Other Agents IRRITABLE BOWEL SYNDROME. SECTION 4 Gastrointestinal Disorders EPIDEMIOLOGY. Prevention LAXATIVE ABUSE SYNDROME PATHOPHYSIOLOGY

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1 628 SECTION 4 Gastrointestinal Disorders Other Agents Tap-water enemas may be used to treat simple constipation. The administration of 200 ml of tap water by enema to an adult often results in a bowel movement within 30 minutes. Soap-suds enemas are no longer recommended as their use may result in proctitis or colitis. Prevention For certain groups of patients, such as those recovering from myocardial infarction or rectal surgery, straining at defecation is to be avoided. The basis of preventive therapy in these patients should be bulk-forming laxatives. Additionally, the use of docusate is popular, although its effectiveness is debated. In pregnant patients, constipation may result because of alterations in anatomy or iron supplementation. As described earlier, bulk-forming laxatives and docusates should be the first line of prevention. LAXATIVE ABUSE SYNDROME Misconceptions about normal bowel patterns and the effect of laxatives have contributed to a syndrome of laxative abuse that is relatively common in the United States. The availability of laxatives as chocolates or gums conveys to the public that the use of these agents is without adverse consequences. Abuse of laxatives has occurred traditionally in persons trying to maintain daily bowel function, but more recently has extended to others who use laxatives for the purpose of controlling weight. In either case, the consistent abuse of strong laxatives and cathartics may lead to serious illness. Laxative abuse for the purpose of maintaining daily bowel function begins with misconceptions about the frequency, quantity, or consistency of stools. With the use of strong purgatives, the colon may be so thoroughly cleansed that a bowel movement may not occur normally until a few days later. This delay reinforces the need for more purgatives and the cycle of laxative dependence is begun. Eventually the patient may require daily laxatives to maintain bowel function. A variation of laxative abuse is seen in persons who use them as a means of weight loss. The laxative abuser may present with contradictory findings of diarrhea and weight loss. In addition, long-term abusers of laxatives lend to have vomiting, abdominal pain, lassitude, weakness, thirst, edema, and bone pain (caused by osteomalacia). With prolonged use of laxatives a number of serious illnesses may arise, including fluid and electrolyte imbalances (including acid base imbalances and hypokalemia), protein-losing gastroenteropathy with hypoalbuminemia, and syndromes resembling colitis. The determination of laxative abuse syndrome can be difficult because many laxative abusers vigorously deny laxative use. Middleaged women tend to be the most common laxative abusers. The chronic laxative abuse problem should be addressed by a combination of measures, including psychiatric evaluation, dietary modification with reliance on bulk-forming laxatives, and specific guidelines to the patient for the withdrawal of stimulant laxatives. EVALUATION OF THERAPEUTIC OUTCOMES The ultimate goal of treatment for constipation is alteration of lifestyle (particularly diet) to prevent further episodes of constipation. Short-term goals include alleviation of acute constipation with relief from symptoms. For patients with chronic constipation, the goals are more long-term and include use of proper diet and decreased reliance on laxatives. Effective treatment of constipation requires the patient to become more knowledgeable about the causes of constipation, proper diet, and appropriate use of laxatives. IRRITABLE BOWEL SYNDROME Irritable bowel syndrome (IBS) is a gastrointestinal syndrome characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. It is the most commonly diagnosed gastrointestinal condition. EPIDEMIOLOGY The prevalence of IBS is approximately 10% to 15% based on North American and European population-based studies; however, there is a wide variation in prevalence by individual country IBS affects men and women, young patients, and the elderly. However, younger patients and women are more likely to be diagnosed with IBS. A systematic review estimated that there is an overall 2:1 female predominance in North America. 34 Although only 15% of those affected actually seek medical attention, IBS is the cause of between 25% and 50% of all referrals to gastroenterologists. 37 PATHOPHYSIOLOGY Although the exact pathophysiologic abnormalities with IBS are still being actively investigated, it is currently thought that IBS results from altered somatovisceral and motor dysfunction of the intestine from a variety of causes. Abnormal central nervous system processing of afferent signals may lead to visceral hypersensitivity, with the specific nerve pathway affected determining the exact symptomatology expressed. This visceral hypersensitivity is a neuroenteric phenomenon that is independent of motility and psychological disturbances. 27 Factors known to contribute to these alterations include genetics, motility factors, inflammation, colonic infections, mechanical irritation to local nerves, stress, and other psychological factors. Serotonin-Type Receptors The enteric nervous system contains a significant percentage of the body s 5-hydroxytryptamine (serotonin, 5-HT). 38 Two types of serotonin exists within the gut: serotonin type 3 (HT 3 ) and serotonin type 4 (HT 4 ), which are responsible for secretion, sensitization, and motility. 39 Previous studies show that there is an increase in the postprandial levels of 5-HT in those who suffer from diarrhea predominant IBS when compared with nonsufferers. 38 Therefore, stimulation and antagonism of these serotonin receptors has become a focused area for research on new drug therapies for both diarrhea- and constipation-predominant disease. CLINICAL PRESENTATION Irritable bowel syndrome presents as either diarrhea-predominant or constipation-predominant disease and can be defined as lower abdominal pain, disturbed defecation (constipation, diarrhea, or an alternating pattern of both), and bloating in the absence of structural or biochemical factors that might explain these symptoms (Table 38 10). Because IBS can consist of a variable number of signs and symptoms, two diagnostic criteria check lists are commonly used to aid in the workup of a patient suspected of having IBS. The Manning criteria was first proposed in 1978, whereas the Rome criteria was initially proposed in 1999 and revised as recently as 2006 by an international working group in an effort to help standardize the diagnostic criteria used in clinical research protocols. Table shows the symptom criteria for both of the Manning 40 and Rome III 41 symptom-based criteria. Additional diagnostic steps that can be taken include sigmoidoscopy or colonoscopy; examination of the stool for occult blood and ova and parasites; complete blood cell count; erythrocyte sedimen-

2 629 TABLE Clinical Presentation of Irritable Bowel Syndrome Signs and symptoms Lower abdominal pain Abdominal bloating and distension Diarrhea symptoms, >3 stools/day Extreme urgency Mucus passage Constipation symptoms, <3 stools/wk, straining, incomplete evacuation Psychological symptoms such as depression and anxiety Nongastrointestinal symptoms Urinary symptoms Fatigue Dyspareunia Other concurrent conditions Fibromyalgia Functional dyspepsia Chronic fatigue syndrome Reduced health-related quality of life tation rate; and serum electrolytes. In some cases, radiographic imaging studies, such as computed tomography scans or barium swallows or enemas, may also be necessary if the findings of the above assessment are not typical for IBS. 42 TREATMENT Irritable Bowel Syndrome GENERAL APPROACH TO TREATMENT The treatment approach to IBS is based upon the predominant symptoms and their severity (Fig. 38 3). Milder, less frequent episodes can be managed with dietary restrictions and a higher-fiber diet, with addition of bulk-forming laxatives, if necessary. More persistent disease may require as-needed uses of various antispasmodic or antidiarrheal agents such as loperamide. Lastly, the mostsevere forms of this disease may call for pharmacologic agents directed specifically at the underlying neurohormonal imbalance, such as the 5-HT 4 agonists, such as tegaserod, or the 5-HT 3 receptor antagonists, such as alosetron. TABLE Symptom-Based Criteria for Irritable Bowel Syndrome The Manning criteria 40 Chronic or recurrent abdominal pain for at least 6 months and two or more of the following: 1. Abdominal pain relieved with defecation 2. Abdominal pain associated with more frequent stools 3. Abdominal pain associated with looser stools 4. Abdominal distension 5. Feeling of incomplete evacuation after defecation 6. Mucus in stools Rome III diagnostic criteria for irritable bowel syndrome 41 Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following: 1. Relieved with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool CONSTIPATION-PREDOMINANT DISEASE In the constipation-predominant patient, dietary fiber may be beneficial. Patients should be instructed to begin with 1 tablespoonful of fiber with 1 meal daily and gradually increase the dose to include fiber with 2 and 3 meals a day until the desired outcome is achieved. End points that the patient should aim for include bulkier and more easily passed stools. For patients unable to tolerate dietary Constipation predominant Diagnosis of irritable bowel syndrome Symptomatic treatment including stress management and patient education Diarrhea predominant CHAPTER 38 Diarrhea, Constipation, and Irritable Bowel Syndrome CLINICAL CONTROVERSY The newer serotonin receptor agonists and antagonists tegaserod and alosetron act on GI-specific serotonin receptors to treat constipation-predominant and diarrhea predominant IBS, respectively. However, both drugs are currently only indicated for women. Efficacy and safety in men has not been established because the initial manufacturer s sponsored clinical trials contained insufficient numbers of men with IBS to provide the necessary statistical power to prove efficacy and safety. Ongoing studies should determine if these drugs are indicated in men. Increase dietary fiber and fluid intake Add bulk-forming laxatives and consider antispasmodic agents Add serotonin-4 agonist (e.g., tegaserod) a Lactose-free, caffeine-free diet. Counsel patient on other diarrheainducing foods and drugs to avoid Add loperamide or other antispasmodic Add serotonin-3 antagonists (e.g., alosetron) a Alosetron, a 5-HT 3 receptor antagonist, was withdrawn from the U.S. market in 2000 as a result of serious adverse effects, including severe constipation and ischemic colitis that did not appear in the initial clinical trials. It was reintroduced in 2002 and is now limited to an FDA-approved restricted-use program in lower initial doses, and requires extensive postmarketing surveillance. Results of these trials are necessary to definitively determine alosetron s true safety profile, especially with regard to its association with or causation of fatal ischemic colitis. Add psychotherapeutic behavior modifications, including stress reduction, and consider antidepressants for associated pain symptoms FIGURE A general stepwise approach to the management of both constipation- and diarrhea-predominant irritable bowel syndrome. a Consider manufacturer sponsored patient access program.

3 630 SECTION 4 Gastrointestinal Disorders bran, bulking agents such as psyllium may be substituted. 30 Laxative use is not encouraged in these patients, and it should only be used in the smallest dose for the least amount of time in cases of severe constipation. The 5-HT 4 partial agonist tegaserod was the first therapy approved by the FDA specifically for short-term, intermittent treatment of constipation-predominant IBS. 42 Tegaseride was suspended from marketing in early 2007 at the request of the FDA due to an analysis of clinical trial data showing a small, yet significant, increase in ischemia events (MI < CVA, and unstable angina) in patients with pre-existing cardiovascular disease and/or cardiovascular risk factors. In July 2007, the drug s manufacturer, Novartis, began tegaseride (Zelnorm ) restricted access program to patients in the United States via either a manufacturer sponsored FDA-approved investigational new drug (IND) protocol or through the FDA via an emergency INID protocol. Tegaserod is a serotonin derivative that activates 5-HT 4 receptors on the neurons in the gastrointestinal tract, increasing GI motility and decreasing visceral sensations. It is approved as 2-mg or 6-mg doses given twice daily 30 minutes prior to a meal with water for up to 12 weeks. 43 Stimulation of the 5-HT 4 receptors by tegaserod increases gastric secretions and promotes motility, with improvement in symptoms generally occurring within the first week of therapy. Currently this therapy is only approved for use in women, as efficacy and safety in men has not been established because of inadequate numbers of men enrolled in clinical trials to date. 44 In addition, length of effective therapy has only been approved for 12 weeks 45 ; however, tegaserod may provide safe and effective therapy for up to 12 months. 44,46 Diarrhea was the most common adverse effect, resulting in drug discontinuation in 1.6% of study subjects. DIARRHEA-PREDOMINANT DISEASE For patients in whom diarrhea is the primary complaint, avoidance of certain food products may be necessary. Caffeine, alcohol, and artificial sweeteners (sorbitol, fructose, and mannitol) are known to irritate the gut and produce a laxative effect. Lactose intolerance should be considered in certain patients; however, the prevalence of this condition may be exaggerated. Herbal medicines or teas often contain senna, which may produce diarrhea. In patients with disease persistence following dietary modification, loperamide may be used for episodic management of urgent diarrhea, or in situations in which the patient wishes to avoid the possibility of an acute onset of symptoms. 43 This drug decreases intestinal transit, enhances water and electrolyte absorption, and strengthens rectal sphincter tone. Some patients may require continuous therapy, and careful dosage titration can usually be undertaken to prevent the development of constipation. Bile acid sequestrants such as cholestyramine may be useful in patients with diarrhea related to idiopathic bile acid malabsorption or following cholecystectomy. 42 Diarrhea-predominant IBS caused by excessive stimulation of the 5-HT 3 receptor can be relieved by the drug alosetron. Alosetron was the first truly effective treatment for diarrhea-predominant IBS. However, in November 2000 it was voluntarily withdrawn from the market because of severe GI adverse effects, including 113 reported cases of serious constipation and 8 cases of possible ischemic colitis and death. This decision was met with a great public outcry, as many who had suffered for years had experienced relief for the first time. Because this drug was highly effective in many patients, the FDA approved restricted use of alosetron in June Alosetron is now available via an FDA-approved restricted-use program in conjunction with GlaxoSmithKline as detailed at It is now indicated, in lower initial doses of 0.5 mg twice daily, for women with diarrhea-predominant symptoms of longer than 6 months duration that are not relieved by conventional therapy. Healthcare providers must use extreme caution in therapy with this drug, and must follow strict FDA-mandated guidelines. Use of Antidepressants in IBS Tricyclic antidepressants have shown some benefit in treatment of diarrhea-predominant IBS associated with moderate to severe abdominal pain, by modulating perception of visceral pain, altering GI transit time, and treating underlying comorbidities. 47,48 Selective serotonin reuptake inhibitors are less-well studied, with only one report with paroxetine showing some improvement in stool passage and well being but no decrease in abdominal pain. 49 Figure 38 3 shows a general stepwise approach to the management of both constipation and diarrhea-predominant irritable bowel syndrome. PAIN IN IBS Select patients with IBS suffer significant pain associated with their disease. Data supporting the use of antispasmodic agents in these patients are conflicting. 50,51 In these cases, a trial of low-dose antidepressant therapy is indicated, especially if pain is associated with eating. Both tricyclic antidepressants and serotonin reuptake inhibitors produce analgesia, and may relieve depressive symptoms if present. Preprandial doses of drugs containing anticholinergic properties may suppress pain (and/or diarrhea) associated with an overactive postprandial gastrocolonic response. Tricyclic antidepressants should be avoided in patients with pain and constipation. In addition, psychotherapy, including cognitive behavioral therapy, relaxation therapy, and hypnotherapy, has been shown to decrease IBS symptoms. 52 DRUG CLASSES CURRENTLY UNDER INVESTIGATION FOR THE TREATMENT OF IBS Probiotics (see Diarrhea above) such as Lactobacillus and Bifidobacterium reduced IBS symptoms in several investigation trials. 53,54 Another 5-HT 3 antagonist, cilansetron, has demonstrated similar efficacy to that of alosetron in phase II trials and enrolled enough male patients to show benefit in males as well. This drug is currently in phase III trials. In addition, other compounds being evaluated include neurokinin 1 (NK1) and neurokinin 3 (NK3) receptor antagonists, gut-selective calcium channel blockers, cholecystokinin receptor antagonists, and agents capable of stimulating motilin receptors (motilin mimetics). 55 EVALUATION OF THERAPEUTIC OUTCOMES IBS is usually classified as constipation-predominant, diarrheapredominant, or IBS with abdominal pain and bloating. Therapeutic goals in IBS should focus on the patient s primary complaint. Dietary and drug therapy goals should focus on end-organ treatment to relieve abdominal pain (antispasmodic drugs) or disturbed bowel habits (antidiarrheals and bulk-forming agents). Additionally, severe symptoms from central nervous system dysregulation should be treated with antidepressants, psychotherapy, relaxation/stress management, cognitive behavior treatment, and/or hypnosis aimed at specific affective disorders. 55 Lastly, the serotonin receptor agonists and antagonists can be used in carefully selected patients whose symptoms are not adequately controlled with other agents. The American Gastroenterology Association recommends that patients with severe IBS consider psychological treatments such as psychotherapy, relaxation/stress management, and/or cognitive behavior treatment. ABBREVIATIONS 5-HT: serotonin IBS: irritable bowel syndrome ORS: oral rehydration solution

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