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Irritable bowel syndrome in the United States has a prevalence of about 10%-15% of the population. There is a definite female preponderance with a ratio of up to 3 to 1 female to male. In a gastroenterology practice referrals are often 40% or more for irritable bowel. Primary care practices will have 10%-15% of their patients with irritable bowel complaints as the primary presentation. The estimate is that of 8 billion dollars a year in medical expenses and lost wages related to this disorder. Certainly, the diagnosis of irritable bowel syndrome includes ruling out other structural problems. These structural problems will include issues related to bowel blockage including diverticular disease as well as prior history of gynecologic surgery, etc. Structural problems such as tumor certainly need evaluation and the patient will sometimes have irritable bowel like complaints but have an underlying problem of inflammatory bowel disease. Additional specific disorders such as Helicobacter pylori as well as gastroparesis would be a consideration. Bacterial overgrowth syndrome associated with scleroderma, diabetes, or surgical changes should also be evaluated.
The pathophysiology of irritable bowel syndrome has finally evolved to the point where one can define this as a neurologic bowel disease rather than strictly “functional.” The term functional is somewhat of a negative term since it suggests that there is nothing wrong. It has been shown that there is familial clustering suggesting that there may be a genetic component. There is also an interesting clinical observation that post infectious gastroenteritis can lead to the development of irritable bowel in up to 25% of patients who present with such problems. This may reflect an intrinsic gain in gut hypersensitivity. Limited pathology studies have been performed and have since shown that some patients with irritable bowel have increased numbers of lymphocytes seen in the myenteric plexus region of the jejunum. Additionally, colonic mass cell number appears potentially increased as well as entero-endocrine cells may also be excessively represented in patients who have irritable bowel. Currently the histopathology does not allow quantification of such problems on a routine basis at a clinical level. Irritable bowel syndrome, therefore, represents a mixture of problems that are associated with a triad of problems which include altered GI motility, central nervous system effects including anxiety and phobia, as well as an overall visceral sensitivity issue of increased gut awareness.
This combination of problems may account for some of the remarkable responses to placebo therapy alone since the CNS component of this disorder is difficult to quantify as well as the overall character of gut symptoms. Traditional therapies for irritable bowel syndrome have focused on the underlying primary symptom complex. Patients with abdominal pain and discomfort have often been give various antispasmodics as well as tricyclic antidepressants and a component of analgesics. When constipation is the major issue fiber as well as various laxatives would be considered. Laxatives such as Lactulose are associated with sugar malabsorption, increased gas, and in fact amplification of the underlying symptoms. Use of polyethylene glycol derivatives such as Miralax may prove an interesting agent to study in an organized fashion in irritable bowel since this is not associated with significant gaseous distention. Other classic therapies such as Perdiem with senna for constipation has recently been modified since the company making the compound, which was so popular for chronic constipation, has changed its format to a tablet form which may not work as well. The problems of bloating and distention have been treated with dietary modification as well as antispasmodics and a variety of anti-flatulents available in the over-the-counter market. Use of digestive enzymes has also been advocated, but again not in controlled studies for confirmation.
Intermittent use of an antibiotic on occasion has been of use to change the overall gut flora. It is likely that various forms of probiotics will prove useful in the future as the underlying pathophysiology of irritable bowel becomes better defined. Serotonin is known to be a major neurotransmitter and has been associated with IBS. Serotonin (5HT) has a major component of the brain–gut connection. Approximately 95% of the serotonin in the human body is in gut-related tissue while 5% is CNS. Interestingly, the gut-related tissue serotonin has a predominance (90%) in the interochromaffin cells as well as the enteric neurons (10%). CNS function certainly has a major role with serotonin and is involved in appetite, sexual, and mood components. Interestingly, serotonin uptake agents have been used in the past for appetite suppressant which includes the major now defamed Phen-Fen story. Overall, in serotonin receptors there would appear to be seven families of receptors and at least 21 subtypes. The major receptors involved in the GI tract include 5HT3 and 5HT4. A number of serotonin modulating agents have been studies or are currently being studied. The 5HT3 antagonist alosetron (Lotronex) showed good initial response with selected patients but has been removed from the market for general use because of potential side effects including bowel perforation and ischemic bowel. The latter agent is still available in selected patients, usually in the hands of a gastroenterologist. There are now a number of 5HT4 agonists available, the most recent released in the United States is that of tagaserod (Zelnorm). Sisapride has been successfully used in the past as a 5HT4 agonist but was removed by the FDA because of concern regarding arrhythmias. There is another drug Prucalopride which was also developed by Janssen Pharmaceuticals. The latter drug is a potent 5HT4 receptor agonist. Initial enthusiasm has dwindled since small bowel tumors were related in animal studies and this drug is not likely to come to the U.S. market. The relationship of the prominent receptor pathways for 5HT3 and 5HT4 are shown in the accompanying slide at the end of the lecture. It is noted that the 5HT3 receptor and the 5HT4 have primary involvement with a number of components of the paracrine, neurocrine, and endocrine systems. Secondary release of a number of different compounds are outlined in the accompanying slide that include vasoactive peptides, nitrous oxide derivatives, substance p, as well as acetylcholine. The recently released drug tagaserod (Zelnorm) represents a 5HT4 agonist and is now approved for use with irritable bowel, primarily of the constipation/pain/bloating component. This drug does simulate proximal peristalsis as well as intestinal secretions. It also has an effect on visceral sensitivity cutting down the increased awareness that these patients feel. When one looks at the drug effect itself it tends to cause proximal peristalsis but a relaxation distally again through the complex mechanism of feedback systems that are difficult to describe. Motor activity is outlined in the accompanying slide, however. The drug itself has been shown in clinical trials directed at irritable bowel patients with a predominance of constipation to have beneficial effects. Of note is that the issues of abdominal discomfort and constipation improved as well as a decreased sense of bloating and a decrease of stool-related straining. The issue of stool frequency improved initially, but often reverts to normal, though leaving a component of increased general well being. The therapeutic gain is 5%-15% in trials lasting up to 12 weeks. Interestingly, the placebo effect in these same trials is as high as 40%. The use of this drug needs to be carefully modified in regard to food since food will impede absorption significantly. There is also a component of acid sensitivity which suggests that a significant component of this drug will be deactivated in the presence of significant acid. The relationship of this drug in effect associated with acid-reducing agents has not been described in available literature I have had to review. One would hold off on use of the drug if a patient has severe renal or hepatic impairment. Additionally, a history of bowel obstruction would suggest caution in the use of this drug.
Interestingly, gallbladder dysfunction may be amplified by this drug. There is a vague sense that increased gallbladder surgery might be related to its use, though that was not statistically significant. The drug may increase dysfunction of the sphincter of Oddi if such dysfunction is already present. The presence of abdominal adhesions also would be contraindicated with the use of this drug. The side effects of nausea, diarrhea, and abdominal pain are usually well tolerated, though some patients have related significant cramps, and headaches have also been noted. Irritable bowel treatment in the future will remain difficult until markers of a biologic nature can be utilized to define the syndrome–and therefore define appropriate therapy. Current problems with studies are strictly interrelated to the difficulty in finding appropriate control studies given the vague nature of the disorder in the first place. One also must note that the placebo effect is better than the net improvement associated with drug effect in the sense that irritable bowel interrelated to the gut CNS axis will have to be better defined. I look forward to hearing the trials of polyethylene glycol derivatives such as Miralax would be in order. Of note, a cholecystokinin blocking agent has now been described and that may be of some use in irritable bowel. Use of prostaglandin type agents such as misoprostol may have an interesting off label use. Clonidine has some effect on irritable bowel but this antihypertensive agent can certainly give enough symptoms on its own to potentially not be utilized in this syndrome of multiple symptoms. There are other alpha-2 agonists that might be considered in the future. It is also of note whether irritable bowel therapy should be continuous versus on demand, so to speak. Many of these patients wax and wane in symptom complex depending upon personal issues, diet, etc. Interestingly, tagaserod is likely to be tested for additional therapeutic options. Preliminary results show that as a gut motility agent low doses of this drug may improve GERD symptoms. Additionally, the also vague diagnosis of “functional dyspepsia” will be tested with this drug, but again lack of biologic markers for controlled studies are likely to make this utilization fairly vague indeed. The overall therapy for the disorder of irritable bowel syndrome therefore, continues to require vigilance and understanding of both the patient and the doctor.
Roger Orth, M.D.