Editorial Understanding Irritable Bowel Syndrome and Gastrointestinal Motility Irritable bowel syndrome (IBS) is a well-defined symptom complex characterized by abdominal pain and altered bowel habit that occurs in the absence of identifiable structural disease.'> Specific symptoms that may support the diagnosis of IBS have been identified and include the following: (1) visible abdominal distention, (2) pain relieved by defecation, (3) more frequent stools in conjunction with the onset of pain, (4) looser stools associated with the onset of pain, (5) passage of mucus per rectum, and (6) a sensation of incomplete evacuation.' Because IBS has been defined as a clinical symptom complex without specific organic disease, therapy for IBS is usually empirical and directed toward specific symptoms.
Findings With Use of Improved Measurement Techniques.-In recent years, improved techniques to measure intestinal motility and transit in humans have led to a better understanding of normal motor function in the small bowel and colon.v' Normal motor responses to food, external stress, hormonal stimulation, and intraluminal contents (for example, bile acids) have been characterized. In addition, specific sensory and motor abnormalities of the gastrointestinal tract in patients with IBS have been identified. Abnormalities in colonic motor activity noted in IBS include an altered gastrocolonic motor response, an exaggerated colonic motor response to pain, stress, or hormonal stimulation, and increased sensation and motor activity in response to balloon distention of the rectosigmoid region.' Similarly, abnormalities in motor activity of the small bowel noted in IBS include an exaggerated motor response to fatty meals, ileal balloon distention, or hormonal stimulation, altered ileocecal transit, an increase in specific motility patterns during fasting (discrete clustered contractions, propagating propulsive contractions), and increased sensitivity to pain with these contractile patterns during fasting."? Interestingly, the motor abnormalities in the small bowel and colon in IBS have been detected only in conscious patients, when control of intestinal motility by the enteric nervous system is under greater modulation by input from the central nervous system. Likewise, the motor abnormalities and symptoms in IBS are often Address reprint requests to Dr. C. D. Lind, 1414 TVC-GI Facility, Vanderbilt University Medical Center, Nashville, TN 372325280. Mayo Clin Proc 67:804-806, 1992
more pronounced under the influence of external stressors (such as pain, psychologic stress, or anger) or after meals; this finding suggests that central nervous system modulation of enteric nervous system control of intestinal motility (through the autonomic nervous system) may be important in the pathogenesis ofIBS.5 Current Mayo Studies.-In this issue of the Mayo Clinic Proceedings, two important studies of the pathophysiologic features and treatment of IBS are reported. Vassallo and colleagues (pages 725 to 731) carefully assessed motor activity and tone in the descending colon, using a barostatmanometric assembly, in eight healthy subjects and eight patients with diarrhea-predominant IBS. On the basis of background studies, they hypothesized that patients with diarrhea-predominant IBS would exhibit higher levels of colonic tone than would normal control subjects. Unfortunately, these investigators found no differences in colonic tone between the patients with IBS and the control subjects during nocturnal, fasting, and fed states. Patients with diarrhea-predominant IBS had an increased fasting motility index (that is, increased contractile activity) in comparison with control subjects, but no other significant differences between groups were noted. In a related article, Steadman and colleagues (pages 732 to 738) describe a pilot study in which they used a selective 5-hydroxytryptamine type 3 receptor antagonist, ondansetron hydrochloride, as treatment for diarrhea-predominant IBS. They had previously shown that ondansetron slows colonic transit in healthy volunteers," and they expected patients with diarrhea-predominant IBS to be helped by this drug. In the current study, they report the results of using ondansetron in a randomized, placebo-controlled, double-blind crossover trial for 11 patients with well-characterized diarrhea-predominant IBS. The clinical variables measured were colonic transit, small intestinal and orocecal transit, peptide hormone responses, stool weight, and symptoms. No significant differences in transit times, hormone responses, or stool weights were found between treatment groups. Ondansetron did significantly improve stool consistency in comparison with placebo, but no other symptom was significantly altered by treatment. Interestingly, overall symptom scores were improved during both placebo and ondansetron treatment periods, in comparison with baseline ("pretreatment") scores. Methodologic Difficulties in Studies of IBS.-Both reports on IBS in this issue of the Mayo Clinic Proceedings describe well-designed, carefully analyzed, controlled studies that fail to show expected differences between experimental groups. In both studies, the expected differences 804
Mayo Clin Proc, August 1992, Vol 67
between experimental groups (in one case, health versus IBS; in the other case, active treatment versus placebo in IBS) may exist, but the limitations of sample size, variability in symptoms, and heterogeneity of patients with IBS have led to these "negative" studies. In fact, almost all controlled treatment trials in patients with IBS that have shown significant differences between treatment groups have been hampered by methodologic limitations unique to the study of IBS. 9 For better interpretation of clinical studies of IBS, the difficulties of evaluating this heterogeneous syndrome must be recognized. Clinical studies designed to evaluate the pathophysiologic features of IBS are hampered on several levels. First, by definition, IBS is a clinical syndrome based on specific symptoms such as diarrhea, constipation, and pain during defecation. Physiologic studies suggest that various abnormalities in intestinal transit or motility may be identified, the findings being based on different symptomatic subsets of IBS (for example, diarrhea-predominant versus constipation-predominant IBS).lO,ll Consequently, the pathophysiologic factors to follow may differ, depending on the symptom complex being evaluated. Second, symptoms and the associated gastrointestinal motor disturbances in IBS are episodic and may be variable over time. Normal, asymptomatic control subjects may have the same intestinal motor disturbances noted in IBS, but they do so less frequently and with less severe symptoms.?? Hence, prolonged assessment of motility and transit in the small bowel and colon is necessary for effective study of the pathophysiologic aspects of IBS, and a careful correlation between symptoms and motor disturbances may be needed. Third, the motility disturbances identified in health and in IBS seem to occur only during the conscious, awake state and are considerably influenced by external stressors,? Therefore, assessment of symptoms and intestinal motility and transit in the baseline home environment (rather than the hospitalized, clinical research center) may provide the best clues to the pathogenesis of IBS. Finally, appropriate "normal" control subjects may be difficult to identify in pathophysiologic studies of IBS, inasmuch as 15 to 20% of the healthy population have symptoms diagnostic of IBS but never seek medical attention." In addition, the motility disturbances noted in IBS have been identified in patients with psychoneuroses who do not have symptoms of IBS.13 Similarly, normal control subjects with external stressors (pain, psychologic stress, or anger) may exhibit the intestinal motor changes detected in patients with IBS. 14 Can ambulatory studies that compare patients with IBS and normal subjects effectively control for external stressors? If so, are the motility changes noted in IBS related to lack of adaptation to these stressors? Clearly, the better defined the populations of patients with IBS and "normal" control subjects are, the better will be our understand-
EDITORIAL
805
ing of specific pathophysiologic abnormalities that may be identified. Clinical treatment trials in patients with IBS are hampered by the same limitations as trials for evaluating the pathophysiologic characteristics of IBS. This syndrome and the clinical subset (for example, diarrhea-predominant IBS) being studied must be carefully defined. Variability of symptoms and motility abnormality over time necessitates long-term studies for effective evaluation of response to treatment. Objective factors of intestinal activity or transit and associated symptoms, when used as endpoints for effect of treatment, must be well described and evaluated. Appropriate clinical control groups must also be well characterized (that is, asymptomatic, psychoneurotic, those with organic gastrointestinal disease, and so forth), and in crossover trials, efforts need to be made to avoid a "carryover effect" from one treatment to another." An additional problem in treatment trials of IBS is the exceedingly high rate of response to placebo (up to 70%) noted in some clinical trials, including the study reported by Steadman and colleagues in this issue. Therefore, for identification of effective therapy, placebo controls must be used in IBS treatment trials. Placed in this context of the difficulties with clinical studies of IBS, both investigations of IBS reported in this issue of the Mayo Clinic Proceedings may be viewed in a somewhat different light. Both studies assessed a welldefined subset of patients with diarrhea-predominant IBS, and both studies used appropriate clinical control groups. Although the study by Vassallo and colleagues failed to show a significant difference in basal colonic tone between patients with IBS and normal control subjects, a significantly increased motility index during fasting and a trend toward increased colonic tone during fasting were noted in the patients with IBS. Studies that include larger numbers of patients and, perhaps, more prolonged recordings may provide additional information. Similarly, the study by Steadman and co-workers failed to show a significant difference in colonic transit between ondansetron- and placebo-treated patients with diarrhea-predominant IBS. Nevertheless, both a trend toward slower colonic transit and a significant improvement in stool consistency were noted in the patients who received ondansetron. As these investigators state, the improvement in stool consistency noted during ondansetron treatment may be the result of 5-hydroxytryptamine type 3 receptor blockade altering sensation rather than motor function and transit." Regardless, their results suggest that further studies on the effects of such receptor blockade in IBS are needed. Conclusion.-Because of the aforementioned pitfalls with clinical studies of IBS, I agree with Steadman and associates that further studies of the efficacy of selective agents (such as ondansetron) for subgroups of patients with
806
Mayo Clin Proc, August 1992, Vol 67
EDITORIAL
IBS should assess larger, parallel groups in randomized, double-blind, placebo-controlled trials of longer duration. Although these studies may seem difficult to perform, our understanding of IBS and its effective treatment depend on the careful design and implementation of these important clinical trials. Christopher D. Lind, M.D. Division of Gastroenterology Vanderbilt University School of Medicine Nashville, Tennessee REFERENCES 1. Manning AP, Thompson WG, Heaton KW, Morris AF: Towards positive diagnosis of the irritable bowel. Br Med J 2:653-654, 1978 2. Talley NJ, Phillips SF, Melton U, Mulvihill C, Wiltgen C, Zinsmeister AR: Diagnostic value of the Manning criteria in irritable bowel syndrome. Gut 31:77-81,1990 3. Kellow JE, BorodyTJ, Phillips SF, Tucker RL, Haddad AC: Human interdigestive motility: variations in patterns from esophagus to colon, Gastroenterology 91:386-395, 1986 4. Narducci F, Bassotti G, Gaburri M, Morelli A: Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 28:17-25, 1987 5. Lind CD: Motility disorders in the irritable bowel syndrome. Gastroenterol Clin North Am 20:279-295, June 1991 6. Kellow JE, Phillips SF: Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 92:1885-1893,1987
7.
8.
9.
10.
11.
12. 13.
14. 15.
Kellow JE, Gill RC, Wingate DL: Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology 98: 12081218, 1990 Talley NJ, Phillips SF, Haddad A, Miller LJ, Twomey C, Zinsmeister AR, MacCarty RL, Ciociola A: GR 38032F (ondansetron), a selective 5HT 3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci 35:477-480, 1990 Klein KB: Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology 95:232-241, 1988 Whitehead WE, Engel BT, Schuster MM: Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 25:404-413, 1980 Prior A, Maxton DG, Whorwell PJ: Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects. Gut 31:458-462, 1990 Thompson WG, Heaton KW: Functional bowel disorders in apparently healthy people. Gastroenterology 79:283-288, 1980 Latimer P, Sarna S, Campbell D, Latimer M, Waterfall W, Daniel EE: Colonic motor and myoelectrical activity: a comparative study of normal subjects, psychoneurotic patients, and patients with irritable bowel syndrome. Gastroenterology 80:893-901, 1981 Welgan P, Meshkinpour H, Beeler M: Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome. Gastroenterology 94:1150-1156,1988 Costall B, Naylor RJ: 5-Hydroxytryptarnine: new receptors and novel drugs for gastrointestinal motor disorders. Scand J Gastroenterol 25:769-787,1990
Findings With Use of Improved Measurement Techniques.-In recent years, improved techniques to measure intestinal motility and transit in humans have led to a better understanding of normal motor function in the small bowel and colon.v' Normal motor responses to food, external stress, hormonal stimulation, and intraluminal contents (for example, bile acids) have been characterized. In addition, specific sensory and motor abnormalities of the gastrointestinal tract in patients with IBS have been identified. Abnormalities in colonic motor activity noted in IBS include an altered gastrocolonic motor response, an exaggerated colonic motor response to pain, stress, or hormonal stimulation, and increased sensation and motor activity in response to balloon distention of the rectosigmoid region.' Similarly, abnormalities in motor activity of the small bowel noted in IBS include an exaggerated motor response to fatty meals, ileal balloon distention, or hormonal stimulation, altered ileocecal transit, an increase in specific motility patterns during fasting (discrete clustered contractions, propagating propulsive contractions), and increased sensitivity to pain with these contractile patterns during fasting."? Interestingly, the motor abnormalities in the small bowel and colon in IBS have been detected only in conscious patients, when control of intestinal motility by the enteric nervous system is under greater modulation by input from the central nervous system. Likewise, the motor abnormalities and symptoms in IBS are often Address reprint requests to Dr. C. D. Lind, 1414 TVC-GI Facility, Vanderbilt University Medical Center, Nashville, TN 372325280. Mayo Clin Proc 67:804-806, 1992
more pronounced under the influence of external stressors (such as pain, psychologic stress, or anger) or after meals; this finding suggests that central nervous system modulation of enteric nervous system control of intestinal motility (through the autonomic nervous system) may be important in the pathogenesis ofIBS.5 Current Mayo Studies.-In this issue of the Mayo Clinic Proceedings, two important studies of the pathophysiologic features and treatment of IBS are reported. Vassallo and colleagues (pages 725 to 731) carefully assessed motor activity and tone in the descending colon, using a barostatmanometric assembly, in eight healthy subjects and eight patients with diarrhea-predominant IBS. On the basis of background studies, they hypothesized that patients with diarrhea-predominant IBS would exhibit higher levels of colonic tone than would normal control subjects. Unfortunately, these investigators found no differences in colonic tone between the patients with IBS and the control subjects during nocturnal, fasting, and fed states. Patients with diarrhea-predominant IBS had an increased fasting motility index (that is, increased contractile activity) in comparison with control subjects, but no other significant differences between groups were noted. In a related article, Steadman and colleagues (pages 732 to 738) describe a pilot study in which they used a selective 5-hydroxytryptamine type 3 receptor antagonist, ondansetron hydrochloride, as treatment for diarrhea-predominant IBS. They had previously shown that ondansetron slows colonic transit in healthy volunteers," and they expected patients with diarrhea-predominant IBS to be helped by this drug. In the current study, they report the results of using ondansetron in a randomized, placebo-controlled, double-blind crossover trial for 11 patients with well-characterized diarrhea-predominant IBS. The clinical variables measured were colonic transit, small intestinal and orocecal transit, peptide hormone responses, stool weight, and symptoms. No significant differences in transit times, hormone responses, or stool weights were found between treatment groups. Ondansetron did significantly improve stool consistency in comparison with placebo, but no other symptom was significantly altered by treatment. Interestingly, overall symptom scores were improved during both placebo and ondansetron treatment periods, in comparison with baseline ("pretreatment") scores. Methodologic Difficulties in Studies of IBS.-Both reports on IBS in this issue of the Mayo Clinic Proceedings describe well-designed, carefully analyzed, controlled studies that fail to show expected differences between experimental groups. In both studies, the expected differences 804
Mayo Clin Proc, August 1992, Vol 67
between experimental groups (in one case, health versus IBS; in the other case, active treatment versus placebo in IBS) may exist, but the limitations of sample size, variability in symptoms, and heterogeneity of patients with IBS have led to these "negative" studies. In fact, almost all controlled treatment trials in patients with IBS that have shown significant differences between treatment groups have been hampered by methodologic limitations unique to the study of IBS. 9 For better interpretation of clinical studies of IBS, the difficulties of evaluating this heterogeneous syndrome must be recognized. Clinical studies designed to evaluate the pathophysiologic features of IBS are hampered on several levels. First, by definition, IBS is a clinical syndrome based on specific symptoms such as diarrhea, constipation, and pain during defecation. Physiologic studies suggest that various abnormalities in intestinal transit or motility may be identified, the findings being based on different symptomatic subsets of IBS (for example, diarrhea-predominant versus constipation-predominant IBS).lO,ll Consequently, the pathophysiologic factors to follow may differ, depending on the symptom complex being evaluated. Second, symptoms and the associated gastrointestinal motor disturbances in IBS are episodic and may be variable over time. Normal, asymptomatic control subjects may have the same intestinal motor disturbances noted in IBS, but they do so less frequently and with less severe symptoms.?? Hence, prolonged assessment of motility and transit in the small bowel and colon is necessary for effective study of the pathophysiologic aspects of IBS, and a careful correlation between symptoms and motor disturbances may be needed. Third, the motility disturbances identified in health and in IBS seem to occur only during the conscious, awake state and are considerably influenced by external stressors,? Therefore, assessment of symptoms and intestinal motility and transit in the baseline home environment (rather than the hospitalized, clinical research center) may provide the best clues to the pathogenesis of IBS. Finally, appropriate "normal" control subjects may be difficult to identify in pathophysiologic studies of IBS, inasmuch as 15 to 20% of the healthy population have symptoms diagnostic of IBS but never seek medical attention." In addition, the motility disturbances noted in IBS have been identified in patients with psychoneuroses who do not have symptoms of IBS.13 Similarly, normal control subjects with external stressors (pain, psychologic stress, or anger) may exhibit the intestinal motor changes detected in patients with IBS. 14 Can ambulatory studies that compare patients with IBS and normal subjects effectively control for external stressors? If so, are the motility changes noted in IBS related to lack of adaptation to these stressors? Clearly, the better defined the populations of patients with IBS and "normal" control subjects are, the better will be our understand-
EDITORIAL
805
ing of specific pathophysiologic abnormalities that may be identified. Clinical treatment trials in patients with IBS are hampered by the same limitations as trials for evaluating the pathophysiologic characteristics of IBS. This syndrome and the clinical subset (for example, diarrhea-predominant IBS) being studied must be carefully defined. Variability of symptoms and motility abnormality over time necessitates long-term studies for effective evaluation of response to treatment. Objective factors of intestinal activity or transit and associated symptoms, when used as endpoints for effect of treatment, must be well described and evaluated. Appropriate clinical control groups must also be well characterized (that is, asymptomatic, psychoneurotic, those with organic gastrointestinal disease, and so forth), and in crossover trials, efforts need to be made to avoid a "carryover effect" from one treatment to another." An additional problem in treatment trials of IBS is the exceedingly high rate of response to placebo (up to 70%) noted in some clinical trials, including the study reported by Steadman and colleagues in this issue. Therefore, for identification of effective therapy, placebo controls must be used in IBS treatment trials. Placed in this context of the difficulties with clinical studies of IBS, both investigations of IBS reported in this issue of the Mayo Clinic Proceedings may be viewed in a somewhat different light. Both studies assessed a welldefined subset of patients with diarrhea-predominant IBS, and both studies used appropriate clinical control groups. Although the study by Vassallo and colleagues failed to show a significant difference in basal colonic tone between patients with IBS and normal control subjects, a significantly increased motility index during fasting and a trend toward increased colonic tone during fasting were noted in the patients with IBS. Studies that include larger numbers of patients and, perhaps, more prolonged recordings may provide additional information. Similarly, the study by Steadman and co-workers failed to show a significant difference in colonic transit between ondansetron- and placebo-treated patients with diarrhea-predominant IBS. Nevertheless, both a trend toward slower colonic transit and a significant improvement in stool consistency were noted in the patients who received ondansetron. As these investigators state, the improvement in stool consistency noted during ondansetron treatment may be the result of 5-hydroxytryptamine type 3 receptor blockade altering sensation rather than motor function and transit." Regardless, their results suggest that further studies on the effects of such receptor blockade in IBS are needed. Conclusion.-Because of the aforementioned pitfalls with clinical studies of IBS, I agree with Steadman and associates that further studies of the efficacy of selective agents (such as ondansetron) for subgroups of patients with
806
Mayo Clin Proc, August 1992, Vol 67
EDITORIAL
IBS should assess larger, parallel groups in randomized, double-blind, placebo-controlled trials of longer duration. Although these studies may seem difficult to perform, our understanding of IBS and its effective treatment depend on the careful design and implementation of these important clinical trials. Christopher D. Lind, M.D. Division of Gastroenterology Vanderbilt University School of Medicine Nashville, Tennessee REFERENCES 1. Manning AP, Thompson WG, Heaton KW, Morris AF: Towards positive diagnosis of the irritable bowel. Br Med J 2:653-654, 1978 2. Talley NJ, Phillips SF, Melton U, Mulvihill C, Wiltgen C, Zinsmeister AR: Diagnostic value of the Manning criteria in irritable bowel syndrome. Gut 31:77-81,1990 3. Kellow JE, BorodyTJ, Phillips SF, Tucker RL, Haddad AC: Human interdigestive motility: variations in patterns from esophagus to colon, Gastroenterology 91:386-395, 1986 4. Narducci F, Bassotti G, Gaburri M, Morelli A: Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 28:17-25, 1987 5. Lind CD: Motility disorders in the irritable bowel syndrome. Gastroenterol Clin North Am 20:279-295, June 1991 6. Kellow JE, Phillips SF: Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 92:1885-1893,1987
7.
8.
9.
10.
11.
12. 13.
14. 15.
Kellow JE, Gill RC, Wingate DL: Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology 98: 12081218, 1990 Talley NJ, Phillips SF, Haddad A, Miller LJ, Twomey C, Zinsmeister AR, MacCarty RL, Ciociola A: GR 38032F (ondansetron), a selective 5HT 3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci 35:477-480, 1990 Klein KB: Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology 95:232-241, 1988 Whitehead WE, Engel BT, Schuster MM: Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 25:404-413, 1980 Prior A, Maxton DG, Whorwell PJ: Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects. Gut 31:458-462, 1990 Thompson WG, Heaton KW: Functional bowel disorders in apparently healthy people. Gastroenterology 79:283-288, 1980 Latimer P, Sarna S, Campbell D, Latimer M, Waterfall W, Daniel EE: Colonic motor and myoelectrical activity: a comparative study of normal subjects, psychoneurotic patients, and patients with irritable bowel syndrome. Gastroenterology 80:893-901, 1981 Welgan P, Meshkinpour H, Beeler M: Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome. Gastroenterology 94:1150-1156,1988 Costall B, Naylor RJ: 5-Hydroxytryptarnine: new receptors and novel drugs for gastrointestinal motor disorders. Scand J Gastroenterol 25:769-787,1990
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