Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habits in the absence of detectable structural abnormalities. No clear diagnostic markers exist for IBS, thus the diagnosis of the disorder is based on clinical presentation. In 2006, the Rome II criteria for the diagnosis of IBS were revised (Table 296-1). Throughout the world, about 10–20% of adults and adolescents have symptoms consistent with IBS, and most studies show a female predominance. IBS symptoms tend to come and go over time and often overlap with other functional disorders such as fibromyalgia, headache, backache, and genitourinary symptoms. Severity of symptoms varies and can significantly impair quality of life, resulting in high health care costs. Advances in basic, mechanistic, and clinical investigations have improved our understanding of this disorder and its physiologic and psychosocial determinants. Altered gastrointestinal (GI) motility, visceral hyperalgesia, disturbance of brain-gut interaction, abnormal central processing, autonomic and hormonal events, genetic and environmental factors, and psychosocial disturbances are variably involved, depending on the individual. This progress may result in improved methods of treatment.
IBS is a disorder that affects all ages, although most patients have their first symptoms before age 45. Older individuals have a lower reporting frequency. Women are diagnosed with IBS two to three times as often as men and make up 80% of the population with severe IBS. As indicated in Table 296-1, pain or abdominal discomfort is a key symptom for the diagnosis of IBS. These symptoms should be improved with defecation and/or have their onset associated with a change in frequency or form of stool. Painless diarrhea or constipation does not fulfill the diagnostic criteria to be classified as IBS. Supportive symptoms that are not part of the diagnostic criteria include defecation straining, urgency or a feeling of incomplete bowel movement, passing mucus, and bloating.
According to the current IBS diagnostic criteria, abdominal pain or discomfort is a prerequisite clinical feature of IBS. Abdominal pain in IBS is highly variable in intensity and location. It is frequently episodic and crampy, but it may be superimposed on a background of constant ache. Pain may be mild enough to be ignored or it may interfere with daily activities. Despite this, malnutrition due to inadequate caloric intake is exceedingly rare with IBS. Sleep deprivation is also unusual because abdominal pain is almost uniformly present only during waking hours. However, patients with severe IBS frequently wake repeatedly during the night; thus, nocturnal pain is a poor discriminating factor between organic and functional bowel disease. Pain is often exacerbated by eating or emotional stress and improved by passage of flatus or stools. In addition, female patients with IBS commonly report worsening symptoms during the premenstrual and menstrual phases.
Alteration in bowel habits is the most consistent clinical feature in IBS. The most common pattern is constipation alternating with diarrhea, usually with one of these symptoms predominating. At first, constipation may be episodic, but eventually it becomes continuous and increasingly intractable to treatment with laxatives. Stools are usually hard with narrowed caliber, possibly reflecting excessive dehydration caused by prolonged colonic retention and spasm. Most patients also experience a sense of incomplete evacuation, thus leading to repeated attempts at defecation in a short time span. Patients whose predominant symptom is constipation may have weeks or months of constipation interrupted with brief periods of diarrhea. In other patients, diarrhea may be the predominant symptom. Diarrhea resulting from IBS usually consists of small volumes of loose stools. Most patients have stool volumes of <200 mL. Nocturnal diarrhea does not occur in IBS. Diarrhea may be aggravated by emotional stress or eating. Stool may be accompanied by passage of large amounts of mucus. Bleeding is not a feature of IBS unless hemorrhoids are present, and malabsorption or weight loss does not occur.
Bowel pattern subtypes are highly unstable. In a patient population with ˜33% prevalence rates of IBS-diarrhea predominant (IBS-D), IBS-constipation predominant (IBS-C), and IBS-mixed (IBS-M) forms, 75% of patients change subtypes and 29% switch between IBS-C and IBS-D over 1 year. The heterogeneity and variable natural history of bowel habits in IBS increase the difficulty of conducting pathophysiology studies and clinical trials.
Patients with IBS frequently complain of abdominal distention and increased belching or flatulence, all of which they attribute to increased gas. Although some patients with these symptoms actually may have a larger amount of gas, quantitative measurements reveal that most patients who complain of increased gas generate no more than a normal amount of intestinal gas. Most IBS patients have impaired transit and tolerance of intestinal gas loads. In addition, patients with IBS tend to reflux gas from the distal to the more proximal intestine, which may explain the belching.
Some patients with bloating may also experience visible distention with increase in abdominal girth. Both symptoms are more common among female patients and in those with higher overall Somatic Symptom Checklist scores. IBS patients who experienced bloating alone have been shown to have lower thresholds for pain and desire to defecate compared to those with concomitant distention irrespective of bowel habit. When patients were grouped according to sensory threshold, hyposensitive individuals had distention significantly more than those with hypersensitivity and this was observed more in the constipation subgroup. This suggests that the pathogenesis of bloating and distention may not be the same.
Upper Gastrointestinal Symptoms
Between 25 and 50% of patients with IBS complain of dyspepsia, heartburn, nausea, and vomiting. This suggests that other areas of the gut apart from the colon may be involved. Prolonged ambulant recordings of small-bowel motility in patients with IBS show a high incidence of abnormalities in the small bowel during the diurnal (waking) period; nocturnal motor patterns are not different from those of healthy controls. The overlap between dyspepsia and IBS is great. The prevalence of IBS is higher among patients with dyspepsia (31.7%) than among those who reported no symptoms of dyspepsia (7.9%). Conversely, among patients with IBS, 55.6% reported symptoms of dyspepsia. In addition, the functional abdominal symptoms can change over time. Those with predominant dyspepsia or IBS can flux between the two. Although the prevalence of functional gastrointestinal disorders is stable over time, the turnover in symptom status is high. Many episodes of symptom disappearance are due to subjects changing symptoms rather than total symptom resolution. Thus it is conceivable that functional dyspepsia and IBS are two manifestations of a single, more extensive digestive system disorder. Furthermore, IBS symptoms are prevalent in noncardiac chest pain patients, suggesting overlap with other functional gut disorders.
The pathogenesis of IBS is poorly understood, although roles of abnormal gut motor and sensory activity, central neural dysfunction, psychological disturbances, mucosal inflammation, stress, and luminal factors have been proposed.
Gastrointestinal Motor Abnormalities
Studies of colonic myoelectrical and motor activity under unstimulated conditions have not shown consistent abnormalities in IBS. In contrast, colonic motor abnormalities are more prominent under stimulated conditions in IBS. IBS patients may exhibit increased rectosigmoid motor activity for up to 3 h after eating. Similarly, inflation of rectal balloons both in IBS-D and IBS-C patients leads to marked and prolonged distention-evoked contractile activity. Recordings from the transverse, descending, and sigmoid colon showed that the motility index and peak amplitude of high-amplitude propagating contractions (HAPCs) in diarrhea-prone IBS patients were greatly increased compared to those in healthy subjects and were associated with rapid colonic transit and accompanied by abdominal pain.
As with studies of motor activity, IBS patients frequently exhibit exaggerated sensory responses to visceral stimulation. Postprandial pain has been temporally related to entry of the food bolus into the cecum in 74% of patients. Rectal balloon inflation produces nonpainful and painful sensations at lower volumes in IBS patients than in healthy controls without altering rectal tension, suggestive of visceral afferent dysfunction in IBS. Similar studies show gastric and esophageal hypersensitivity in patients with nonulcer dyspepsia and noncardiac chest pain, raising the possibility that these conditions have a similar pathophysiologic basis. Lipids lower the thresholds for the first sensation of gas, discomfort, and pain in IBS patients. Hence, postprandial symptoms in IBS patients may be explained in part by a nutrient-dependent exaggerated sensory component of the gastrocolonic response. In contrast to enhanced gut sensitivity, IBS patients do not exhibit heightened sensitivity elsewhere in the body. Thus, the afferent pathway disturbances in IBS appear to be selective for visceral innervation with sparing of somatic pathways. The mechanisms responsible for visceral hypersensitivity are still under investigation. It has been proposed that these exaggerated responses may be due to (1) increased end-organ sensitivity with recruitment of “silent” nociceptors; (2) spinal hyperexcitability with activation of nitric oxide and possibly other neurotransmitters; (3) endogenous (cortical and brainstem) modulation of caudad nociceptive transmission; and (4) over time, the possible development of long-term hyperalgesia due to development of neuroplasticity, resulting in permanent or semipermanent changes in neural responses to chronic or recurrent visceral stimulation (Table 296-2).
Table 296-2 Proposed Mechanisms for Visceral Hypersensitivity |Favorite Table|Download (.pdf)
Table 296-2 Proposed Mechanisms for Visceral Hypersensitivity
|End-organ sensitivity||Long-term hyperalgesia|
|“Silent” nociceptors||Tonic cortical regulation|
Central Neural Dysregulation
The role of central nervous system (CNS) factors in the pathogenesis of IBS is strongly suggested by the clinical association of emotional disorders and stress with symptom exacerbation and the therapeutic response to therapies that act on cerebral cortical sites. Functional brain imaging studies such as MRI have shown that in response to distal colonic stimulation, the mid-cingulate cortex—a brain region concerned with attention processes and response selection—shows greater activation in IBS patients. Modulation of this region is associated with changes in the subjective unpleasantness of pain. In addition, IBS patients also show preferential activation of the prefrontal lobe, which contains a vigilance network within the brain that increases alertness. These may represent a form of cerebral dysfunction leading to the increased perception of visceral pain.
Abnormal Psychological Features
Abnormal psychiatric features are recorded in up to 80% of IBS patients, especially in referral centers; however, no single psychiatric diagnosis predominates. Most of these patients demonstrated exaggerated symptoms in response to visceral distention, and this abnormality persists even after exclusion of psychological factors.
Psychological factors influence pain thresholds in IBS patients, as stress alters sensory thresholds. An association between prior sexual or physical abuse and development of IBS has been reported. Abuse is associated with greater pain reporting, psychological distress, and poor health outcome. Brain functional MRI studies show greater activation of the posterior and middle dorsal cingulate cortex, which is implicated in affect processing in IBS patients with a past history of sexual abuse.
Thus, patients with IBS frequently demonstrate increased motor reactivity of the colon and small bowel to a variety of stimuli and altered visceral sensation associated with lowered sensation thresholds. These may result from CNS—enteric nervous system dysregulation (Fig. 296-1).
Therapeutic targets for irritable bowel syndrome. Patients with mild to moderate symptoms usually have intermittent symptoms that correlate with altered gut physiology. Treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, fiber supplements, and gut serotonin modulators. Patients who have severe symptoms usually have constant pain and psychosocial difficulties. This group of patients is best managed with antidepressants and other psychosocial treatments. CNS, central nervous system; ENS, enteric nervous system.
IBS may be induced by GI infection. In an investigation of 544 patients with confirmed bacterial gastroenteritis, one-quarter developed IBS subsequently. Conversely, about a third of IBS patients experienced an acute “gastroenteritis-like” illness at the onset of their chronic IBS symptomatology. This group of “postinfective” IBS occurs more commonly in females and affects younger rather than older patients. Risk factors for developing post-infectious IBS include, in order of importance, prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse-life events in the preceding 3 months. Age older than 60 years might protect against post-infectious IBS, whereas treatment with antibiotics has been associated with increased risk. The microbes involved in the initial infection are Campylobacter, Salmonella, and Shigella. Those patients with Campylobacter infection who are toxin-positive are more likely to develop postinfective IBS. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability are acute changes following Campylobacter enteritis that could persist for more than a year and may contribute to postinfective IBS.
Immune Activation and Mucosal Inflammation
Some patients with IBS display persistent signs of low-grade mucosal inflammation with activated lymphocytes, mast cells, and enhanced expression of proinflammatory cytokines. These abnormalities may contribute to abnormal epithelial secretion and visceral hypersensitivity. Interestingly, clinical studies have shown increased intestinal permeability in patients with IBS-D. Psychological stress and anxiety can increase the release of proinflammatory cytokine and this in turn may alter intestinal permeability. This provides a functional link between psychological stress, immune activation, and symptom generation in patients with IBS.
A high prevalence of small intestinal bacterial overgrowth in IBS patients has been noted based on positive lactulose hydrogen breath test. This finding, however, has been challenged by a number of other studies that found no increased incidence of bacterial overgrowth based on jejunal aspirate culture. Abnormal H2 breath test can occur because of small bowel rapid transit and may lead to erroneous interpretation. Hence, the role of testing for small intestinal bacterial overgrowth in IBS patients remains unclear.
A number of studies found significant differences between the molecular profile of the fecal microbiota of IBS patients compared with that of healthy subjects. Several bacterial genera with Lactobacillus sequence appear to be absent from IBS, and Collinsella sequences were greatly reduced in this group of patients. Currently it is unclear whether such changes are causal, consequential, or merely the result of constipation and diarrhea. In addition, the stability of the changes in the microbiota needs to be determined.
Abnormal Serotonin Pathways
The serotonin (5HT)-containing enterochromaffin cells in the colon are increased in a subset of IBS-D patients compared to healthy individuals or patients with ulcerative colitis. Furthermore, postprandial plasma 5HT levels were significantly higher in this group of patients compared to healthy controls. Since serotonin plays an important role in the regulation of GI motility and visceral perception, the increased release of serotonin may contribute to the postprandial symptoms of these patients and provides a rationale for the use of serotonin antagonists in the treatment of this disorder.
Approach to the Patient: Irritable Bowel Syndrome
Because IBS is a disorder for which no pathognomonic abnormalities have been identified, its diagnosis relies on recognition of positive clinical features and elimination of other organic diseases. A careful history and physical examination are frequently helpful in establishing the diagnosis. Clinical features suggestive of IBS include the following: recurrence of lower abdominal pain with altered bowel habits over a period of time without progressive deterioration, onset of symptoms during periods of stress or emotional upset, absence of other systemic symptoms such as fever and weight loss, and small-volume stool without any evidence of blood.
On the other hand, the appearance of the disorder for the first time in old age, progressive course from time of onset, persistent diarrhea after a 48-h fast, and presence of nocturnal diarrhea or steatorrheal stools argue against the diagnosis of IBS.
Because the major symptoms of IBS—abdominal pain, abdominal bloating, and alteration in bowel habits—are common complaints of many GI organic disorders, the list of differential diagnoses is a long one. The quality, location, and timing of pain may be helpful to suggest specific disorders. Pain due to IBS that occurs in the epigastric or periumbilical area must be differentiated from biliary tract disease, peptic ulcer disorders, intestinal ischemia, and carcinoma of the stomach and pancreas. If pain occurs mainly in the lower abdomen, the possibility of diverticular disease of the colon, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and carcinoma of the colon must be considered. Postprandial pain accompanied by bloating, nausea, and vomiting suggests gastroparesis or partial intestinal obstruction. Intestinal infestation with Giardia lamblia or other parasites may cause similar symptoms. When diarrhea is the major complaint, the possibility of lactase deficiency, laxative abuse, malabsorption, celiac sprue, hyperthyroidism, inflammatory bowel disease, and infectious diarrhea must be ruled out. On the other hand, constipation may be a side effect of many different drugs, such as anticholinergic, antihypertensive, and antidepressant medications. Endocrinopathies such as hypothyroidism and hypoparathyroidism must also be considered in the differential diagnosis of constipation, particularly if other systemic signs or symptoms of these endocrinopathies are present. In addition, acute intermittent porphyria and lead poisoning may present in a fashion similar to IBS, with painful constipation as the major complaint. These possibilities are suspected on the basis of their clinical presentations and are confirmed by appropriate serum and urine tests.
Few tests are required for patients who have typical IBS symptoms and no alarm features. Unnecessary investigations may be costly and even harmful. The American Gastroenterological Association has delineated factors to be considered when determining the aggressiveness of the diagnostic evaluation. These include the duration of symptoms, the change in symptoms over time, the age and sex of the patient, the referral status of the patient, prior diagnostic studies, a family history of colorectal malignancy, and the degree of psychosocial dysfunction. Thus, a younger individual with mild symptoms requires a minimal diagnostic evaluation, while an older person or an individual with rapidly progressive symptoms should undergo a more thorough exclusion of organic disease. Most patients should have a complete blood count and sigmoidoscopic examination; in addition, stool specimens should be examined for ova and parasites in those who have diarrhea. In patients with persistent diarrhea not responding to simple anti-diarrhea agents, a sigmoid colon biopsy should be performed to rule out microscopic colitis. In those aged >40 years, an air-contrast barium enema or colonoscopy should also be performed. If the main symptoms are diarrhea and increased gas, the possibility of lactase deficiency should be ruled out with a hydrogen breath test or with evaluation after a 3-week lactose-free diet. Some patients with IBS-D may have undiagnosed celiac sprue. Because the symptoms of celiac sprue respond to a gluten-free diet, testing for celiac sprue in IBS may prevent years of morbidity and attendant expense. Decision-analysis studies show that serology testing for celiac sprue in patients with IBS-D has an acceptable cost when the prevalence of celiac sprue is >1% and is the dominant strategy when the prevalence is >8%. In patients with concurrent symptoms of dyspepsia, upper GI radiographs or esophagogastroduodenoscopy may be advisable. In patients with postprandial right upper quadrant pain, an ultrasonogram of the gallbladder should be obtained. Laboratory features that argue against IBS include evidence of anemia, elevated sedimentation rate, presence of leukocytes or blood in stool, and stool volume >200–300 mL/d. These findings would necessitate other diagnostic considerations.
Treatment: Irritable Bowel Syndrome
Patient Counseling and Dietary Alterations
Reassurance and careful explanation of the functional nature of the disorder and of how to avoid obvious food precipitants are important first steps in patient counseling and dietary change. Occasionally, a meticulous dietary history may reveal substances (such as coffee, disaccharides, legumes, and cabbage) that aggravate symptoms. Excessive fructose and artificial sweeteners, such as sorbitol or mannitol, may cause diarrhea, bloating, cramping or flatulence. As a therapeutic trial, patients should be encouraged to eliminate any foodstuffs that appear to produce symptoms. However patients should avoid nutritionally depleted diets. Patients with IBS-D anecdotally report symptom improvement after initiating a low-carbohydrate diet. A prospective study has shown marked symptomatic improvement in stool frequency, consistency, pain scores, and quality of life following 4 weeks of a very-low-carbohydrate (CHO) diet (20 g CHO/day). This diet may be tried in IBS patients who report intolerance to certain carbohydrates.
High-fiber diets and bulking agents, such as bran or hydrophilic colloid, are frequently used in treating IBS. The water-holding action of fibers may contribute to increased stool bulk because of the ability of fiber to increase fecal output of bacteria. Fiber also speeds up colonic transit in most persons. In diarrhea-prone patients, whole-colonic transit is faster than average; however, dietary fiber can delay transit. Furthermore, because of their hydrophilic properties, stool-bulking agents bind water and thus prevent both excessive hydration and dehydration of stool. The latter observation may explain the clinical experience that a high-fiber diet relieves diarrhea in some IBS patients. Fiber supplementation with psyllium has been shown to reduce perception of rectal distention, indicating that fiber may have a positive effect on visceral afferent function.
The beneficial effects of dietary fiber on colonic physiology suggest that dietary fiber should be an effective treatment for IBS patients, but controlled trials of dietary fiber have produced variable results. This is not surprising since IBS is a heterogeneous disorder, with some patients being constipated and other having predominant diarrhea. Most investigations report increases in stool weight, decreases in colonic transit times, and improvement in constipation. Others have noted benefits in patients with alternating diarrhea and constipation, pain, and bloating. However, most studies observe no responses in patients with diarrhea- or pain-predominant IBS. It is possible that different fiber preparations may have dissimilar effects on selected symptoms in IBS. A cross-over comparison of different fiber preparations found that psyllium produced greater improvements in stool pattern and abdominal pain than bran. Furthermore, psyllium preparations tend to produce less bloating and distention. Despite the equivocal data regarding efficacy, most gastroenterologists consider stool-bulking agents worth trying in patients with IBS-C.
Clinicians have observed that anticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasm. Although controlled clinical trials have produced mixed results, evidence generally supports beneficial effects of anticholinergic drugs for pain. A meta-analysis of 26 double-blind clinical trials of antispasmodic agents in IBS reported better global improvement (62%) and abdominal pain reductions (64%) compared to placebo (35% and 45%, respectively), suggesting efficacy in some patients. The drugs are most effective when prescribed in anticipation of predictable pain. Physiologic studies demonstrate that anticholinergic drugs inhibit the gastrocolic reflex; hence, postprandial pain is best managed by giving antispasmodics 30 min before meals so that effective blood levels are achieved shortly before the anticipated onset of pain. Most anticholinergics contain natural belladonna alkaloids, which may cause xerostomia, urinary hesitancy and retention, blurred vision, and drowsiness. They should be used in the elderly with caution. Some physicians prefer to use synthetic anticholinergics such as dicyclomine that have less effect on mucous membrane secretions and produce fewer undesirable side effects.
Peripherally acting opiate-based agents are the initial therapy of choice for IBS-D. Physiologic studies demonstrate increases in segmenting colonic contractions, delays in fecal transit, increases in anal pressures, and reductions in rectal perception with these drugs. When diarrhea is severe, especially in the painless diarrhea variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed. These agents are less addictive than paregoric, codeine, or tincture of opium. In general, the intestines do not become tolerant of the antidiarrheal effect of opiates, and increasing doses are not required to maintain antidiarrheal potency. These agents are most useful if taken before anticipated stressful events that are known to cause diarrhea. However, not infrequently, a high dose of loperamide may cause cramping because of increases in segmenting colonic contractions. Another anti-diarrhea agent that may be used in IBS patients is the bile acid binder cholestyramine resin.
In addition to their mood-elevating effects, antidepressant medications have several physiologic effects that suggest they may be beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imipramine slows jejunal migrating motor complex transit propagation and delays orocecal and whole-gut transit, indicative of a motor inhibitory effect. Some studies also suggest that tricyclic agents may alter visceral afferent neural function.
A number of studies indicate that tricyclic antidepressants may be effective in some IBS patients. In a 2-month study of desipramine, abdominal pain improved in 86% of patients compared to 59% given placebo. Another study of desipramine in 28 IBS patients showed improvement in stool frequency, diarrhea, pain, and depression. When stratified according to the predominant symptoms, improvements were observed in IBS-D patients, with no improvement being noted in IBS-C patients. The beneficial effects of the tricyclic compounds in the treatment of IBS appear to be independent of their effects on depression. The therapeutic benefits for the bowel symptoms occur faster and at a lower dosage. The efficacy of antidepressant agents in other chemical classes in the management of IBS is less well evaluated. In contrast to tricyclic agents, the selective serotonin reuptake inhibitor (SSRI) paroxetine accelerates orocecal transit, raising the possibility that this drug class may be useful in IBS-C patients. The SSRI citalopram blunts perception of rectal distention and reduces the magnitude of the gastrocolonic response in healthy volunteers. A small placebo-controlled study of citalopram in IBS patients reported reductions in pain. However, these findings could not be confirmed in another randomized controlled trial which showed that citalopram at 20 mg/day for 4 weeks was not superior to placebo in treating non-depressed IBS patients. Hence, the efficacy of SSRIs in the treatment of IBS needs further confirmation.
The management of excessive gas is seldom satisfactory, except when there is obvious aerophagia or disaccharidase deficiency. Patients should be advised to eat slowly and not chew gum or drink carbonated beverages. Bloating may decrease if an associated gut syndrome such as IBS or constipation is improved. If bloating is accompanied by diarrhea and worsens after ingesting dairy products, fresh fruits, vegetables, or juices, further investigation or a dietary exclusion trial may be worthwhile. Avoiding flatogenic foods, exercising, losing excess weight, and taking activated charcoal are safe but unproven remedies. Data regarding the use of surfactants such as simethicone are conflicting. Antibiotics may help in a subgroup of IBS patients with predominant symptoms of bloating. Beano, an over-the-counter oral β-glycosidase solution, may reduce rectal passage of gas without decreasing bloating and pain. Pancreatic enzymes reduce bloating, gas, and fullness during and after high-calorie, high-fat meal ingestion.
Antibiotic treatment benefits a subset of IBS patients. In a double-blind randomized placebo controlled study, neomycin dosed at 500 mg twice daily for 10 days was more effective than placebo at improving symptom scores among IBS patients. The non-absorbed oral antibiotic rifaximin is the most thoroughly studied antibiotic for the treatment of IBS. Patients receiving rifaximin at a dose of 400 mg three times daily experienced substantial improvement of global IBS symptoms over placebo. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients. The drug has a favorable safety and tolerability profile compared with systemic antibiotics. However, currently there is still insufficient data to recommend routine use of this antibiotic in the treatment of IBS.
Since altered colonic flora may contribute to the pathogenesis of IBS, this has led to great interest in using probiotics to naturally alter the flora. Bifidobacterium infantis 35624 showed significant improvement in the composite score for abdominal pain, bloating/distention, and/or bowel movement compared with placebo in two placebo-controlled trials. Currently, there are inadequate data to comment on the efficacy of other probiotics.
Serotonin Receptor Agonist and Antagonists
Serotonin receptor antagonists have been evaluated as therapies for IBS-D. Serotonin acting on 5-HT3 receptors enhances the sensitivity of afferent neurons projecting from the gut. In humans, a 5-HT3 receptor antagonist such as alosetron reduces perception of painful visceral stimulation in IBS. It also induces rectal relaxation, increases rectal compliance, and delays colonic transit. Meta-analysis of 14 randomized controlled trials of alosetron or cilansetron showed that these antagonists are more effective than placebo in achieving global improvement in IBS symptoms and relief of abdominal pain and discomfort. These agents are more likely to cause constipation in IBS patients with diarrhea alternating with constipation. 0.2% of patients using 5HT3 antagonist developed ischemic colitis versus none in the control group. In postrelease surveillance, 84 cases of ischemic colitis were observed, including 44 cases that required surgery and 4 deaths. As a consequence, the medication was voluntarily withdrawn by the manufacturer in 2000. Alosetron has been reintroduced under a new risk-management program where patients have to sign a patient-physician agreement. This has significantly limited its usage.
Novel 5-HT4 receptor agonists such as tegaserod exhibit prokinetic activity by stimulating peristalsis. In IBS patients with constipation, tegaserod accelerated intestinal and ascending colon transit. Clinical trials involving >4000 IBS-C patients reported reductions in discomfort and improvements in constipation and bloating, compared to placebo. Diarrhea is the major side effect. However, tegaserod has been withdrawn from the market; a meta-analysis revealed an increase in serious cardiovascular events.
Chloride Channel Activators
Lubiprostone is a bicyclic fatty acid that stimulates chloride channels in the apical membrane of intestinal epithelial cells. Chloride secretion induces passive movement of sodium and water into the bowel lumen and improves bowel function. Oral lubiprostone was effective in the treatment of patients with constipation-predominant IBS in large phase II and phase III randomized double-blinded placebo-controlled multicenter trials. Responses were significantly greater in patients receiving lubiprostone 8 μg twice daily for 3 months than in those receiving placebo. In general, the drug was quite well tolerated. The major side effects are nausea and diarrhea. Lubiprostone is a new class of compounds for treatment of chronic constipation with or without IBS.
The treatment strategy of IBS depends on the severity of the disorder (Table 296-3). Most of the IBS patients have mild symptoms. They are usually cared for in primary care practices, have little or no psychosocial difficulties, and do not seek health care often. Treatment usually involves education, reassurance, and dietary/lifestyle changes. A smaller portion have moderate symptoms that are usually intermittent and correlate with altered gut physiology, e.g., worsened with eating or stress and relieved by defecation. Treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, fiber supplements, and the newer gut serotonin modulators (Table 296-4). A small proportion of IBS patients have severe and refractory symptoms, are usually seen in referral centers, and frequently have constant pain and psychosocial difficulties (Fig. 296-1). This group of patients is best managed with antidepressants and other psychological treatments (Table 296-4).
Table 296-3 Spectrum of Severity in IBS |Favorite Table|Download (.pdf)
Table 296-3 Spectrum of Severity in IBS
|Correlations with gut physiology||+++||++||+|
|Health care issues||+||++||+++|
Table 296-4 Possible Drugs for a Dominant Symptom in IBS |Favorite Table|Download (.pdf)
Table 296-4 Possible Drugs for a Dominant Symptom in IBS
|Diarrhea||Loperamide||2–4 mg when necessary/maximum 12 g/d|
|Cholestyramine resin||4 g with meals|
|Alosetron*||0.5–1 mg bid (for severe IBS, women)|
|Constipation||Psyllium husk||3–4 g bid with meals, then adjust|
|Methylcellulose||2 g bid with meals, then adjust|
|Calciumpolycarbophil||1 g qd to qid|
|Lactulose syrup||10–20 g bid|
|70% sorbitol||15 mL bid|
|Polyethylene glycol 3350||17 g in 250 mL water qd|
|Lubiprostone (Amitiza)||24 mg bid|
|Magnesium hydroxide||30–60 mL qd|
|Abdominal pain||Smooth-muscle relaxant||qd to qid ac|
|Tricyclic antidepressants||Start 25–50 mg hs, then adjust|
|Selective serotonin reuptake inhibitors||Begin small dose, increase as needed|