Irritable Bowel Syndrome: Rational Therapy

Irritable bowel syndrome (IBS) was once considered a psychosomatic or nonaorganic condition.¹ Such early views have proved to be incorrect. IBS is clearly not just part of a somatization syndrome, and the symptoms are not imagined. Accumulating evidence indicates that there is an organic gut component to IBS, and that the disease can substantially impair the health and well-being of affected patients.^1,2

Recent research, in addition to shedding new light on the pathophysiology of IBS, has also suggested new treatments. In this article, I present the latest thinking about this common problem, and I will discuss the pros and cons of the many therapeutic options now available.

SYMPTOMS AND SIGNS
The principal symptoms of IBS are abdominal discomfort or pain, bloating, and constipation or diarrhea (which can be represented by the simple mnemonic "ABCDE" [Table 1]).¹ Stool consistency in the disease varies, and individual cases of IBS are typically classed as 1 of the following 4 types:

•IBS with constipation, in which stools are usually firm and hard (as a result of slow intestinal transit).

•IBS with diarrhea, in which stools are usually loose or watery (as a result of rapid intestinal transit).²

•Mixed IBS pattern, in which patients have both types of stool form (sometimes within as short a period as a single day).

•IBS with alternating stool pattern, in which patients have a prolonged period of constipation or diarrhea before a different stool consistency predominates.

The feelings of bloatedness that are common in patients with IBS are sometimes associated with abdominal distention. Increased abdominal girth has been identified using plethysmography.³ In some patients the distention is visible,¹ and a few may even appear pregnant. Distention typically occurs later in the day or after meals.

In addition, patients may complain of other GI symptoms, especially heartburn and nausea. However, these rarely dominate the clinical presentation unless another problem is present.¹

CAUSES
Although IBS is still not fully understood, some facts about its origins and pathophysiology have been established.^1,2 In addition, there are a number of intriguing theories for which some supporting evidence is available.

Genetic basis. IBS probably has a genetic component.⁴ The disease runs in families, and this familial clustering is not fully explained by the learning of abnormal behavior from parents or others. However, the exact genes involved remain to be identified. There is some evidence to suggest that the culprit genes may be ones that affect multiple systems, such as those that regulate the inflammatory process or serotonin reuptake; this might explain both the intestinal and extraintestinal manifestations of the disease.

Infectious origins. IBS can occur after infection.^5,6 In about 10% of patients, a clear-cut bacterial, viral, or parasitic gut infection seems to have precipitated their chronic symptoms.

Role of inflammation. Activation of the immune system is seen in some patients with IBS, which suggests an ongoing low-grade inflammatory disease process.⁷ Subtle inflammatory changes--increases in the number of mast cells in the colon and in the number of lymphocytes⁸ (Figure)--are seen in at least some patients with IBS.^1,8 The mast cells seem to localize close to nerves; this phenomenon has been correlated with the abdominal pain associated with IBS.⁹ Inflammation can affect GI motor and sensory function, both of which are known to be disturbed in IBS. Thus, disturbed gut motility, which accounts at least in part for the symptoms of constipation and diarrhea in the syndrome,¹⁰ may well be secondary to subtle inflammation.

Gut hypersensitivity to balloon distention. This has been suggested as a biologic marker for IBS. However, gut hypersensitivity to distention is relatively difficult to test in clinical practice.¹⁰ It is also uncertain whether gut hypersensitivity is a direct cause of symptoms.

Small-bowel bacterial overgrowth. Recent research has focused on the possibility that small- bowel bacterial overgrowth may be a factor in IBS.¹¹ It is hypothesized that slowed intestinal transit predisposes to increased numbers of normal bacteria, with the possibility that abnormal flora may then colonize the gut as well. Bacterial fermentation of food products may release gas that can cause distention of the bowel, bloating, and discomfort or pain in those with a hypersensitive gut. However, this hypothesis remains controversial.

In a subset of the population, the intestinal flora include methane-producing bacteria. Methane gas appears to be able to induce constipation.¹¹ Some research suggests that results of hydrogen breath testing are more likely to be abnormal in patients with IBS, but others have not been able to replicate these findings. Trials of antibiotic therapy for IBS have shown positive results, with up to one third of patients responding; however, no data from long-term trials are available.^12,13

Neurologic component. The brain plays a central role in the perception of pain.¹ The brain can heighten or diminish the sensation of pain originating in the gut or anywhere else. Positron emission tomography and MRI show that key pain signaling areas in the brain are activated more often in patients with IBS than they are in controls.¹⁴

In addition, psychological factors may amplify pain sensations. This may explain why patients with IBS are more likely than others to be anxious or depressed.¹ However, anxiety or depression in patients with IBS might be secondary to living with a chronic disease. Alternatively, intriguing data suggest that inflammation may itself induce anxiety or depression.¹⁵ Finally, it is possible that any genetic predisposition to IBS may also genetically predispose to the development of anxiety or depression.⁴ Not every patient with IBS is anxious or depressed; thus, the relationship between IBS and psychological disturbances is likely complex.

DIAGNOSIS
The diagnosis of IBS can be simply and safely made by taking a short history. IBS is not a diagnosis of exclusion.^1,2 The answers to the following questions determine whether the patient meets the Rome III criteria²:

•Is your pain or discomfort often relieved by defecation?

•When the pain or discomfort begins, do you often have either looser or harder stools?

•When the pain or discomfort begins, do you often have either more frequent or less frequent stools?

If the patient answers yes to 2 of the 3 questions above, the provisional diagnosis is IBS until proved otherwise.

In addition to evaluating for the Rome III criteria, always ask about "alarm" symptoms or signs (Table 2) that can signal the presence of an important structural disease.² If any of these are present, prompt investigation to exclude serious disease is warranted. If none are present, confidence in the diagnosis of IBS is increased and further workup is seldom needed.¹⁶

In the past, it was recommended that patients with suspected IBS be screened for a number of conditions, including thyroid disease, anemia, and structural disease of the colon. However, evidence indicates that a diagnostic test panel is no more likely to show significant abnormalities in a patient with typical symptoms of IBS than it would be if randomly administered to someone in the population at large (Table 3).¹⁷ In other words, the yield of such tests is so low that they cannot be generally recommended.

In a patient who is older than 50 years and has not had a screening colonoscopy, it is reasonable to evaluate the structure of the colon with a colonoscopy or flexible sigmoidoscopy and barium enema to exclude colon cancer. However, in younger patients in whom no alarm features are present, a structural evaluation of the colon is usually unrevealing.^16,17

If findings in the history or physical examination suggest another disease, appropriate testing is warranted. For example, celiac disease may present with IBS-like features (even constipation). Although such a presentation of celiac disease is uncommon, measurement of tissue transglutaminase antibody is helpful if you suspect this possibility.^16-18

If a patient responds well to an initial trial of treatment for IBS, testing is not needed. On the other hand, if alarm symptoms or signs are present or develop or if the patient fails to respond to standard therapies, further evaluation and consideration of referral to a gastroenterologist are indicated.

TREATMENT
Providing patients with a positive diagnosis and an explanation for their symptoms is important to the success of any treatment. Although IBS is still not fully understood, you can discuss with patients the information in the section on causes on page 82. I always emphasize to patients that, in my view, IBS is a real disease of the gut that we are just beginning to understand.

Keep in mind that there is a robust placebo response (about 40%) in patients with IBS.¹⁹ Reassurance, education, and a positive diagnosis (Table 4) probably help maximize the placebo response.⁹

Avoid unnecessary surgery. Patients with IBS often are referred to surgeons and as a result may have surgery (eg, cholecystectomy, hysterectomy) that may not address the cause of pain.²⁰ Patients may experience temporary relief after such procedures, but IBS symptoms almost invariably return.

General treatments. A number of conservative measures can help ameliorate symptoms. These include fiber therapy, other dietary interventions, and other measures to regulate bowel function.

Fiber. Fiber can help regulate bowel function.²¹ Adding fiber to the diet can be particularly helpful in patients who have IBS with constipation. A daily intake of 20 to 30 g of fiber is considered healthy; however, most Americans consume only about half of this. Supplementation with unprocessed wheat bran is often recommended, but there is no evidence that it actually helps with most IBS symptoms.²² Commercial fiber supplements may be more effective. I use a starting dosage of about 3 g/d and increase this every 1 to 2 weeks until a dosage of about 15 g/d is reached. Keep in mind that all fiber supplements may worsen gas and bloating.

Other dietary interventions. Advise patients who have IBS with diarrhea to avoid artificial sweeteners, which can cause osmotic diarrhea. Avoiding high-fat foods may also prove helpful to some patients, since these can increase gas and cause dyspepsia, as well as aggravate diarrhea.

Some patients with IBS are lactose-intolerant and may benefit from limiting their consumption of milk products. A 2-week trial of a lactose-free diet will usually reveal whether lactose has been a contributing factor in a particular patient's IBS symptoms and whether he or she will benefit from avoiding milk products.²¹ A hydrogen breath test with a substrate such as lactose can also be used to diagnose lactose intolerance. Keep in mind that most patients who are lactose-intolerant can usually drink a glass of milk or the equivalent daily without experiencing any symptoms.

Many patients with IBS report that other specific foods seem to aggravate their symptoms. In part, this may reflect their gut hypersensitivity. However, there is evidence that food-elimination diets may help some patients, particularly those with diarrhea-predominant IBS. A randomized trial investigated whether an optimal elimination diet could be constructed based on the presence of IgG antibodies to particular foods.²³ In patients treated with a true elimination diet, foods for which IgG antibodies were detected were removed, whereas in those treated with a sham diet, the only foods removed were those for which no antibodies were found. A small but significant benefit of the food-elimination diet was reported. More data are needed to test the value of this approach, however. Moreover, appropriate standardized methods of IgG testing are not available in the United States.

Regulation of bowel function. Most patients feel better when they are able to move their bowels regularly.²¹ However, reassure patients that normal bowel regularity varies from 2 movements per day to 3 per week and that a daily bowel movement is not necessary for good health. Not delaying the urge to defecate, not hurrying to have a bowel movement, and avoiding excessive straining may help some patients.

Patients who strain excessively, who feel as though there is a blockage in the anal area, or who self-digitate may have dyscoordinated evacuation. This phenomenon is characterized by contraction--rather than relaxation--of the external anal sphincter during straining (a malfunction known as pelvic floor dyssynergia or pelvic outlet obstruction); the result is obstruction of defecation.²⁴ Dyscoordinated evacuation can be identified by anorectal manometry testing; in about 75% of patients, it responds to biofeedback training.²²

Treatments for IBS with constipation. Tegaserod has been approved by the FDA for this indication.²² The usual dosage is 6 mg bid. If a patient has not responded after a month of treatment, continuing tegaserod longer seldom proves helpful. If the patient does respond, it is reasonable to prescribe a 3-month course followed by a drug holiday; however, most patients relapse while they are off therapy and require long-term treatment. Long-term therapy with tegaserod is not approved for IBS (although it is for chronic constipation).

The major adverse effects of tegaserod are diarrhea, which is usually self-limited, and headache. There have been scattered reports of ischemic colitis in patients receiving the drug. However, these incidents do not seem necessarily to be drug- related; the risk of ischemic colitis is increased in IBS regardless of drug treatment.²¹

Another medication used to treat constipation in IBS is polyethylene glycol (PEG), although it is not FDA-approved for IBS. PEG can be a useful adjunctive treatment for constipation; the dose can be titrated to response, and this approach seems safe. Another drug recently approved for chronic constipation (although not for IBS) is lubiprostone, a chloride channel activator whose usual dosage is 24 mg bid; it can induce nausea.²⁵

Treatments for IBS with diarrhea. In patients who have IBS with diarrhea, the best initial treatment for the diarrhea is loperamide.^22,23 Titrate the dose until diarrhea is controlled (this may require reasonably high doses taken regularly before diarrhea occurs). If loperamide therapy fails and the patient clearly has only IBS with diarrhea, alosetron may be tried.^25,26 Alosetron, which is FDA- approved specifically for women with diarrhea-predominant IBS,²² is superior to placebo but carries a small risk of ischemic colitis and severe constipation; ischemic colitis occurs in about 1 in 250 patients who receive the drug. Thus, when you prescribe alosetron, have the patient sign a patient-physician agreement and monitor her regularly. A tricyclic antidepressant, which can slow intestinal transit, is another option for the treatment of diarrhea in IBS.

Treatments for abdominal pain. This is often the symptom of most concern to patients. Peppermint oil may provide some relief.²¹ In patients with coexisting heartburn or dyspepsia, consider a trial of acid suppression therapy. Fiber supplements may help abdominal pain, in part by relieving constipation.

If these simple measures fail, the next step to consider is either an agent specifically for IBS (alosetron or tegaserod, depending on whether the patient has IBS with constipation or with diarrhea) or a centrally acting agent that may be helpful for pain. Both alosetron and tegaserod, although they have shown benefit in the treatment of abdominal pain, are only modestly more effective than placebo for this purpose.

To treat the pain of IBS effectively, antispasmodic medications (which are anticholinergic) probably need to be given in doses that induce dry mouth; however, most patients cannot tolerate such high doses. I do try them, but clinical trials have not provided very convincing evidence that these drugs are better than placebo for the treatment of pain in IBS.²²

Low-dose tricyclic antidepressants can be used to treat pain in IBS. Here they are not prescribed to treat depression, but as a direct treatment for IBS. There is evidence that patients who tolerate these medications and take them as prescribed can benefit.²⁷ I generally use an agent, such as desipramine or imipramine, that is least likely to induce anticholinergic side effects. I usually start at the lowest dosage (eg, 10 mg/d, taken at night) and build up slowly, in weekly 10-mg increments, to a nightly dose of 50 to 75 mg. Drugs in this class may be most useful in patients who have IBS with diarrhea, but in low doses, these agents do not usually worsen constipation significantly. If a patient has a good response, I continue treatment for 6 months and then stop the medication in the hope that a long symptom-free period will ensue before therapy is required again. Data supporting long-term use of antidepressant therapy in IBS are not available. Warn patients about the potential toxicity of tricyclic antidepressant therapy.

An alternative approach is to use a selective serotonin reuptake inhibitor (SSRI). Because SSRIs speed up intestinal transit, this class of drugs would theoretically be most useful in patients with constipation-predominant IBS. However, the evidence for efficacy of SSRIs in IBS is limited.²⁸

Treatments for bloating, belching, and flatus. If bloating is a major component of a patient's abdominal discomfort, consider treatments to reduce gas. A low-fiber diet may be helpful in this setting (because fiber aggravates gas). In addition, try to reduce any excessive air swallowing by having the patient eat more slowly and avoid chewing gum and smoking.²¹ Simethicone and charcoal are probably of little benefit.²²

There is some evidence that probiotic therapy may help reduce bloating.²⁹ The strongest evidence is for bifidobacteria.²⁹ The proposed mechanism of action for probiotics is re- placement of existing intestinal flora with the ingested "good" bacteria. Another option is to give a short course of a nonabsorbable antibiotic such as rifaximin. However, the long-term benefit of this type of drug is unclear, and it is difficult to recommend antibiotics in the absence of better data.

For patients in whom belching is a concern, recommend that they try to reduce air swallowing by the means outlined above. Some patients with repeated belching have a nervous habit of swallowing air excessively (aerophagia). Training in diaphragmatic breathing can be helpful for such patients.³⁰

If the patient has excessive flatus, consider recommending a diet that avoids flatus-producing foods, such as meat, fowl, fish, and eggs.²¹ Products that contain chlorophyll or a charcoal cushion can reduce the odor from flatus if this is a major problem.²¹

Other treatment options. Anxiolytics are probably of only limited benefit in IBS and can be habituating. Thus, long-term use of agents in this class is not recommended in patients with IBS.²²

Melatonin, 3 mg/d, taken at bedtime for 2 weeks seemed to be of some benefit in patients with IBS; the apparent mechanism of action was not improvement of sleep.³¹ However, more data on melatonin are needed.

The role of alternative therapies in IBS is generally unclear. Some herbal products may be effective, as was shown in one trial of Chinese herbal medicine.³² Relaxation therapy--including progressive relaxation, massage, and yoga--might help, but data are lacking.²¹

Psychological treatments, including hypnotherapy, cognitive behavioral therapy, and psychotherapy, do seem to be of benefit to patients with IBS, but mostly improve general well-being.^27,33,34 Unfortunately, the availability of such therapies specifically targeting IBS is limited.

CREATING A MANAGEMENT PLAN
Good management plans for IBS have clear and realistic goals to which both the patient and clinician are committed. Such agreed-on goals might include symptom reduction (but not elimination) and improved well-being. Some patients need little besides good dietary advice and general health tips (see Table 4). Because no drug is disease-modifying, use medications judiciously to treat symptom exacerbations.

Some patients may want to seek more information on the Internet. Both good and very bad information on IBS can be found on the World Wide Web. For those who wish to avail themselves of this resource, I explain the difference between testimonials and evidence and I strongly encourage them to discuss their search with me.

Patient self-help groups such as the International Foundation for Functional Gastrointestinal Disorders (IFFGD) (www.IFFGD.org) are a great resource. Some excellent books are also available. The Functional Gastrointestinal Disorders (third edition), by the Rome Committees, is one example, even though it is aimed more at caregivers than patients (can be ordered at www.romecriteria.org). Conquering Irritable Bowel Syndrome, by this author, is written for patients and is available from the IFFGD.²¹

References:

REFERENCES:1. Talley N, Spiller RC. Irritable bowel syndrome: A little understood organic bowel disease? Lancet. 2002;360:555-564.
2. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006; 130:1480-1491.
3. Houghton LA, Whorwell PJ. Towards a better understanding of abdominal bloating and distension in functional gastrointestinal disorders. Neurogastroenterol Motil. 2005;17:500-511.
4. Saito YA, Petersen GM, Locke GRI, Talley NJ. The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:1057-1065.
5. Cremonini F, Talley NJ. Irritable bowel syndrome: epidemiology, natural history, health-care seeking and emerging risk factors. Gastroenterol Clin North Am. 2005;34:189-204.
6. Okhuysen PC, Jiang ZD, Carlin L, et al. Post- diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol. 2004;99:1774-1778.
7. Quigley EM. Germs, gas and the gut; the evolving role of the enteric flora in IBS. Am J Gastroenterol. 2006;101:334-335.
8. Tornblom H, Abrahamsson H, Barbara G, et al. Inflammation as a cause of functional bowel disorders. Scand J Gastroenterol. 2005;40:1140-1148.
9. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693-702.
10. Camilleri M, Talley NJ. Pathophysiology as a basis for understanding symptom complexes and therapeutic targets. Neurogastroenterol Motil. 2004; 16:135-142.
11. Lee HR, Pimentel M. Bacteria and irritable bowel syndrome: the evidence for small intestinal bacterial overgrowth. Curr Gastroenterol Rep. 2006; 8:305-311.
12. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412-419.
13. Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome. Ann Intern Med. 2006;145:557-563.
14. Naliboff BD, Berman S, Suyenobu B, et al. Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients. Gastroenterology. 2006;131:352-365.
15. Elenkov IJ, Iezzoni DG, Daly A, et al. Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation. 2005;12:255-269.
16. Talley NJ. When to conduct testing in patients with suspected irritable bowel syndrome. Rev Gastroenterol Disord. 2003;3(suppl 3):S18-S24.
17. Cash BD, Chey WD. Irritable bowel syndrome--an evidence-based approach to diagnosis. Aliment Pharmacol Ther. 2004;19:1235-1245.
18. Locke GR 3rd, Murray JA, Zinsmeister AR, et al. Celiac disease serology in irritable bowel syndrome and dyspepsia: a population-based case-control study. Mayo Clin Proc. 2004;79:476-482.
19. Tack J, Fried M, Houghton LA, et al. Systematic review: the efficacy of treatments for irritable bowel syndrome--a European perspective. Aliment Pharmacol Ther. 2006;24:183-205.
20. Talley NJ. Unnecessary abdominal and back surgery in irritable bowel syndrome: time to stem the flood now? Gastroenterology. 2004;126:1899-1903.
21. Talley NJ. Conquering Irritable Bowel Syndrome. Lewiston, NY: BC Decker Inc; 2005.
22. Brandt L, Bjorkman D, Fennerty M, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97(suppl 11):S7-S26.
23. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004;53:1459-1464.
24.Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only patients with outlet dysfunction, not patients with isolated slow transit constipation. Gastroenterology. 2005;129:86-97.
25. Chang HY, Kelly EC, Lembo AJ. Current gut--directed therapies for irritable bowel syndrome. Curr Treat OptionsGastroenterol. 2006;9:314-323.
26. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol. 2006;101:1069-1079.
27. Drossman D, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003; 125:19-31.
28. Tack J, Broekaert D, Fischler B, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006;55:1095-1103.
29. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:1581-1590.
30. Chitkara DK, Bredenoord AJ, Talley NJ, Whitehead WE. Aerophagia and rumination: recognition and therapy. Curr Treat Options Gastroenterol. 2006; 9:305-313.
31. Song GH, Leng PH, Gwee KA, et al. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. 2005;54: 1402-1407.
32. Bensoussan A, Talley NJ, Hing M, et al. Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized contolled trial. JAMA. 1998;280:1585-1589.
33. Creed F, Guthrie E, Ratcliffe J, et al. Does psychological treatment help only those patients with severe irritable bowel syndrome who also have a concurrent psychiatric disorder? Aust N Z J Psychiatry. 2005;39:807-815.
34. Gonsalkorale WM, Whorwell PJ. Hypnotherapy in the treatment of irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2005;17:15-20.
35. Talley NJ, Martin CJ, eds. Clinical Gastroenterology. Sydney, Australia: Maclennan & Petty; 2005.
36. Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review. Am J Gastroenterol. 2002; 97:2812-2819.