# American College of Gastroenterology 65th Annual Meeting: New Insights into IBS



## JeanG (Oct 20, 1999)

The url for this article is: http://www.medscape.com/Medscape/CNO/2000/...m?story_id=1713 Oct 16 - 18, 2000, New York, NYAmerican College of Gastroenterology 65th Annual Scientific MeetingNew Insights Into Irritable Bowel SyndromeKevin W. Olden, MD Introduction Irritable bowel syndrome (IBS) is a well-known disorder for both gastroenterologists and primary care physicians. It has been described traditionally as affecting 15% of the North American population. However, the diagnosis of IBS has suffered in the past from a lack of precise diagnostic criteria and difficulties in defining adequate treatment and measuring the impact of that treatment in an effective manner. A number of research and clinical symposia were presented at the Annual Meeting of the American College of Gastroenterology that shed new light on the epidemiology, treatment, and economics of the disease burden of IBS. The Challenge of Diagnosis The Rome Criteria In an attempt to develop standardized diagnostic criteria for clinical practice and research in IBS, international working teams developed the ROME I diagnostic criteria in 1990. In 1999, those criteria were revised and simplified, resulting in the ROME II criteria. Investigators have now begun to evaluate the sensitivity, specificity, and congruence of the ROME II criteria with the ROME I criteria. In one study, Grant Thompson, MD, and colleagues[1] from the University of Ottawa and McMaster University in Ontario, Canada, compared the congruence of both the ROME I and II criteria prospectively in a large population of Canadians. Using standard random telephone polling, the investigators recruited 1149 people, adjusting for demographic variables including age and gender. The prevalence of IBS by ROME II criteria was 12% compared with 13% using the ROME I criteria. When gender was evaluated, the prevalence of IBS was found to be 15% in females and close to 9% in males using ROME II, compared with 18.1% and 18.5% in females and males, respectively, using the ROME I criteria. Investigators concluded that the new ROME II criteria produced similar results when compared with the older ROME I criteria. These findings suggest that the ROME II criteria may indeed provide equal efficacy in identifying patients with IBS while being much simpler to use. A very different study was presented by M. Zuckerman, MD, from Texas Tech University in El Paso, and G. Nguyen, MD, from Cho Ray Hospital in Ho Chi Minh City, Vietnam.[2] These investigators surveyed 516 predominately healthy Vietnamese healthcare workers and relatives of patients treated at the Cho Ray Hospital. The individuals were surveyed using an instrument that included the ROME I criteria. A total of 233 individuals (42%) responded. A 6% prevalence of IBS was reported in this sample. Five percent of males and 7% of females met the ROME I diagnostic criteria for IBS. Of interest, the gender difference was not significant, putting this study at odds with research done in North America and Europe where the female-to-male ratio in IBS is skewed toward a higher prevalence in women. The investigators concluded that IBS in a Vietnamese population may present different epidemiologic factors, including lower overall presence and less gender variation. This study is important in that it demonstrates that further epidemiologic studies in populations outside of North America and Europe are needed to better understand the nature of IBS around the world. Disease Burden The issue of the disease burden of IBS has been investigated only recently. Previous studies have demonstrated the cost of morbidity due to IBS in the United States to be over $8 billion. To further evaluate the economic burden of IBS, Eisen and colleagues[3] sampled 2354 individuals from large health maintenance organizations in New Mexico. Of the total contacted, 1032 (44%) agreed to participate in a telephone survey. Data collected included demographic characteristics, the presence of a diagnosis of IBS by ROME I criteria, and quality of life measured by the SF-36 questionnaire, a validated general quality-of-life measure and the IBS-QOL, an instrument that is specific for IBS. Patients were screened psychologically with a checklist that measured psychiatric comorbidity and levels of psychosocial distress. The investigators found that 9% of their sample (94 individuals) met the diagnosis of IBS by the ROME I criteria. There were no demographic differences, including age, gender, race, marital status, education, or income between IBS patients and nonpatient responders. The respondents with IBS were found, on review of their medical records, to have had greater number of outpatient visits in the year preceding the survey compared with non-IBS respondents. However, IBS responders did not differ from non-IBS responders in number of hospitalizations. The patients with IBS tended to use more medications and incurred increased charges for both outpatient visits and prescription drugs. There was also a trend towards higher total costs for all healthcare services for IBS patients during the year that healthcare utilization was measured compared with non-IBS responders. The patients who met the ROME I criteria for IBS had significantly lower scores on the SF-36 compared with non-IBS responders (P < .0001). The investigators concluded that using a cohort of patients in a managed care organization where healthcare utilization and costs could be tracked easily demonstrated that IBS sufferers had significantly more outpatient visits and use of prescription medications than patients without IBS. Further, IBS patients experienced decreased levels of health-related quality of life as opposed to non-IBS respondents. The investigators believed that these findings demonstrated a significant disease burden for IBS. Levy and colleagues[4] presented a similar study that was performed at a large health maintenance organization (HMO) in the Puget Sound area of Washington State. These investigators performed a retrospective study of patients who had been diagnosed with IBS. The medical records of 3153 patients who were diagnosed with IBS were examined and compared with 3153 age- and gender-matched controls from the same HMO who were not diagnosed with IBS and an additional 3153 individuals who were also age- and gender-matched who presented for routine checkups and new medical complaints. Cost of overall care and GI-related costs of care were measured for a 3-year period. The investigators found that for the index year of diagnosis, the total cost of care for IBS patients was $4044, or $1415 higher than for controls. In addition, the IBS patients continued to have healthcare utilization costs approximately $1000 more per person than in the 2 subsequent years of tracking after the initial diagnosis was made. When GI-related care was specifically measured, the IBS group consumed $582 in the index year; that was reduced to some degree in the 2 subsequent years after diagnosis. The largest components of GI-related costs in the first year of the IBS diagnosis were primary care visits ($178), medications ($108), outpatient procedures ($98), radiographic procedures ($77), and specialists' visits ($64). Of interest, there were no significant differences in the number of emergency department visits, inpatient care, or laboratory tests between IBS and non-IBS patients. When all medical problems in both the IBS patients and controls were examined, it was found that less than half of the difference in costs was explained by the cost of IBS-related care. The investigators concluded that IBS indeed had a greater cost-of-care burden, particularly in the first year of diagnosis. Innovations in Treatment Significant advances in the treatment of IBS have been evolving over the last few years. The increase in our understanding of the enteric nervous system and the importance of neurotransmitters present in the gut have been described by various investigators. These findings, in turn, have led to an explosion in research to develop specific agents that can positively affect neurotransmitter function in the treatment of IBS patients. Consequently, the American College of Gastroenterology sponsored a symposium on the treatment of IBS, which was moderated by Drs. Kevin Olden and Arnold Wald.[5] The symposium addressed the difficulties of designing valid clinical trials for IBS and identified the psychosocial and gender factors associated with treatment response as well as the psychiatric and psychological comorbidity that can influence a patient's behavior and treatment response. The use of antidepressant medications and active agents now being developed and entering clinical practice were all discussed in detail. The Difficulties in Designing Clinical Trials Dr. Nicholas Talley[5] from the University of Sydney, Australia, began the symposium by outlining the difficulties associated with performing high-quality clinical trials for any therapeutic approaches to IBS and the methodologic deficiencies of trials published over the last 30 years (including issues of patient recruitment, lack of standardized diagnostic criteria, lack of controls, inadequate consideration to the high placebo response rate seen in IBS, and inadequate outcome measures). Dr. Talley concluded that over these last 3 decades, we have yet to produce a clinical trial that meets the "gold standard." Nor was there any one trial that we could point to and declare unequivocally the efficacy of any particular treatment approach. The absolute importance of maximizing methodologic quality in testing any proposed treatment for IBS was emphasized, lest erroneous or inaccurate conclusions be drawn. Important to further emphasize is that this literature, although advancing quite rapidly, is still immature and thus there are additional lessons to be learned in planning the "ideal" IBS clinical trial. The Role of Psychosocial and Hereditary Factors Dr. Rona Levy[5] from the University of Washington focused on recent research on family dynamics and heredity as they influence IBS expression in patients. In her research, Dr. Levy found that patients with IBS were slightly more likely to have children who would also develop IBS. However, Dr. Levy was quick to emphasize that the reasons for this association remain unclear. Whether this finding represents a genetic phenomenon, as proposed by some investigators, or socialization, family dynamics, or learned healthcare behavior needs to be further determined. Identifying these issues has important treatment implications because there may be a strong level of concern and anxiety within a family about the significance of IBS and its effect on that family that in turn, can influence patient behavior. Data were also presented demonstrating that women have a tendency to respond differently from men to visceral pain, which in turn may influence response to drug treatment. The importance of designing trials adequately balanced between men and women and paying attention to gender-based response differences is clearly important for generating high-quality data on drug and other interventions for IBS. Psychologic Comorbidity Dr. Arnold Wald from the University of Pittsburgh Medical Center reviewed the prevalence of psychiatric comorbidity in patients with IBS.[5] Dr. Wald discussed well-established data showing the high prevalence of anxiety disorders, particularly panic disorder, mood disorders, and somatization disorder in patients with IBS. It should be emphasized that IBS is not a psychological disorder and does not represent "a form fruste" of a psychiatric disorder. Rather, it is important to understand psychiatric disorders as comorbid conditions that can influence presentation, healthcare seeking, drug response, and prognosis. Using case studies, Dr. Wald presented psychiatric-disorder patients from his practice who, at first view, would seem to have IBS. Likewise, he presented patients with IBS who, although distressed, did not have a diagnosable psychiatric disorder on further investigation but who could have easily been misperceived as having one. Dr. Wald presented illustrative cases to demonstrate the importance of taking an adequate history and the utility of office-based psychological screening instruments for identification of psychological issues. Dr. Wald stressed the ease of using these screening instruments in this setting, their applicability to office-based practice, and how to present them to the patient in a positive and helpful manner. The Role of Antidepressants* The use of antidepressants in IBS was discussed by Kevin Olden, MD, of the Mayo Clinic in Scottsdale, Arizona.[5] Dr. Olden reviewed the history of antidepressants in gastroenterology. Specifically, the anticholinergic properties of the older tricyclic antidepressants and their presumed effect on GI motility and the usefulness of tricyclic antidepressants in the treatment of neuropathic nongastrointestinal pain syndrome, such as peripheral neuropathy, were addressed. Dr. Olden also described the effect of neurotransmitter systems found in the gut. He reviewed clinical trials, particularly those by Greenbaum, Cannon, and Clouse, that investigated the use of desipramine,* imipramine,* and trazodone,* respectively, for treating functional gastrointestinal disorders. Dr. Olden emphasized the commonality of the findings of these separate trials using 3 different antidepressants. In all of them, the subjects had no significant demonstrable changes in gastrointestinal motility nor any significant changes in their psychiatric status as a result of the antidepressant intervention. However, the patients did have significant improvement in their GI symptom ratings as well as -- most important -- significant improvement in their overall sense of well being. Dr. Olden emphasized that these findings suggest a site of action of antidepressants both in the gut as well as in the central nervous system where the sensations produced in the gut by IBS are processed and modulated to produce the patient's "report" of his or her symptoms. Patients can begin on low doses of these antidepressants and are less likely to experience troublesome side effects. Dr. Olden stressed the importance of understanding that these drugs, when used in the setting of IBS, are an "off-label" indication, and, therefore, physicians should proceed with caution and ensure their patients' understanding of the reasons for their use. Finally, Dr. Olden reviewed the opportunities that are emerging for the use of antidepressants in gastroenterologic practice. The development of an ever increasing number of new antidepressive agents, including the selective serotonin reuptake inhibitors (SSRIs) and agents that tend to have lower side effect profiles, all deserve further study in GI practice to help define their role in treating IBS and other functional gastrointestinal disorders (such as functional dyspepsia, esophageal dysmotility, and functional abdominal pain). The Role of Serotonin The session was concluded by Dr. Lin Chang from the UCLA School of Medicine, who addressed the use of newer serotonergically active agents for IBS. Dr. Chang reviewed the significance of serotonin as a target neurotransmitter in the therapeutic intervention of the functional gastrointestinal disorders. She emphasized that 95% of serotonin contained in the body is located in the gastrointestinal tract, with the extraneous 5% being primarily located within the brain. Dr. Chang presented the latest data on alosetron (Lotronex), a 5HT3 antagonist and a significant inhibitor of gastrointestinal motility. This inhibitive property makes alosetron an ideal agent for the treatment of diarrhea-predominant IBS. Dr. Chang also discussed the clinical data supporting the efficacy of alosetron in reducing stool frequency in patients with diarrhea-predominant IBS and its ability to decrease abdominal pain and rectal urgency. Other properties of the drug include a lack of adverse interactions, the need for dose adjustment with age, and the absence of metabolic changes in patients with renal or liver dysfunction. Because of its significant antiprokinetic effect, alosetron can commonly produce constipation, which occasionally can be severe. It is important for the physician to be proactive in treating constipation early if seen in these patients. Dr. Chang also presented data on agents still in development, including tegaserod and prucalopride, both of which act on 5HT4 receptor sites. These drugs are being developed specifically for the treatment of constipation-predominant IBS because of their prokinetic effect. Preliminary data published to date studying the effect of tegaserod on gastrointestinal transit and its ability to decrease bloating and abdominal pain in patients with constipation-predominant IBS appear promising. Additional Studies and Strategies for IBS Drotaverine In addition to this symposium on the treatment of IBS, a number of clinically relevant research abstracts were presented. Misra and colleagues[6] from the University of New Delhi Medical School in India presented the results of a randomized double-blind, placebo-controlled trial of drotaverine for the treatment of IBS. Drotaverine is a selective inhibitor of phosphodiesterase isoenzyme IV, which has been found useful in smooth muscle motility disorders. Seventy consecutive patients between the ages of 18 and 60 diagnosed with IBS using their own criteria were studied in this prospective trial. Patients were treated with drotaverine 80 mg 3 times a day and compared with placebo during a 4-week trial and an additional 4-week follow-up period. These investigators found that drotaverine significantly reduced pain compared with placebo (P < .001). Pain severity scores also increased significantly in the drotaverine group compared with placebo (P < .001). Patients treated with drotaverine also experienced significant improvement in global relief of abdominal pain, again compared with placebo (P < .001), and significant improvement in stool frequency (P < .001). No adverse effects were observed in any of the patients either in the placebo or treatment groups. The study authors concluded that drotaverine produced significant global improvement in abdominal pain in patients with IBS. Alosetron Recently, the 5-HT3 antagonist alosetron was approved by the FDA for the treatment of diarrhea-predominant IBS in women. And, in the wake of this, a number of new studies were presented. Jhingran and colleagues[7] studied patient satisfaction in individuals with nonconstipated IBS treated with alosetron. A total of 801 women were studied using a 12-week randomized, double-blind, placebo-controlled multicenter trial of alosetron 1 mg twice daily. These investigators found that overall satisfaction in those patients treated with alosetron was significantly higher than in the placebo group (P < .001). On entry into the trial, less than 10% of all subjects reported that they were either satisfied or extremely satisfied with their previous IBS treatment regimens. In contrast, at the conclusion of the alosetron trial, 12 (69%) of the subjects treated with alosetron reported that they were either satisfied or extremely satisfied with treatment compared with only 42% of the controls (P < .001). They also found a high correlation between overall patient satisfaction as well as satisfactory control of rectal urgency and global improvement of all IBS symptoms. Constipation was the only adverse event reported significantly more frequently in the treatment group (39% vs 14% of controls). The study authors concluded that above and beyond standard outcome measures such as decreased pain and change in bowel movements, patients treated with alosetron also experienced high levels of satisfaction with their care. In a related study, Markowits and colleagues[8] studied the efficacy of alosetron in patients with rectal urgency. Over 800 patients were studied in a 12-week randomized, double-blind, placebo-controlled multicenter trial of the efficacy and tolerability of alosetron 1 mg twice a day. (During the screening period, subjects had reported a lack of satisfaction with control of their symptoms of bowel and rectal urgency at least 50% of the time.) This factor was followed throughout the course of the clinical trial over 12 weeks. The study authors found that patients treated with alosetron were significantly more likely to report improvement in rectal or bowel urgency (P < .001). There was a high correlation seen between improvement in global well-being and satisfactory control of rectal urgency at week 12 (r = 0.54). The investigators concluded that alosetron selectively improved control of rectal urgency in the context of global improvement of IBS symptoms compared with placebo. [Ed. note: Recently the FDA announced the development of a medication guide (FDA-approved patient labeling) to help ensure that women using the prescription drug alosetron hydrochloride for treatment of the diarrhea-predominant form of IBS will understand the rare but serious risks of this drug and how they can recognize those risks and take early action to prevent serious harm. These risks include complications from constipation and the risk of ischemic colitis, which is caused by reduced blood flow to the intestines.] Acupuncture? Lu and colleagues[9] discussed the use of acupuncture, investigated in a randomized, controlled trial of 27 patients with IBS diagnosed by their own criteria and assigned to receive acupuncture treatment or relaxation sessions. Using a crossover design method, the subjects received both modalities. In addition to demographic information and specific IBS symptoms reported, patients also rated their overall quality of life on entry to and exit from the study. The study authors treated the patients with acupuncture or relaxation sessions 3 times a week for a period of 2 weeks. A follow-up observation run was then performed for 4 weeks. These investigators found that patients' quality-of-life and gastrointestinal symptom scores were improved equally in the 23 who completed both the acupuncture trial and the relaxation sessions. A statistically significant reduction in abdominal pain was observed in both groups at the end of the trial. However, when the patients were followed for the 4-week period posttrial, only in the acupuncture group did pain reduction persist (P < .05). Furthermore, a significant reduction in stress perception was also observed in the acupuncture group, but not in the relaxation group (P < .05). It was concluded that acupuncture appears to be an effective modality in the treatment of IBS, particularly for pain and disease-related stress, and exceeds standard relaxation treatment. This intriguing finding is of particular interest because of the increasing attention paid to so-called alternative treatments for IBS by patients and the medical community itself. Additional studies will be needed to confirm these results. The work of Lu and colleagues, however, is an important step in this direction. Clearly, acupuncture as well as other alternative modalities deserve additional study in this disease setting. Conclusion Irritable bowel syndrome continues to pose a significant challenge to the physician in terms of both diagnosis and management. The material presented during these meeting proceedings serves to underscore not only the progress that has been made in recognizing this disease entity (eg, establishment of the Rome Criteria), but also the promise of new therapeutic interventions (eg, tegaserod) that are waiting in the wings. * The United States Food and Drug Administration has not approved this medication for this use. References 1.Thompson GW, Irvine JE, Pare P, et al. Comparing Rome I and Rome II criteria for irritable bowel syndrome in a prospective survey of the Canadian population. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Poster 312, p. 461. 2.Zuckerman MJ, Nguyen G, Ho H, et al. Prevalence of irritable bowel syndrome according to the Rome criteria in a Vietnamese population. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Poster 314, p. 462. 3.Eisen GM, Weinfurt KP, Hurley J, et al. The burden of irritable bowel syndrome in a community sample. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 20, p. 175. 4.Levy R, Stang P, Von Korff M, et al. Longitudinal study of the comparative costs of IBS in an HMO. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 28, p. 186. 5.Olden KO, Wald A, et al. Treatment of irritable bowel syndrome. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. p. 51. 6.Misra S, Pandey R. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled trial. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 29, p. 187. 7.Jhingran P, Bagby B, Decker C, et. al. Patient satisfaction in Lotronex[R] (alosetron HCL) treated nonconstipation irritable bowel syndrome in females. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Poster 387, p. 518. 8.Markowits M, Bagby B, Gordon S, et al. Satisfactory control of bowel urgency and global improvement in irritable bowel syndrome with LotronexR (alosetron therapy). Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Poster 489, p. 596. 9.Lu B, Hu Y, Tenner S. A randomized controlled trial of acupuncture for irritable bowel syndrome. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Poster 268, p. 428. [This message has been edited by JeanG (edited 11-02-2000).]


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## Mike NoLomotil (Jun 6, 2000)

It is interesting to oberve that this years annual meeting of the ACG' report on IBS continues to be a reflection of the fact that the only area of study remains symptomatic intervention via pharmacotherapy, since the source of funding remains driven by drug-product therapeutic outcomes.It is encouraging that the understanding of neurotransmission mechanisms and mediators will improve the quality of the interventional drugs available for IBS, since new drugs continue to be brought into the pipeline and eventually to market.But the primary focus remains not on the origins of the symptomologic sets but intervening after the fact with various pharmacotherapies designed to disrupt a portion of the transmission system elicited as a consequence of an underlying event, not the underlying reactions themselves.What is also encouraging is the increasing focus on the psychological complications of IBS...the confirmation that this is an issue of psychologic comorbidity, not something to be passed-off, or over, when treating IBS. Treatment must be integrative. Gee, if we could at least get all the gastroenterologists to acknowledge this, then maybe somebody somewhere will figure out how to teach it to the primary care practitioners.Thursday night Iws with a group of docs of several different backgrounds, and this subject came up. For fun, in the conversation,I baited them stating "I know you guys do not like to work with IBS all that much because the patients are such head cases"...and it was really rewarding (I have been in remission so long they forget I AM ONE) to hear each one of them in the room actually spew their annoyance and objections without hesitation..."They are NOT headcases, the damn disease MAKES them head cases. I (we) would like to rap every doc on the head we hear this from...on the other hand all their patients come to us anyway out of frustration so maybe its good they think that (yuk-yuk)." This is progress, since these same docs 3 years ago would not have reacted this way. I know, I remember.The most interesting comments in the accupuncture study were not that is effective at attenuating pain perception (heck this has been known for, what, 5,000 years? how old is the practice)...but that the conclusion was reached post-study that accupuncture was better at sustianing perceived quality of life improvement than relaxation methods when the patients left th study protocol.Well, if the patient is practicing stress-reduction methods and these are found (as expected) to alter the perception of pain and improve quality of life perception, if you stop doing it the effect Will go away.So, that is all that says, and how that results in the statements that accu was more effective than SR is another one of those weird conclusions.The conclusion would seem that they work better together. What is surprising about stopping doing the exercises and the effect ceasing? Anyway, takes nothing away from the findings...same thing can happen with biofeedback methods or hypno. Any method which alters perception and attitudinal response towards a physiologic consequence will attenuate the perceived consequence and improve the patients condition. But you have to DO it. So carry on!A very useful tutorial, though, showing where the work is and IS NOT going at this time as represented by the presentations by memebers of that group.This is consistent with the information in the trenches from the docs who are accessing the clinical trials and research funding sources as a matter of daily practice (practitioners who get the study funding awarded and implement the protocols). There are more pharmaceutical interventions under investigation whose Stage I Trials will be implemented in the coming year (patients being sought now).One of those will be conducted by a group of practitioners I work with in this area, so when I have the protocols I will post them here, as they will be seeking IBS patients in this area for this trial, and there may be some members of this Board in this geographic area who may wish to participate in a "new drug trial". (PS there is a stipend as well...)I should have the info next week and will put it out for the interested locals (if there are any in the community here from the SE Florida area).MNL_________________ www.leapallergy.com


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