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The identification, diagnosis, and treatment of irritable bowel syndrome (IBS) have a tremendous impact on the large number of patients with this syndrome and on physicians representing a wide variety of general and specialty practices. There are well-established diagnostic criteria and algorithms for the initial evaluation of patients presenting with the symptoms of IBS. The symptoms can be targeted for therapy with a variety of pharmaceutical and nonpharmaceutical agents. Therapy should be individualized for the patient, and the cornerstone for any effective treatment strategy should be a solid patient-physician relationship. Medications released in the past several years are based on the understanding of serotonin receptors in the gut and their role in the pathogenesis of IBS.
The understanding of irritable bowel syndrome (IBS) has undergone a rapid evolution with scientific advancement, but historically it was recognized over 150 years ago. In 1849, Cumming reported, “The bowels are at one time constipated, another lax, in the same person. How the disease has two such different symptoms I do not profess to explain.”1 IBS is a common functional bowel disorder that generates a significant health care burden. The percentage of patients seeking health care related to IBS approaches 12% in primary care practices and is by far the largest subgroup seen in gastroenterology clinics.2 It has been well documented that these patients exhibit a poorer quality of life and utilize the health care system to a greater degree than patients without this diagnosis.3,4 Five large population-based IBS prevalence studies in North America have demonstrated a wide range of prevalence, probably because of study design and different definitions of IBS.5 Most concentrated estimates based on these studies place the prevalence between 10% and 15%. Female predominance in a 2:1 ratio seems repetitive throughout the literature.
Diagnostic criteria have evolved since 1978, when Manning et al6 first published their criteria. The changes have included the cumbersome Rome I criteria, which were revised to the current Rome II guidelines,7 to allow ease of diagnosis. However, these criteria are probably geared more for research protocols and not daily clinical practice. The Rome II criteria state that a patient must have abdominal pain or discomfort for at least 12 weeks, which need not to be consecutive during the past 12 months. This pain or discomfort must have at least two of the following three features: relief with defecation, association with a change in stool frequency, or association with a change in stool consistency. Boyce et al8 demonstrated that the new Rome II criteria might be unnecessarily restrictive for research and practice. They randomly selected 4500 subjects and mailed them a questionnaire to evaluate the prevalence of IBS using all three criteria. In their 72% response rate, 13.6% met the Manning criteria, 4.4% met the Rome I criteria, and 6.9% met the Rome II criteria. They concluded that the current requirements might be too stringent.
Understanding the pathogenesis of IBS is important because today's newer pharmacotherapy agents are beginning to target the known pathophysiologic mechanisms of IBS. Altered motility, visceral hypersensitivity, brain-gut interactions, and inflammation have all been implicated in IBS patients. However, the perceived symptoms from these mechanisms consist of abdominal pain or discomfort, bloating, diarrhea, and constipation. Historically, medical management has focused on symptomatic treatment of these individual complaints. Also, our current pharmaceutical repertoire is usually limited to treatment for only one symptom. However, newer medications are beginning to focus on the molecular level with serotonin receptor agonists and antagonists.
The role of psychosocial factors in IBS also must be considered because these factors influence treatment options and patients' expectations. According to an American Gastroenterology Association technical review,2 research into this area has yielded four general observations. First, psychological stress exacerbates gastrointestinal symptoms, meaning that IBS patients are more susceptible. Next, psychological and psychiatric comorbidity is often represented among IBS patients. Also, these psychosocial factors influence the illness experience and treatment outcome of IBS patients. Lastly, the technical review emphasizes that these factors also dictate which patients consult physicians. All these considerations must be kept in mind when considering long-term treatment goals through pharmacotherapy or psychological management.
Before discussing treatment options with patients suspected of IBS, the physician should carefully perform a detailed history and physical to exclude other diagnoses with symptoms similar to those of IBS. The American College of Gastroenterology Functional GI Disorders Task Force stated that the current data do not support extensive testing in IBS patients.5 IBS patients do not appear to have a higher prevalence of organic disease than the general population. If no alarming findings exist such as weight loss, hematochezia, or iron deficiency, routine diagnostic testing should be sufficient. This testing should include complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level (if constipation is predominating). If diarrhea is predominating, fecal leukocytes, stool for Clostridium difficile when appropriate (such as patients with antibiotic use within 3 months or recent chemotherapy), and serology for celiac disease should be performed. Sanders et al demonstrated that a higher prevalence of celiac disease exists in IBS patients (4.67%) compared with the general population (less than 1%).9 Colonoscopy is acceptable in patients with a family history of inflammatory bowel disease or colon cancer. Iron deficiency anemia would be another indication for colonoscopy. These are generalized suggestions, as each individual patient presents with unique characteristics.
The physician must realize that a strong physician-patient relationship is the foundation for effective treatment and realistic expectations. Many patients with IBS have bounced around the medical field for many years with varying diagnoses because of the lack of interest or profound frustration of the physician in treating IBS, possible stigmata of this disease as being a psychiatric entity, or lack of clinical, physical, or laboratory diagnostic criteria. The medical literature supports gaining the confidence of the patient on the first clinical interview through attentive listening and detailed explanations of the pathophysiology, natural history, management, and prognosis of IBS.10,11 Responding to all the patient's concerns and questions and spending time in the initial visit substantiate the validity of their problem. This reassurance aids in the patient's attempts to understand and accept his or her affliction. Setting appropriate goals and limits gives patients a more structured environment and a sense of purpose and allows them to participate in their own health care strategy. Once a rapport with the patient has been established, long-term goals for this chronic illness are easier to obtain as evident from a decrease in the number of health care visits, reduction in symptoms, and improved patient satisfaction.2 The physician should also emphasize the chronic nature of this syndrome because nearly 75% of patients continue to have a diagnosis of IBS 5 years later.12
Patients with IBS commonly complain that dietary misadventures contribute to their symptoms of abdominal discomfort, bloating, or exaggerated gastric-colic reflex. The truth is that no specific food is likely to be the culprit because true food allergies are rare. It is merely the act of eating that most likely initiates these postprandial symptoms. Patients may begin to associate ingestion of certain foods such as fatty foods, caffeine, alcoholic beverages, carbonated foods, or gas-producing foods as the etiology of their complaints.2 The physician does not want to restrict the patients' diet excessively because of the risk of encountering nutritional deficiencies. However, it may be a good idea to instruct the patient to limit suspected foods and slowly reintroduce these items individually to see whether similar symptoms reoccur. Patients can record their food encounters and subsequent symptoms with a food diary. Maintaining a daily food diary can empower patients by allowing them to take an active role in their management. Cash et al demonstrated that lactose intolerance, one of the most common genetic disorders worldwide, was equally prevalent among IBS patients and the general population.13 Nonetheless, it is prudent that the physician have a low index of suspicion when symptoms of bloating, abdominal distention, and flatulence occur. By giving the patient a short course of a lactose-free diet, one can make a presumptive diagnosis of lactose intolerance if symptoms resolve. One should always query the patient about intake of foods containing sorbitol (i.e., sugar-free or diabetic candy and gum) as this may also lead to similar symptoms.
In the past, pharmacotherapy management of IBS has consisted of medicines targeting individual symptoms of IBS such as bloating, abdominal pain, diarrhea, and constipation. Newer agents are beginning to treat the suspected underlying pathophysiology of IBS and are statistically significant in improving multiple symptoms. The problem is that no one drug fits all, meaning that the IBS population is very diverse, with each individual presenting with different prevailing complaints. The heterogeneity of the IBS population exists because of the wide range of complaints and the varying degree of symptom severity. Tailoring medical care to the individual's concerns and complaints should be the norm. The medical literature regarding IBS therapy is hopelessly inconsistent because of poorly designed studies and ill-defined outcomes.14,15 The placebo response in IBS patients is quite significant, with short-term trials reporting a 30% to 80% response.16 One can imagine the conundrum of treating a syndrome that is heterogeneous in its presentation, lacks significant supporting medical literature, and has a remarkably high placebo response rate. Even though patients' symptoms overlap, addressing them individually allows the physician to simplify and organize the appropriate medical therapy.
Visceral hypersensitivity is felt to be a major contributing factor in abdominal pain experienced by IBS patients. Managing abdominal pain in IBS has changed very little over the past few decades: antispasmodics remain a cornerstone of therapy. Antispasmodic agents can work either by direct smooth muscle relaxation, such as mebeverine and pinaverium (neither is available in the United States), or through anticholinergic or antimuscarinic properties, such as dicyclomine and hyoscyamine. The evidence of the effectiveness of these agents is lacking, as even the meta-analyses for smooth muscle relaxants are conflicting. One meta-analysis demonstrated an advantage over placebo for antispasmodics in terms of abdominal pain and distention.17 Brandt et al examined 18 randomized controlled trials, of which only 3 included dicyclomine and hyoscyamine,5 but concluded that the trials were of suboptimal quality based on study design with inadequate duration of treatment. With only one of those previously mentioned three studies demonstrating a statistically significant improvement in global IBS symptoms and abdominal pain18 and more frequent anticholinergic side effects versus placebo (69% versus 16%), it is easy to understand why insufficient data exist about antispasmodics. Even though the antispasmodic medications have not demonstrated an overwhelming statistically significant advantage,14 it is common practice in the United States to utilize these agents. The anticholinergic effects, including constipation, dry mouth, visual disturbances, and urinary retention, can lead to discontinuation of these medications. These medications can be given as an oral formulation, a sublingual tablet, or a suppository preparation and be dosed on an as-needed basis and preferably 30 minutes before meals. If known exacerbating factors such as a particular diet or stress are anticipated, these medications can be given as a prophylactic measure. It has also been noted that medicines such as dicyclomine can lose effectiveness with chronic use and should be reserved for an as-needed basis.2 Given the potential side effect of constipation, these medications should be used cautiously in IBS with constipation predominating.5
When addressing abdominal pain in the IBS patient, it is helpful to distinguish whether the pain is constant or chronic versus intermittent with known exacerbating factors. The latter has better results when treated with the antispasmodics, whereas the former may have a better response to low-dose tricyclic antidepressants (TCAs). TCAs in IBS patients can act centrally as an analgesic reducing the afferent nerve conduction from the gastrointestinal tract.2,16 The goal is to reduce the visceral hypersensitivity, allowing better management of the chronic pain. Reducing abdominal pain allows decreased anxiety and a distraction from these patient's IBS complaints.5 Support has been rendered by a meta-analysis that demonstrated a benefit versus placebo for low-dose TCAs in treating pain and improving functional gastrointestinal symptoms.19 The quality of these trials has been questioned,14 and subsequently further published reviews discount their effectiveness in ameliorating global IBS symptoms.5 The same review of low-dose TCAs demonstrated a benefit in relieving abdominal pain in IBS patients.5
Some patients hesitate to use TCAs because of the associated stigma of an antidepressant medication; therefore, the management of chronic pain should be emphasized. Counseling the patient regarding the potential side effects of constipation and sedation is essential, and caution should be used when prescribing these medications in constipation-predominant IBS.5 Treatment with TCAs generally starts with a very low dose given before bedtime and even with gradual increases never reaches the same doses that are used to treat depression. Currently, the evidence for using selective serotonin reuptake inhibitors (SSRIs) is limited because the few published studies present conflicting conclusions.16 These agents may be more beneficial in treating concomitant psychiatric illnesses and exhibit fewer side effects.
This IBS symptom is unfortunately a very subjective complaint among patients and remains extremely difficult to treat. The majority of medications designed for this indication have not been helpful. Simethicone and activated charcoal theoretically should aid in alleviating bloating but have not demonstrated a true clinical or even statistical benefit.16 The role of prokinetic agents has yet to be defined, and further well-designed studies are needed.16 Because even IBS treatments such as dietary fiber supplementation can actually worsen bloating secondary to colonic metabolism of nondigestible fiber, care must be taken in prescribing fiber in patients with a significant bloating problem.16,20 Nonabsorbable sugars such as lactulose potentially used for patients with constipation predominating can exacerbate gaseous distention. The physician should instruct the patient to be mindful of gaseous food (e.g., beans, carbonated beverages) and attempt to elicit any aerophagia symptoms. One current agent that has statically demonstrated an improvement is tegaserod2,21; however, care should be taken to ensure that constipation is the predominant feature of the symptom complex because of its potential side effect of diarrhea.5
Dietary and lifestyle modifications should be the initial management tools when treating mild to moderate symptoms of constipation-predominant IBS. Patients should increase their consumption of fiber-enriched foods, and the physician needs to encourage fluid intake to prevent stool dehydration. Teaching the patient to schedule times for bowel evacuations with the aid of stimulating substances such as coffee or prunes allows a regimental routine, thus eliminating previously unrecognizable bad habits. Bulking agents (corn fiber, bran, psyllium, polycarbophil, ispaghula husk, and methylcellulose) are a simple and inexpensive next treatment option. In theory, adding a hydrophilic substance increases luminal water, which adds bulk to the stool and allows easier stool passage. One meta-analysis of 13 trials using bulking agents concluded that evidence was lacking to demonstrate firmly an advantage, with only polycarbophil and ispaghula husk in three trials exhibiting improvement in constipation.14 Not surprisingly, no benefit was seen with abdominal pain or bloating. Furthermore, a systematic review summarized that all 13 trials were flawed in methodology and fiber was merely no more effective than placebo.5 In essence, there are no conclusive data to support the use of bulking agents. However, given that these agents possess a relatively safe profile, it is reasonable to prescribe a trial as initial management for constipation with the understanding that these agents can worsen bloating and abdominal discomfort. Currently, there are no randomized controlled trials examining laxatives and IBS patients,5 but polyethylene glycol can be considered for refractory cases.16
A newer agent that is targeting the pathophysiology of IBS is the 5-hydroxytryptamine (serotonin) 4 receptor partial agonist tegaserod. A thorough review of the medical literature presented evidence that this medication can expedite intestinal and colonic transit, initiate the peristaltic reflex, and reduce visceral sensitivity.5 The efficacy of tegaserod compared with placebo has been documented with statistical evidence demonstrating improved global IBS symptoms among women.5,16,21 Secondary endpoints that were also statistically significant were reduced bloating, improved abdominal pain or discomfort, increased weekly bowel movements, and improved stool consistency.5,21 The efficacy of tegaserod for multiple IBS symptoms allows reduction in the number of medications used by this population of patients. Based on these results from quality studies, the American College of Gastroenterology Functional GI Disorders Task Force has bestowed the highest possible recommendation for this drug in treating women with constipation-predominant IBS.5 The most recognizable side effect is diarrhea, which is found about 10% of the time versus 5% with placebo.5 The diarrhea is usually noticed within the first several days of therapy and typically relents with continued usage. However, the physician should observe for any signs of volume depletion and treat accordingly, as well as reduce or discontinue tegaserod. The makers of tegaserod, Novartis, cautioned physicians in April 2004 to be aware of serious complications such as unrelenting diarrhea and the rare phenomenon of ischemic colitis. Currently, the data are insufficient to make recommendations regarding therapy in men or for alternating bowel habits.5,16
When considering treatment for diarrhea-predominant IBS, the physician should attempt to elicit any particular stressors that can initiate the patient's exaggerated gastric-colic reflex. The anecdotal event could include eating, walking, traveling with the fear of not being near a restroom, or stressful encounters in a social setting or even at work. As previously mentioned, keeping a diary of not only foods but events or situations that correlate with the onset of diarrhea can help the patient in recognizing these stressors and allow the physician to better coordinate therapy. Once these predictable episodes of diarrhea are known, the physician can begin to utilize conservative, first-line treatment with antidiarrhea agents. Of the two most commonly used antidiarrhea agents, loperamide and diphenoxylate HCl–atropine, loperamide is the only one to have been studied for diarrhea-predominant IBS. These medications increase gastrointestinal transit time by interacting with the gastrointestinal musculature, thus allowing more water absorption.16 Of the few randomized controlled trials, the data indicated a decrease in diarrhea without any effect on global IBS symptoms or abdominal pain.5 The physician should instruct the patient to discontinue these medications when the diarrhea has subsided to prevent constipation. Because of this side effect, the physician should have a higher threshold in prescribing these agents in IBS patients with alternating diarrhea and constipation.5
Although opioid medications can decrease diarrhea because of their side effect of constipation, they should be used with extreme caution not only because of the constipation but also for the addiction potential. As a result, most physicians avoid using these agents. Cholestyramine may have a role in the treatment of diarrhea-predominant IBS, but further evidence is needed to better elucidate the role of bile acid malabsorption and treatment in IBS.16 Cholestyramine's side effect of constipation should be remembered. Patients with multiple IBS symptoms that include abdominal pain and diarrhea may benefit from the low-dose TCAs, which can decrease the frequency of bowel movements and treat the visceral hypersensitivity.
The highest recommendation by the American College of Gastroenterology Functional GI Disorders Task Force was given to the 5-hydroxytryptamine (serotonin) 3 receptor antagonist alosetron because multiple randomized controlled trials demonstrated its efficacy in relieving global IBS symptoms in women with diarrhea-predominant IBS. These trials demonstrated alosetron's effectiveness versus placebo for improvement of abdominal discomfort, stool frequency, consistency, and urgency.2,5 However, constipation was reported in approximately one third of patients using alosetron.2,5 Severe constipation and ischemic colitis were rarely reported as well as some potential drug-related fatalities.5,16 After being withdrawn from the market, it was reapproved by the Food and Drug Administration with restrictive guidelines.2
Numerous different treatments have been attempted in IBS patients. One interesting approach is the utilization of antibiotics after assessment for small intestine bacterial overgrowth. By using lactulose hydrogen breath testing on 202 IBS patients, Pimentel et al found that 157 or 75% had abnormal test results signifying bacterial overgrowth.22 All patients with diagnosed bacterial overgrowth received open label antibiotics. Unfortunately, only 47 patients returned for a subsequent breath test to document eradication of the small intestine bacterial overgrowth. However, the study did reflect that patients with successful eradication had statistically significant improvement in abdominal pain and diarrhea. Pimentel et al subsequently published a double-blinded randomized controlled trial substantiating that the normalization of the lactulose breath test with antibiotics in IBS patients led to significant reduction of IBS symptoms.23 Confirmative studies with larger populations of patients are needed to better delineate the relationship between IBS and small intestine bacterial overgrowth treatment.
Many IBS patients turn to herbal preparations because of a widespread perception that they are safe and effective for a variety of aliments. An excellent review by Spanier et al examined these alternative therapies.24 Although unstudied in IBS, aloe has been frequently used in treating constipation-predominant IBS. Peppermint oil, which has antispasmodic properties by relaxing smooth muscle, demonstrated at best modest efficacy over placebo in IBS patients in two meta-analyses,14,24 but study design flaws in both reviews limited interpretability. Perhaps the most common strategy employed by patients is to alter the native flora of their intestines with “probiotics” such as the commercially available preparations of Lactobacillus species.14,24 Trials to date remain conflicting, and no clear benefit has yet been established. Many patients report improved symptoms, but one must be mindful of the previously mentioned high placebo response in IBS, making definitive conclusions difficult. Also, one well-designed study examining Chinese herbal medicine potentially showed a benefit,14,16 but further extensive analysis is needed. The role of psychological therapies, which can be grouped into relaxation therapy, biofeedback, hypnotherapy, cognitive therapy, and psychotherapy, has been analyzed in multiple studies.5,24 The methodological design of the bulk of these studies was inadequate; therefore, unequivocal evidence is lacking. However, a benefit was noted in IBS and psychological symptoms in patients with comorbid psychological disorders.5
Discussion so far has centered on the treatment of the various gastrointestinal symptoms of IBS. However, this population of patients has a wide variety of other symptoms. A study by Gralnek et al of the health-related quality of life (QOL) of patients with IBS showed significant other symptomatology.25 Surprisingly, patients with IBS had lower scores on the SF 36,26 a QOL scale, than comparative groups of diabetics. This was specifically noted in areas such as bodily pain, emotional well-being, fatigue, and poor social functioning. These factors appear to be independent of depression, which may of course coexist with IBS. Bringing a treatment strategy into play that addresses these other mental and physical symptoms is difficult; again, the relationship and rapport between the physician and patient is very important.
The treatment of IBS must be a multifaceted approach and not limited to pharmacotherapy. It is pivotal to establish a cohesive and respectful relationship with the patient. Trust and validation are of singular importance and essential for patients to accept the reality of their often chronic affliction. Pharmacotherapy directed at individual symptoms has been the standard of care up to now, but with newer modalities targeting a molecular level and addressing multiple IBS symptoms, the dawn of a new IBS medical treatment era is fast approaching.