self-limiting.[47] The diarrhea tends to be seen most commonly in the first 2 weeks of treatment, with bowel movements normalizing after about 2 weeks of use. In clinical trials, the incidence of headache (not migraine) was slightly more common in patients receiving tegaserod than in patients receiving controls.[48] This finding seems to be less of a problem in clinical practice, however. The recommended dosage of tegaserod is 6.0 mg twice a day. Bioavailability is reduced by approximately 20% to 40% when the drug is taken with food, so the recommendation is that tegaserod be taken away from mealtime hours. In the tegaserod trials, global improvement was measured. Using a measure called the Global Symptom Assessment (GSA), tegaserod was shown to be significantly better than placebo in producing a sense of global well-being in IBS patients.[45] Tegaserod represents a significant advance in the treatment of IBS with constipation.

Putting the Newer Agents in Perspective

The development of alosetron and tegaserod represent major advances not just in the treatment of IBS, but also in our understanding of how IBS symptoms are generated. These drugs clearly represent a paradigm shift in the treatment of IBS and represent most likely the first of a number of new agents that will emerge in the coming years. The exact role for these drugs is yet to be defined. Should they be first-line drugs? Should they be reserved only for patients with severe disease? These questions should be answered more in terms of the individual patient rather than in terms of overall groups of patients. The patient who may have mild to moderate symptoms of IBS with constipation, but whose life is severely impaired by the symptoms, might represent an ideal candidate for treatment using tegaserod as a first-line drug. In contrast, similar patients whose symptoms are less intrusive may benefit from fiber supplementation. It is clear, however, that patients who fail to respond to traditional treatment for IBS with constipation, such as fiber supplementation, clearly deserve a clinical trial of tegaserod for IBS symptomatology.

The issue of alosetron is somewhat more complex. Because of its adverse event profile, both the FDA and the manufacturer have restricted its usage to patients with severe refractory symptoms. However, given these limitations, it is clear that this drug also represents a major advance in the treatment of patients with debilitating IBS with diarrhea. It should certainly be considered for use in such patients. The restricted prescribing program is not terribly burdensome and should not be a reason for physicians not to use this drug. It is important to recognize that restricted prescribing for alosetron is not under a compassionate use profile, which entails considerable paperwork. It is rather a restricted prescribing program that is open to any physician who can attest to his or her competence in treating IBS. Details of this program are available from the manufacturer.

Given the high prevalence of IBS both in primary and specialty practice, it is clear that physicians need to be aware of and feel comfortable using these available drugs.

 

The Future

IBS is a biopsychosocial disorder. This means that biological, social, and psychological components play a role in disease perception, symptom generation, and healthcare seeking. For a physician to be truly effective in approaching the patient with IBS, all of these factors need to be considered.[49] The patient who has considerable comorbid depression or anxiety and/or the patient who has suffered physical or sexual abuse is much more likely to have refractory symptoms.[50] An effective treatment plan for such a patient would encompass a biopsychosocial approach. There is a clear trend in the medical literature showing that behavioral treatment of IBS, as well as "combined treatment" consisting of medical management, psychological treatment, and judicious use of antidepressants, can be more effective than standard medical treatment alone in treating such patients, particularly patients with severe IBS symptomatology. 39] Defining the role of multicomponent treatment and better defining which treatment modalities work best together will be a major task for IBS investigators over the next few years.

The second major area in the treatment of IBS that clearly is evolving is the development of new drug therapies. The explosion in our understanding of the role of multiple neurotransmitters in the gut and the better understanding of the so-called brain-gut access will undoubtedly lead to the development of new drugs specifically designed to treat IBS. It is likely that IBS in the future will be seen as a series of subtypes going far beyond the traditional nomenclature of IBS with diarrhea, IBS with constipation, and so-called "alternating pattern" of constipation and diarrhea. This in turn will lead to better fine-tuning of drug treatment. The overall future for the treatment of IBS is a bright and exciting one. Clinicians can look forward to significant advances in the approach to this disorder. After 200 years of being essentially identified but then ignored, IBS will be seeing the attention from medical science that it so justly deserves.

Table. Diagnostic Criteria for IBS (Revised Rome Criteria)

At least 12 weeks or more, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has 2 of 3 features:

  • Relieved with defecation and/or
  • Onset associated with a change in frequency of stool and/or
  • Onset associated with a change in form (appearance) of stool

Symptoms that cumulatively support the diagnosis of IBS:

  • Abnormal stool frequency (for research purposes, "abnormal" may be defined as more than 3 bowel movements per day and fewer than 3 bowel movements per week)
  • Abnormal stool form (lumpy/hard or loose/watery stool)
  • Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation)
  • Passage of mucus
  • Bloating or feeling of abdominal distension

Adapted from Drossman et al.[49]

 

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Authors and Disclosures

Authors

Kevin W. Olden, MD

Associate Professor of Medicine, Mayo Clinic Medical School; Consultant, Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona

Disclosure: Kevin W. Olden, MD, has disclosed that he has served as an advisor for Novartis and Braintree Laboratories. Dr. Olden has reported that he discusses the investigational use of cilansetron for the treatment of IBS with diarrhea.

Clinical Editors

David Danar, MD

Program director, Medscape Internal Medicine

Disclosure: David Danar has disclosed that he owns a small quantity of Pfizer, Inc, Schering Plough Corporation, and Diversa Corporation stock.