ABSTRACT: First steps in the treatment of irritable bowel syndrome (IBS) are dietary modification, smoking cessation, and other lifestyle changes. Treatment of mild symptoms includes increased soluble dietary fiber and osmotic laxatives for constipation, antispasmodics for cramping, and over-the-counter antidiarrheals. For moderate disease, serotonergic agents work primarily in the intestine to relieve the global symptoms of IBS. Alosetron decreases gut motility and visceral sensitivity in women with chronic, severe diarrhea-predominant IBS who have not responded to conventional therapies. Tegaserod relieves pain, bloating, and constipation in women with constipation-predominant IBS. Psychotherapy, hypnotherapy, biofeedback, and other nonpharmacologic modalities may also be helpful for patients with IBS. Antidepressants are reserved for refractory symptoms; they can be combined with other modalities if needed.
Irritable bowel syndrome (IBS) is characterized by abdominal pain or discomfort associated with abnormal bowel habits (diarrhea, constipation, or alternation between the two), and related symptoms such as bloating, straining, feelings of incomplete evacuation, and urgency.There is no consensus treatment algorithm for IBS; however, clinical experience, trial results, and recommendations from major gastroenterology organizations can be used to create a treatment plan.
Guidelines and recommendations for treating patients with IBS have been published by the American Gastroenterology Association1,2 and the American College of Gastroenterology (ACG).3,4 During the development of its position statement, the ACG Functional Gastrointestinal Disorders Task Force reviewed the literature on IBS treatment options available in the United States.4 The group's recommendations are summarized in Table 1.
One of the major difficulties in developing a management strategy for patients with IBS is the diverse and unpredictable nature of the symptoms. However, most patients in primary care practices have mild to moderate disease and respond to a combination of lifestyle and pharmacologic therapeutic interventions. In a previous article (CONSULTANT, November 2004, page 1661), I addressed the diagnosis of IBS. In this article, I review a wide range of therapeutic options.
AN APPROACH TO TREATMENT
A general strategy is outlined in the Algorithm. Make a positive diagnosis, based on validated symptom criteria, and explain it clearly and simply. IBS may be described as a chemical imbalance in the intestine that causes abnormal movements and spasms. Reassure patients that although the cause of IBS is not known, it is not life-threatening and that their symptoms are likely to improve with therapy. If triggers (such as gastroenteritis) have been identified, explain how they cause IBS.
It is not possible to educate the patient about every aspect of IBS in the first visit. Schedule visits every 3 weeks until he or she is functioning better. Stress the need to work together toward improved health and, if appropriate, suggest consultation with a physical therapist, nutritionist, or psychiatrist. Recommend that patients record symptoms, aggravating factors, and emotional impact in a diary for 2 to 3 weeks. This can be reviewed at the next visit to help guide diet, lifestyle, and behavioral modifications. End every visit with 2 or 3 written instructions. Tell patients to bring any questions to the next visit.
Smoking cessation. Lifestyle habits that promote overall good health ameliorate the symptoms of IBS. The single most important health intervention is to encourage smokers to quit. Smoking may cause abdominal pain, cramping, and diarrhea. Young women smokers who take oral contraceptives are at risk for blood clots. All smokers run the risk of cardiovascular disease and cancer.
Lifestyle enhancements. A diet that emphasizes soluble fiber and foods low in fat is recommended for patients with IBS. Dietary tips are listed in Table 2. Advise patients to avoid fast food and other fatty foods, carbonated beverages and beverages containing sorbitol or fructose, and junk food. Patients who are flatulent after eating raw vegetables such as broccoli or cabbage should consume vegetable soup instead. Foods containing crude fiber, such as bran, bell peppers, and eggplant skin, are best avoided because they increase cramping and flatulence. Foods high in soluble fiber-including peas, carrots, yams, mango, kiwi, and papaya-are usually well tolerated.
Encourage patients to sleep at least 7 to 8 hours a night. Exercise enhances feelings of well-being in most persons; however, the benefit of increased exercise in IBS is unclear.
FIBER AND BULKING AGENTS
Increased fiber intake is often recommended for patients with constipation-predominant IBS. Although fiber increases stool weight, improves stool consistency, and accelerates stool transit, it does not provide global relief of IBS symptoms.4 Soluble fiber (such as that found in oatmeal and berries) is better tolerated than crude fiber. In one small study, a synthetic fiber, calcium polycarbophil, relieved nausea, pain, bloating, and other symptoms better than placebo.5 Patients can chew one 625-mg tablet once or twice a day. Some patients also tolerate methylcellulose (1 teaspoon at night, increased as needed), although controlled studies in patients with IBS are lacking. Most persons absorb only 80% of the gluten they consume; wheat-based fiber supplements are rarely recommended for patients with IBS because of the risk of flatulence, bloating, and discomfort.
These agents are often used first if reassurance and nonspecific therapies fail to provide relief. Although these medications are generally safe and inexpensive, clinical trial data that support their use in patients with IBS are limited, and few antispasmodics are approved for such use. Antimuscarinics, smooth muscle relaxants, and calcium channel antagonists are all used as antispasmodics; the most commonly prescribed are dicyclomine and hyoscyamine. The combination of chlor- diazepoxide and clidinium is best avoided because it is addictive, and its efficacy has not been demonstrated for IBS. Hyoscyamine is effective for pain.6
The oral disintegrating formulation of hyoscyamine sulfate, 0.125 mg (1 tablet lingually 2 to 4 times a day as needed), is effective and well tolerated in patients with moderate symptoms. It is most effective when used as needed for pain or spasm or, for patients with diarrhea-predominant IBS, when taken about 15 minutes before a meal. Because of anticholinergic side effects (which are generally associated only with higher doses), these drugs should be used with caution in elderly persons.
Loperamide, an opioid that does not affect the CNS, slows transit time through the colon and increases intestinal water resorption; however, it does not affect pain. The usual dosage of oral loperamide is 2 mg 4 times a day as needed. A combination of diphenoxylate and atropine can also be used (2.5 mg, 2 to 4 times a day as needed). This combination, taken 1 hour before a meal or social event, can significantly improve the symptoms of postprandial diarrhea. Be sure to rule out GI infection before prescribing an agent that blocks GI motility. The safety of the long-term use of loperamide and diphenoxylate-atropine is unknown, and there is no evidence to indicate that these agents address any IBS symptom other than diarrhea.
Cholestyramine, a bile-acid binder, may be effective for bile-salt diarrhea, a condition that sometimes occurs following cholecystectomy. It is not recommended as a general antidiarrheal. If a patient presents with diarrhea of new onset weeks or even months after a cholecystectomy, check for hospital-acquired Clostridium difficile and then start cholestyramine tablets (1 g before meals) and increase as needed. Some patients prefer cholestyramine powder (1 packet bid before meals, increased as needed). Patients with moderate diarrhea-predominant IBS may also be treated with anticholinergics, such as scopolamine.
Osmotic laxatives-such as magnesium-are often recommended when dietary and lifestyle changes fail. These agents are poorly absorbed and increase the movement of fluid into the intestines. Magnesium preparations increase bowel movement frequency and ease of stool passage and improve stool consistency. I avoid laxatives such as lactulose or sorbitol, because these often cause bloating and discomfort. Because all patients need calcium, the osmotic laxative I recommend is a calcium-magnesium-zinc formulation taken 3 times a day with meals.
Stimulant laxatives, such as henna, promote intestinal motility and secretion. However, although many of these preparations are available over the counter, they have been associated with electrolyte and volume overload in patients with renal insufficiency or cardiac dysfunction and may cause dependence and/or severe cramping and pain. Long-term daily use of stimulant laxatives can result in severe diarrhea that may subsequently cause hyponatremia, hypokalemia, and dehydration. To end long-term use, instruct patients to taper the dosage and substitute osmotic laxatives (eg, magnesium) and/or tegaserod.
A major advance in the treatment of IBS has been the development of serotonergic drugs that work primarily in the intestine. Unlike traditional therapies, these agents relieve the global symptoms of IBS.
Recent evidence indicates that serotonin plays a major role in regulating gut function, including motility, intestinal secretion, and visceral sensitivity.7-12 More than 95% of the serotonin in the body is located in the intestine; only 3% is found in the CNS.13 As many as 14 serotonin receptor subtypes have been identified.10 Of these, the 5-HT1p, 5-HT3, and 5-HT4 subtypes are considered the most clinically relevant for motor, sensory, and secretory functions of the gut and in the pathophysiology of IBS.9,10,14,15
Alosetron, an antagonist at the 5-HT3 receptor, decreases gut motility and visceral hypersensitivity.16-18 It is indicated for chronic, severe diarrhea-predominant IBS in otherwise healthy women aged 20 to 65 years who have not responded to conventional therapies.19,20
Alosetron was voluntarily withdrawn from the market in 2000 because of reported complications of constipation, ischemic colitis (in 1 of 700 patients), and mesenteric ischemia (Box), although many of these reports were not well documented. The withdrawal of alosetron was met with an outcry from patients who were significantly helped by the drug. After a year of planning, the FDA and the drug's manufacturer created a unique risk management program for prescribing alosetron, and the agent was reapproved in 2002 with new prescribing information. Under these guidelines, patients must sign a consent form and the prescribing physician must sign a certificate. I recommend a starting dosage of 0.5 mg qd. The dosage can be increased gradually to 1 mg bid if needed. If a patient does not respond after 4 weeks of dose escalation, the drug should be discontinued.
I instruct patients to take alosetron before breakfast and not to take it again until their next bowel movement, which may not be for a day or two.Alosetron may take from 1 to 4 weeks to relieve pain, but the antidiarrheal effects are usually seen in the first week of treatment-sometimes even with the first dose. Because the primary side effect of alosetron is constipation, instruct patients to drink plenty of water and to discontinue the medication and notify your office if they have worsening abdominal pain, bleeding, or fever. Alosetron is not recommended in patients with unstable angina or coronary artery disease. It is also not recommended in smokers who use oral contraceptives or hormone therapy because of the increased risk of blood clots and pulmonary emboli.
Alosetron remains one of the best studied and most effective treatments of diarrhea-predominant IBS. It can change the lives of patients "trapped in their homes" by this condition. If the dosage and the patient's bowel functions are carefully monitored, complications can be avoided.
Tegaserod, a partial serotonin-4 agonist at the 5-HT4 receptor, is a prokinetic agent that increases motility and intestinal secretions and inhibits visceral sensitivity.21-23 It is indicated for the short-term treatment of women with constipation-predominant IBS and for adults younger than 65 years with chronic idiopathic constipation.
Results of several well-designed, randomized controlled clinical trials indicate that tegaserod effectively relieves abdominal pain, bloating, and constipation.24-27 It may help patients with dyspepsia and chronic constipation as well.28-32 Tegaserod was well tolerated in both short- and long-term clinical trials, and is not associated with cardiac events.24-27,33-35 The recommended dosage is 6 mg bid for 4 to 6 weeks. An additional 4 to 6 weeks of treatment may be considered for patients who respond to treatment. The drug also is available in a 2-mg strength.
Tegaserod is contraindicated in the presence of severe renal impairment, moderate or severe hepatic impairment, history of bowel obstruction, symptomatic abdominal adhesions, gallbladder disease, or suspected Oddi sphincter dysfunction. There are no known drug interactions, and tegaserod can be used with antidepressants, digoxin, warfarin, and oral contraceptives. Tegaserod does not cross the blood-brain barrier and does not cause weight gain, sexual dysfunction, or fatigue.
Diarrhea, which is transient and usually occurs in the first week of treatment, was the most common side effect of tegaserod in clinical trials. To avoid this effect, treatment can be initiated with the 2-mg dose or half a 6-mg tablet bid. Tegaserod can be broken or crushed and is stable in apple juice.36 The medication works best when taken 15 to 20 minutes before meals. Tegaserod has a pregnancy category B rating.
Although there were no cases of ischemic colitis among tegaserod recipients in the clinical trials (3500 patient-years), a recent package insert update includes a precaution that discusses reported post-marketing cases of ischemic colitis (7 cases per 100,000 patient-years). However, no causal link between tegaserod and ischemic colitis has been established. A warning has also been added to the tegaserod prescribing information because of reports of serious consequences of diarrhea (0.04%; 4 cases per 10,000) in patients in randomized clinical trials; these included hypovolemia, hypotension, and syncope.
BEHAVIORAL AND ALTERNATIVE THERAPIES
Although it is important to recognize the role of psychosocial factors in the pathogenesis of IBS, these factors have no role in the diagnosis of IBS. Patients experiencing trauma or emotional stress may benefit from psychotherapy. Some patients with long-standing illness benefit from cognitive therapy; this includes patients who have IBS as a result of abuse or severe psychosocial problems. These patients may be challenging to treat. I recommend a team approach that involves a psychiatrist, physical therapist, and perhaps a nutritionist. Let the patient know that these team members are working together to optimize his treatment. Arrange a follow-up visit with the patient after his consultations.
For patients who have IBS with pelvic floor dysergia or a myofascial pain component, physical therapy can be very helpful. I write a prescription for physical therapy for "myofascial release" or "pelvic floor dysfunction." Other patients benefit from cognitive therapy and psychiatric counseling, particularly in combination with pharmacotherapy.37,38 In certain patients, alternative treatments such as yoga, acupuncture, and hypnotherapy are helpful, although specific criteria for patient selection and treatment plans are not well defined.39-42
The ACG Task Force recommends that antidepressants be reserved for patients with refractory symptoms.4 Antidepressants have not been approved for IBS symptoms. Low-dose tricyclic antidepressants (TCAs) are sometimes used for severe diarrhea-predominant IBS because they are constipating and can relieve anxiety and pain.43,44 However, they do not alleviate the global symptoms of IBS, and are limited by almost ubiquitous side effects of fatigue, weight gain, and sexual dysfunction, as well as anticholinergic side effects, which result in constipation, dry mouth, blurred vision, and urinary retention. TCAs are the agents most commonly used in drug overdoses in the United States. Furthermore, TCAs prolong the QT interval and may cause cardiac arrhythmias,45 although this effect is rarely seen at low doses. Occasionally, I prescribe desipramine, 10 to 25 mg qhs, for an agitated IBS patient with diarrhea.
Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been used for patients with IBS who have a concomitant mood disorder. However, there is no conclusive evidence that SSRIs are effective for IBS.46 Side effects of the SSRIs include sedation, sexual dysfunction, diarrhea, and weight gain. In my experience, citalopram, 10 to 20 mg qhs, is effective for patients who have IBS with pain and bloating, who suffer from insomnia, and who need to gain weight. The increased serotonin sometimes causes diarrhea, which is an appreciated "side effect" in constipated patients. I occasionally prescribe citalopram with a regimen of exercise, physical therapy, and possibly tegaserod for patients with refractory pain and bloating.
Bupropion, 150 mg once or twice a day, may be prescribed for patients with IBS who smoke. It is taken with a snack around 10 AM. The second dose, if needed, may be taken in the early afternoon. Bupropion may enhance a sense of well-being, promote weight loss, and increase libido. Dizziness and seizures have been reported.
Novel compounds are being developed for IBS. The next FDA-approved treatment of diarrhea-predominant IBS may be cilansetron, a partial 5-HT3 receptor antagonist that will be indicated for men and women.47-50Renzapride, a 5-HT3 receptor antagonist/5-HT4 receptor agonist is being evaluated for use in constipation-dominant IBS.51-54 R-tofisopam is a non-sedating, non-addicting benzodiazepine under investigation for diarrhea-predominant IBS.55 Talnetant is an NK3 receptor antagonist in phase 2 trials for diarrhea-predominant IBS.56 Preclinical data have been reported for MD 1100 (Microbia), an orally available guanylate cyclase C agonist under investigation as a potential treatment of IBS.57
The role of probiotics in the treatment of IBS remains to be delineated.58-61Saccharomyces boulardii is a nonpathogenic yeast that is helpful in antibiotic-associated diarrhea-predominant IBS.62 VSL#3, a combination of 8 strains of beneficial bacteria-including 4 strains of lactobacilli, 3 strains of bifidibacteria, and 1 strain of Streptococcusthermophilus-relieves bloating in patients with diarrhea-predominant IBS.63 Probactrix is a patented strain of Escherichia coli in a liquid suspension that helps restore the microbial balance in the digestive tract.64 It is currently used in Israel for gas and bloating and is under investigation in the United States and Canada. n
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