Volume 344:1846-1850

June 14, 2001

Number 24

The Irritable Bowel Syndrome

Brenda J. Horwitz, M.D. and Robert S. Fisher, M.D. In 1849, Cumming¹ said of the irritable bowel syndrome, "The bowels are at one time constipated, another lax, in the same person. How the disease has two such different symptoms I do not profess to explain." Over the years, the unexplained gastrointestinal symptoms of the irritable bowel syndrome have been described in various terms, including mucous colitis, spastic colitis, nervous colon, and irritable colon. The irritable bowel syndrome and nonulcer dyspepsia are the most common functional gastrointestinal disorders.

The irritable bowel syndrome is defined on the basis of the recently modified Rome criteria as the presence for at least 12 weeks (not necessarily consecutive) in the preceding 12 months of abdominal discomfort or pain that cannot be explained by structural or biochemical abnormalities and that has at least two of the following three features: pain is relieved with defecation, its onset is associated with a change in the frequency of bowel movements (diarrhea or constipation), or its onset is associated with a change in the form of the stool (loose, watery, or pellet-like).² The syndrome can be divided into four subcategories according to whether the predominant symptom is abdominal pain, diarrhea, constipation, or constipation alternating with diarrhea.

Epidemiologic Features

Approximately 15 percent of U.S. adults report symptoms that are consistent with the diagnosis of the irritable bowel syndrome³; the disease affects three times as many women as men. Whether this difference reflects a true predominance of the disorder among women or merely the fact that women are more likely to seek medical care has not been determined. The irritable bowel syndrome is the most common diagnosis made by gastroenterologists in the United States⁴ and accounts for 12 percent of visits to primary care providers.⁵ It is estimated that only 25 percent of persons with this condition seek medical care for it, and studies suggest that those who seek care are more likely to have behavioral and psychiatric problems than are those who do not seek care.⁶ In addition, patients with a diagnosis of the irritable bowel syndrome are at increased risk for other, nongastrointestinal functional disorders such as fibromyalgia and interstitial cystitis.^7,8 The irritable bowel syndrome accounts for an estimated $8 billion in direct medical costs and $25 billion in indirect costs annually in the United States.⁹

Pathophysiologic Features

Altered bowel motility, visceral hypersensitivity, psychosocial factors, an imbalance in neurotransmitters, and infection have all been proposed as playing a part in the development of the irritable bowel syndrome (Figure 1).

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Figure 1. Pathophysiologic Factors in the Development of the Irritable Bowel Syndrome. The double-headed arrows indicate an interaction.

Altered Bowel Motility

Over the past 50 years, alterations in the contractility of the colon and small bowel have been described in patients with the irritable bowel syndrome. Psychological or physical stress¹⁰ and ingestion of food¹¹ may alter the contractility of the colon. Abnormal motility of the small intestine during fasting, such as loss of the migrating motor complex¹² and the presence of both discrete, clustered contractions and prolonged, propagated contractions,¹³ has been described in patients with the irritable bowel syndrome. In addition, an exaggerated contractile response to a high-fat meal has been reported.¹³ Pain is more frequently associated with irregular motor activity of the small intestine in patients with this syndrome than in normal controls or patients with inflammatory bowel disease.¹²

Visceral Hypersensitivity

Balloon-distention studies of the rectosigmoid¹⁴ and the ileum¹⁵ have shown that patients with the irritable bowel syndrome experience pain and bloating at balloon volumes and pressures that are significantly lower than those that induce pain in control subjects, a phenomenon referred to as visceral hypersensitivity. One possible explanation is that the sensitivity of receptors in the viscus is altered through the recruitment of silent nociceptors in response to ischemia, distention, intraluminal contents, infection, or psychiatric factors.

There may be increased excitability of the neurons in the dorsal horn of the spinal cord, an area rich in neurotransmitters such as catecholamines and serotonin. Centrally, there may be differences in the way the brain modulates afferent signals from the dorsal-horn neurons through the ascending pathways. Functional magnetic resonance imaging^16,17 and positron-emission tomography^18,19 of the brain show different levels of activation in the thalamus and the anterior cingulate cortex after balloon distention of the rectum in patients with the irritable bowel syndrome, as compared with normal subjects.

These findings, although controversial, suggest a primary central defect of visceral pain processing. Some authors have suggested that hypervigilance rather than true visceral hypersensitivity may be responsible for the low pain threshold in patients with the irritable bowel syndrome.

Psychosocial Factors

Psychological stress can alter motor function in the small bowel¹¹ and colon,²⁰ both in normal subjects and in patients with the irritable bowel syndrome. Up to 60 percent of patients seen at referral centers have psychiatric symptoms such as somatization, depression, and anxiety, and patients with a diagnosis of the irritable bowel syndrome are more likely to have these symptoms than are persons who have never sought medical care for bowel problems.^21,22 When present, psychiatric disturbances influence overall use of health care services and the ability to cope with symptoms. The presence or absence of a history of abuse in childhood (sexual, physical, or both) is correlated with the severity of symptoms in patients with the irritable bowel syndrome.²³ It has even been proposed that experiences early in life may affect the central nervous system and confer a predisposition to a state of hypervigilance.

Neurotransmitter Imbalance

Recent studies have suggested that neurotransmitters are involved in the pathogenesis of the irritable bowel syndrome. Five percent of serotonin is located in the central nervous system, and the remaining 95 percent is in the gastrointestinal tract, within enterochromaffin cells, neurons, mast cells, and smooth-muscle cells. When released by enterochromaffin cells, serotonin stimulates extrinsic vagal afferent nerve fibers and intrinsic enteric afferent nerve fibers, resulting in such physiological responses as intestinal secretion and the peristaltic reflex and in such symptoms as nausea, vomiting, abdominal pain, and bloating.²⁴ Preliminary evidence suggests that patients with the irritable bowel syndrome have increased serotonin levels in plasma and in the rectosigmoid colon.^25,26

Other neurotransmitters that may have an important role in functional gastrointestinal disorders include calcitonin gene–related peptide, acetylcholine, substance P, pituitary adenylate cyclase–activating polypeptide, nitric oxide, and vasoactive intestinal peptide. These neurotransmitters may provide links not only between bowel contractility and visceral sensitivity, but also between the enteric and central nervous systems.

Infection and Inflammation

There is compelling evidence that inflammation of the enteric mucosa or neural plexuses initiates or contributes to symptoms associated with irritable bowel syndrome.^27,28,29 Mucosal inflammatory cytokines may activate peripheral sensitization or hypermotility. Gwee et al. reported that in patients with infectious enteritis, the presence of hypochondriasis and stressful life events at the time of the acute infection predicted the subsequent development of the irritable bowel syndrome.³⁰ To date, no single conceptual model can explain all cases of the syndrome.

Diagnosis

After a complete history has been obtained, all patients with lower gastrointestinal tract symptoms should undergo a complete physical examination and laboratory testing, including a complete blood count, blood-chemistry tests, liver-function tests, and measurement of thyrotropin. The diagnosis of the irritable bowel syndrome is suggested when a patient's symptoms meet the Rome criteria. In the majority of cases, there are no abnormalities on physical examination or laboratory testing and there are no findings suggestive of a structural disorder — so-called alarm symptoms. Therefore, the irritable bowel syndrome can be reasonably diagnosed on the basis of flexible sigmoidoscopy alone, in patients who are less than 50 years old, or colonoscopy, in those who are 50 or older; barium enema and flexible sigmoidoscopy are often substituted for colonoscopy. In patients with diarrhea, a biopsy specimen should be obtained from the mucosa of the descending colon to rule out microscopic colitis.

If there are abnormalities on physical examination or laboratory testing or if an alarm symptom is present, the irritable bowel syndrome is a diagnosis of exclusion after reasonable diagnostic testing has been performed, such as colonoscopy, computed tomographic scanning of the abdomen and pelvis, and radiographic evaluation of the small intestine. Alarm symptoms include evidence of gastrointestinal bleeding such as occult blood in the stool, rectal bleeding, or anemia; anorexia or weight loss; fever; persistent diarrhea causing dehydration; severe constipation or fecal impaction; a family history of gastrointestinal cancer, inflammatory bowel disease, or celiac sprue; and the onset of symptoms at the age of at least 50 years. In 1985, the American College of Physicians recommended the use of alarm symptoms to guide treatment³¹; however, the validity of this approach has never been established in rigorous, randomized, prospective clinical studies.

A number of structural or metabolic disorders that are responsive to specific treatment cause symptoms similar to those of the irritable bowel syndrome. Lactase deficiency is a common culprit. Other such disorders include cancer of the colon, diverticulitis, mechanical obstruction of the colon or small intestine, inflammatory bowel disease, enteric infection, ischemia, maldigestion or malabsorption, and endometriosis (suggested by the presence of pelvic pain at the time of the menstrual period). In the absence of alarm symptoms, the presence of one of these structural or metabolic disorders is very unlikely.

Treatment

Whether the irritable bowel syndrome is diagnosed on the basis of the history, physical examination, and laboratory tests or after extensive testing (because of the presence of an alarm symptom), the establishment of trust in the physician–patient relationship should be given a high priority in order to maximize the efficacy of treatment and minimize "doctor shopping." A diary of food intake and symptoms can be useful in identifying foods that may be associated with symptoms of the irritable bowel syndrome. Patients often report an exacerbation of symptoms after the consumption of certain foods. Some patients benefit from avoiding or limiting their intake of caffeine, alcohol, fatty foods, gas-producing vegetables, or products containing sorbitol, such as sugarless gum and dietetic candy. The avoidance of constipating foods and the addition of 20 to 30 g of fiber per day either in the diet or in the form of supplements such as bran, polycarbophil, or a psyllium derivative may help relieve constipation^32,33,34,35 and may occasionally improve diarrhea.

A rational approach to treating the irritable bowel syndrome uses the patient's symptoms as a guide (Table 1). For patients in whom the disorder is manifested predominantly as abdominal pain, a variety of medications have been used, and several new agents are under development. Antispasmodic agents may reduce abdominal pain or bloating through anticholinergic pathways; in refractory cases, nitrates are occasionally useful for direct relaxation of smooth muscles. A recent meta-analysis suggested the effectiveness of antispasmodic agents and tricyclic compounds in treating selected patients with the irritable bowel syndrome.³⁶ Unfortunately, many of these agents are not available in the United States, and large-scale, stand-alone studies have not been performed. Small studies have shown that tricyclic compounds in low doses relieve unexplained abdominal pain.³⁷ Side effects — sedation, dry mouth and eyes, and weight gain — limit the use of primary tricyclic amines. Secondary tricyclic amines such as nortriptyline and desipramine may be less likely to have side effects.³⁸

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Table 1. Symptom-Guided Treatment of the Irritable Bowel Syndrome.

Despite speculation that 5-hydroxytryptamine (5-HT), or serotonin, receptors may be involved in the pathogenesis of the irritable bowel syndrome, the results of treatment with selective serotonin-reuptake inhibitors have been disappointing. Nevertheless, serotonin has been implicated in the modulation of visceral nociception, especially through the 5-HT₃ and 5-HT₄ pathways. Two new agents — alosetron, a 5-HT₃–receptor antagonist, and tegaserod, a 5-HT₄ agonist — have been shown to diminish visceral sensitivity to rectal distention in women who have diarrhea as the predominant symptom of the irritable bowel syndrome and in those who have constipation as the predominant symptom, respectively.^39,40 Fedotozine, a kappa-opioid agonist,⁴¹ has shown promise as a visceral antinociceptive agent, and other kappa-opioid agonists are being developed. Finally, in some patients who have abdominal pain that is refractory to all these therapeutic agents, treatment with classic analgesics such as nonsteroidal antiinflammatory agents (perhaps with an initial trial of a cyclooxygenase-2 inhibitor) or, in extreme cases, opioid analogues may control the pain and improve the quality of life. The addictive potential of opioid analogues makes them the last choice for long-term therapy.

For patients in whom diarrhea is the predominant manifestation of the irritable bowel syndrome, classic antidiarrheal agents such as loperamide⁴² and diphenoxylate may help decrease the frequency of bowel movements and improve the consistency of stool. In a study of women with this form of the irritable bowel syndrome, alosetron prolonged colonic transit, reduced the frequency of bowel movements and the urge to defecate, improved the consistency of stool, and decreased abdominal pain.⁴³ However, this drug has been removed from the market because of side effects such as severe constipation, ischemic colitis, and bowel perforation. In cases of diarrhea that cannot be controlled, cholestyramine has been used to bind bile acids that may be responsible for increased secretion and decreased absorption of water in the colon.⁴⁴ In some refractory cases, a short course of antibiotics may reduce the diarrhea, presumably by altering the intestinal flora.⁴⁵

For patients in whom constipation is the predominant manifestation of the irritable bowel syndrome, consumption of fiber may alleviate constipation and related symptoms such as abdominal pain, tenesmus, and dyschezia.³² Constipation can also be safely treated with osmotic laxatives such as nonabsorbable carbohydrates (lactulose and sorbitol), milk of magnesia or magnesium citrate, or a polyethylene glycol solution. Two new classes of compounds, aminoguanidine indoles such as tegaserod and benzofurans such as prucalopride, act specifically on 5-HT₄ receptors. These agents shorten the transit time in the colon and small intestine, increase the frequency of bowel movements, and increase the softness of stools.^46,47,48,49 Studies of prucalopride have been suspended because of concern about tumorigenic effects in animals. Derivatives of anthraquinones (senna and cascara), which act as strong laxatives, may be used as a last resort, but their use is limited by the frequent development of tachyphylaxis. The question of whether anthraquinones and their derivatives damage the enteric nervous system has not been resolved.

Although many pharmacologic agents have been used to treat the irritable bowel syndrome, few have been tested in controlled, double-blind studies with adequate statistical power. The doses of some commonly used agents are shown in Table 2.

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Table 2. Dosage Guidelines for Drugs Commonly Used to Treat the Irritable Bowel Syndrome.

The interaction between psychosocial factors and the genesis of all forms of the irritable bowel syndrome is poorly understood. The most provocative observations in this respect are that persons with the syndrome who seek care are those in whom the syndrome is accompanied by a psychiatric disorder and that the syndrome may develop in patients who have both infectious gastroenteritis and a psychiatric disorder. The potential benefits of supportive therapy, relaxation exercises, hypnosis, cognitive behavioral therapy, and psychodynamic interpersonal psychotherapy are well recognized.⁵⁰

The irritable bowel syndrome is a common disorder that has a pronounced effect on the quality of life and that accounts for a large proportion of health care costs. Common pitfalls in diagnosing and treating this disorder include unnecessary repetition of tests, failure to establish trust in the physician–patient relationship, and failure to provide the patient with realistic expectations regarding the efficacy of medications. A concise diagnostic evaluation and prompt institution of symptom-guided therapy can help alleviate the pain and suffering experienced by patients with the irritable bowel syndrome.

Source Information

From the Gastroenterology Section and the Functional Gastrointestinal Diseases Center, Temple University School of Medicine, Philadelphia.

Address reprint requests to Dr. Fisher at the Gastroenterology Section, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140.

References

1. Cumming W. Electrogalvinism in a particular affliction of mucous membrane of the bowels. London Med Gaz 1948;59:969-73.

2. Thompson WG, Longstreth G, Drossman DA. Functional bowel disorders and functional abdominal pain. In: Drossman DA, Corazziari E, Talley N, Thompson WG, Whitehead W, eds. The functional gastrointestinal disorders: diagnosis, pathophysiology, and treatment. 2nd ed. McLean, Va.: Degnon, 2000:351-75.

3. Camilleri M, Choi M-G. Irritable bowel syndrome. Aliment Pharmacol Ther 1997;11:3-15.

4. Everhart JE, Renault PF. Irritable bowel syndrome in office-based practice in the United States. Gastroenterology 1991;100:998-1005.[Abstract]

5. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology 1997;112:2120-2137.[Medline]

6. Drossman DA, Creed FH, Fava GA, et al. Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterol Int 1995;8:47-90.

7. Azpiroz F, Dapoigny M, Pace F, et al. Nongastrointestinal disorders in the irritable bowel syndrome. Digestion 2000;62:66-72.[Medline]

8. Veale D, Kavanagh G, Fielding JF, Fitzgerald O. Primary fibromyalgia and the irritable bowel syndrome: different expressions of a common pathogenetic process. Br J Rheumatol 1991;30:220-222.[Medline]

9. Talley NJ, Gabriel SE, Harmsen WS, Zinsmeister AR, Evans RW. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology 1995;109:1736-1741.[Abstract]

10. Almy TP. Experimental studies on the irritable colon. Am J Med 1951;10:60-67.

11. Snape WJ Jr, Carlson GM, Matarazzo SA, Cohen S. Evidence that abnormal myoelectrical activity produces colonic motor dysfunction in the irritable bowel syndrome. Gastroenterology 1977;72:383-387.[Abstract]

12. Kumar D, Wingate DL. The irritable bowel syndrome: a paroxysmal motor disorder. Lancet 1985;2:973-977.[Medline]

13. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987;92:1885-1893.[Abstract]

14. Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patterns. Dig Dis Sci 1980;25:404-413.[Medline]

15. Kellow JE, Phillips SF, Miller LJ, Zinsmeister AR. Dysmotility of the small intestine in irritable bowel syndrome. Gut 1988;29:1236-1243.[Abstract]

16. Bonaz BL, Papillon E, Baciu M, et al. Central processing of rectal pain in IBS patients: an fMRI study. Gastroenterology 2000;118:Suppl:A615-A615.abstract

17. Mertz H, Morgan V, Tanner G, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distension. Gastroenterology 2000;118:842-848.[Medline]

18. Ringel Y, Drossman DA, Turkington TG, et al. Dysfunction of the motivational-affective pain system in patients with IBS: pet brain imaging in response to rectal balloon distension. Gastroenterology 2000;118:Suppl:A444-A444.abstract

19. Silverman DHS, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997;112:64-72.[Abstract]

20. Almy TP, Kern F Jr, Tulin M. Alterations in colonic function in man under stress. II. Experimental production of sigmoid spasm in healthy persons. Gastroenterology 1949;12:425-436.

21. Drossman DA, McKee DC, Sandler RS, et al. Psychosocial factors in the irritable bowel syndrome: a multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology 1988;95:701-708.[Abstract]

22. Whitehead WE, Bosmajian L, Zonderman AB, Costa PT Jr, Schuster MM. Symptoms of psychologic distress associated with irritable bowel syndrome: comparison of community and medical clinic samples. Gastroenterology 1988;95:709-714.[Abstract]

23. Drossman DA. Sexual and physical abuse and gastrointestinal illness. Scand J Gastroenterol Suppl 1995;208:90-96.[Medline]

24. Gershon MD. Roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther 1999;13:Suppl 2:15-30.

25. Bearcroft CP, Perrett D, Farthing MJG. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998;42:42-46.[Medline]

26. Bose M, Nickols C, Feakins R, Farthing MJ. 5-Hydroxytryptamine and enterochromaffin cells in the irritable bowel syndrome. Gastroenterology 2000;118:Suppl:A563-A563.abstract

27. Stewart GT. Post-dysenteric colitis. BMJ 1950;1:405-409.

28. Chaudhary NA, Truelove SC. The irritable colon syndrome: a study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med 1962;31:307-322.

29. McKendrick MW, Read NW. Irritable bowel syndrome -- post salmonella infection. J Infect 1994;29:1-3.[Medline]

30. Gwee KA, Leong Y-L, Graham C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999;44:400-406.[Medline]

31. Health and Public Policy Committee, American College of Physicians. Endoscopy in the evaluation of dyspepsia. Ann Intern Med 1985;102:266-269.[Medline]

32. Cann PA, Read NW, Holdsworth CD. What is the benefit of coarse wheat bran in patients with irritable bowel syndrome? Gut 1984;25:168-173.[Abstract]

33. Toskes PP, Connery KL, Ritchey TW. Calcium polycarbophil compared with placebo in irritable bowel syndrome. Aliment Pharmacol Ther 1993;7:87-92.[Medline]

34. Jalihal A, Kurian G. Ispaghula therapy in irritable bowel syndrome: improvement in overall well-being is related to reduction in bowel dissatisfaction. J Gastroenterol Hepatol 1990;5:507-513.[Medline]

35. Prior A, Whorwell PJ. Double blind study of ispaghula in irritable bowel syndrome. Gut 1987;28:1510-1513.[Abstract]

36. Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med 2000;133:136-147.[Medline]

37. Rajagopalan M, Kurian G, Jacob J. Symptom relief with amitriptyline in the irritable bowel syndrome. J Gastroenterol Hepatol 1998;13:738-741.[Medline]

38. Clouse RE. Psychotropic medications for the treatment of functional gastrointestinal disorders. Clin Perspect Gastroenterol 1999;2:348-56.

39. Miura M, Lawson DC, Clary EM, Mangel AW, Pappas TN. Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist. Dig Dis Sci 1999;44:20-24.[Medline]

40. Schikowski A, Mathis C, Thewissen M, Ross H-G, Pak MA, Enck P. Dose-dependent modulation of rectal afferent sensitivity by a 5-HT4 receptor agonist. Gastroenterology 1999;116:A643-A643.abstract

41. Dapoigny M, Abitbol JL, Fraitag B. Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome: a multicenter dose-response study. Dig Dis Sci 1995;40:2244-2249.[Medline]

42. Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig Dis Sci 1984;29:239-247.[Medline]

43. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000;355:1035-1040.[Medline]

44. Sciarretta G, Fagioli G, Furno A, et al. 75Se HCAT test in the detection of bile acid malabsorption in functional diarrhoea and its correlation with small bowel transit. Gut 1987;28:970-975.[Abstract]

45. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503-3506.[Medline]

46. Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000;118:463-468.[Medline]

47. Mueller-Lissner S, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT₄ receptor partial agonist, relieves key symptoms of irritable bowel syndrome (IBS). Gastroenterology 2000;118:Suppl:A175-A175.abstract

48. Johanson JF, Miner PB, Parkman HP, et al. Prucalopride (PRU) improves bowel movement (BM) frequency and symptoms (SX) in patients (PTS) with chronic constipation (CC): results of two double-blind, placebo-controlled trials. Gastroenterology 2000;118:Suppl:A175-A175.abstract

49. Sloots CEJ, Poen AC, Felt-Bersma RJF, et al. Effects of prucalopride (PRU) on colonic transit in patients (PTS) with chronic constipation (CC). Gastroenterology 2000;118:Suppl:A847-A847.abstract

50. Drossman DA, Thompson WG. The irritable bowel syndrome: review and a graduated multicomponent treatment approach. Ann Intern Med 1992;116:1009-1016.[Medline]

Edward E. Rylander, M.D.

Diplomat American Board of Family Practice.

Diplomat American Board of Palliative Medicine.