Recent years have shown an acceleration in the clinical investigation and basic science research of irritable bowel syndrome (IBS), leading to improved diagnosis and treatment.

An update on these advances was provided by leading experts at a heavily attended symposium during the 65th Annual Scientific Meeting of the American College of Gastroenterology (ACG). The session was chaired by Kevin W. Olden, MD, Associate Consultant, Division of Gastroenterology and Hepatology, Graduate School of Medicine, Mayo Clinic, Scottsdale, Arizona.

IBS is a functional bowel disorder characterized by a cluster of symptoms, consisting most commonly of abdominal pain, bloating, constipation, and diarrhea, with some IBS patients experiencing alternating diarrhea and constipation. The disorder occurs in one in five Americans, with higher incidence in women. It usually begins in late adolescence or early adult life.

How Can Drugs be Tested for the Treatment of IBS?

Great progress has been made in the last few years in the design of clinical trials for IBS, particularly in the measurement of outcomes. These new tools will help in the development of new drugs, according to Nicholas J. Talley, MD, PhD, Professor of Medicine, University of Sydney, Australia.

Illustrating the difficulty of designing good trials, he explained that "placebos actually work very well in IBS. In Ireland, the placebo response is close to 90 percent. In Italy, the placebo response is 33 percent, and in the United States, [it is] between 60 and 70 percent."

One of the problems with IBS clinical trials is that they are difficult to design. Several years ago, a group called the Rome Working Team agreed that there were major deficiencies in almost all studies done up to that point (Van Zanten, Talley et al., 1998). The researchers found that the methods of assessing symptoms were particularly flawed.

"Although controversial, the Rome committee suggested that an assessment should integrate the patient's symptoms in a way [that would] provide a global assessment of outcome. This approach has [since] been used in a number of innovative studies."

The pharmaceutical industry has also designed ways of measuring IBS in their studies of new medications. One company, Novartis Pharmaceuticals Corporation, used a five-point subjective global assessment scale in their studies of tegaserod (Zelmac®), a new 5HT4 receptor agonist. A more objective approach was taken by Glaxo-Wellcome, the manufacturer of alosetron (Lotronex®), a new 5HT3 receptor antagonist.

"As with many chronic diseases, IBS has a major impact on quality of life. This element needs to be addressed in clinical trials. New tools are being developed to do this," Dr. Talley said. A systematic review of all trials of IBS from 1966 to 1999 was published recently (Intern Med 2000;133:136-47). This review identified 70 randomized trials including more than 4,000 patients. The investigators concluded that some treatments do work, among them, loperamide (Imodium A-D®) and tricyclic antidepressants.

Social and Gender Factors

Confounding treatment is the fact that IBS is a biopsychosocial illness. Recent research on gender and social dimensions was described by Rona Levy, PhD, Professor of Psychology, University of Washington, Seattle.

Dr. Levy's studies have shown that the children of IBS parents spend significantly more on healthcare -specifically for diarrhea, abdominal pain, and gastrointestinal (GI) visits (Am J Gastroenterol 2000;95:451-456). She said her data provide support for the influence of social learning on specific patterns of illness behavior.

Examining the possibility that the study results might reflect an inherited predisposition to GI illness, Dr. Levy conducted studies of twins (Neurogastroenterology & Motility 2000;12:395).

"The most interesting finding was that a parent with IBS was the best predictor of a twin's report of IBS. We believe these data provide evidence of familial learning patterns that contribute to IBS."

Another fairly well known contributor to IBS is abuse, both emotional and physical. In a recent study, women with IBS ranked significantly higher in characteristics of self-blame and self-silencing than women without IBS (Ali, Toner, and Stuckless 2000).

Gender differences are also noted in IBS patterns-women tend to report more IBS symptoms than men. Finally, healthcare utilization among women with and without IBS is significantly higher than in men.

Treating a Biopsychosocial Disorder: Pitfalls and Best Practices

Although psychological distress is found frequently in patients with IBS, it is not the cause of symptoms, stressed Arnold Wald, MD, Professor of Medicine, University of Pittsburgh, Pennsylvania.

"None of the treatments available will remove symptoms completely-they ameliorate them. The goal is to allow the patient to adjust to a chronic and recurrent condition. Taking care of the emotional and psychosocial issues is equally-if not more-important than simply giving a drug for a specific symptom."

Although IBS is not a psychiatric disorder, between 40 and 60 percent of patients at tertiary care centers will have verifiable psychological disturbances that influence not only the illness experience but the healthcare seeking of the patient.

In evaluating patients, Dr. Wald relies on a 90-item questionnaire called the "SCL-90R," previously known as the Hopkins Symptom Checklist. This checklist reflects the degree of a patient's emotional distress. Patients are asked to respond to questions such as how much they have been bothered by headaches or feelings of faintness in the preceding week.

"Anxiety disorders must also be ruled out," he said. "Do the patient's symptoms represent a panic attack? If not, are they generalized symptoms, or are they symptoms that are related to certain situations? Does the patient have a specific phobia?"

"Patients who tell you that they don't go to social functions may not be going because of GI symptoms. But those symptoms may in fact be an expression of a phobia. Which comes first, the chicken or the egg?"

Some patients will reject psychiatric evaluation but will accept treatment with antidepressants, Dr. Wald explained. For this reason, physicians should learn to use psychotropic medications and refer more complex cases to psychiatrists.

Antidepressants in Functional Gastrointestinal Disorders: New Uses for Old Drugs

Antidepressant medications have been used successfully for some time in patients with functional GI disorders, Dr. Kevin Olden commented.

Explaining the mechanism of drug action, he noted that in the past, IBS was incorrectly defined in some quarters as a psychiatric disorder, but it is very clear now that this is not the case.

"Secondly, the connection between the enteric nervous system and the brain is very close. Brain neurotransmitters have been identified in the gut, and this fact would logically lead to speculation that a drug that affected the neurotransmitters in the brain would also have impact on the gut. And indeed, this seems to be the case."

Paradoxically, the older antidepressants appear to have more efficacy in GI disorders than the newer ones, although that may reflect a lack of research using the newer agents.

A number of recent studies have shown conclusively that when patients were prescribed antidepressants for IBS who did not have depression on entry to the study, their chronic symptoms improved. These patients were not responding to the antidepressant effect of the drug, but to an independent effect (Greenbaum 1987, Cannon 1994, Clouse 1987).

It was speculated that the anticholinergic effects of the drugs were responsible for the improvement, but later studies showed that this was not the case.

"Interestingly, what came to pass was a body of knowledge supporting the conclusion that antidepressants actually work by modifying the neurotransmitter activity in the gut, which in turn influences the visceral hypersensitivity of the gut seen in IBS, which in turn modulates the patient's perception of pain," Dr. Olden explained. "In clinical trials, this was measured as a sense of well-being."

The question remains as to how the antidepressants integrate with the evolving biopsychosocial approach to IBS. Dr. Olden said they "are one arrow in an increasingly large quiver of options. Certainly, we are moving therapeutically toward agents which are specific on neurotransmitter subtypes in the gut rather than working on both the gut and the brain."

Among the new agents he cited were the selective serotonin reuptake inhibitors (SSRIs), which he called "the agents of the new age of psychiatry."

These agents include sertraline (Zoloft®), paroxetine (Paxil®), and fluvoxamine (Luvox®), among others. The biggest problem with these agents is sexual dysfunction-activation of serotonin decreases sex drive. Other side effects include rebound anxiety and mild tremors. Citalopram (Celexa®) is a new SSRI that may have fewer sexual side effects.

Trazodone (Desyrel®, Trazon®, Trialodine®) is a tricyclic antidepressant that is associated with a one percent incidence of priapism (persistent erection accompanied by pain and tenderness), which may interfere with use in men.

Nefazodone (Serzone®), a cousin to trazodone, does not produce priapism and has a potent anxiolytic effect which is not seen with trazodone.

"Clomipramine [Anafranil®] is a potent tricyclic antidepressant that has been available for about ten years in the United States," Dr. Olden noted. "I believe that this drug has been understudied in gastrointestinal disease, and [it] deserves further work."

New drugs are emerging that are both potent noradrenergic blockers-such as the traditional tricyclics-as well as potent SSRIs. The agent currently on the market is venlafaxine (Effexor®). Reboxetine (Edronax®, Vestra®) should soon become available.

Serotonergically Active Agents: New Drugs for an Old Disorder

Dr. Lin Chang, Assistant Professor of Medicine, University of California Los Angeles, described the mechanisms of IBS and the rationale for using serotonin agents.

"In the 1950s, it was thought that IBS was a disorder of abnormal motility," she said. Then it was thought that IBS was a visceral hyperalgesic (increased sensitivity and pain) syndrome in which patients were simply more sensitive to these stimuli.

"Currently, researchers are looking at the different neurotransmitters that are responsible for the transmission of painful signals, or even non-noxious signals that are interpreted as pain by the patient. One of the neurotransmitters that has received much recent attention is 5HT, or serotonin."

Among the new agents is alosetron (Lotronex®), a highly selective and potent 5HT3 receptor antagonist. Studies have shown that patients given alosetron have higher thresholds for both perception and pain, and their left colonic transit is slowed down. In Phase III studies, patients on alosetron had lower stool frequency, and the main adverse event was constipation.

"The conclusion of the Phase III trials is that alosetron relieves abdominal pain and discomfort and improves bowel function in female diarrhea IBS patients," Dr. Chang declared. "Symptom relief is sustained during treatment and is well tolerated." Other new agents are the 5HT4 agonists, which improve colonic motility and transport. One agent-tegaserod (Zelmac™)-should become available soon.

Summarizing current pharmacologic therapy for IBS, Dr. Chang said that she designs therapy according to the patient's most bothersome or predominant symptom.

"In the pain-predominant group [that is] non-constipated, in addition to antispasmodics and antidepressants, 5HT3 antagonists can be used. For diarrhea-predominant patients, 5HT3 antagonists can be used in addition to anti-diarrheal agents. And in the constipated group, in addition to fiber and laxatives, the newer 5HT4 agonists can be used."