Ace Strategies in the Treatment of IBS: From Models to Management

At an industry-sponsored symposium held in conjunction with the American College of Gastroenterology’s 2001 Annual Scientific Meeting, six leaders in gastroenterology, physiology, and behavioral medicine presented the latest information on the prevalence, impact, and treatment of irritable bowel syndrome. Topics included the pathophysiology of disease, effect on quality of life, and application of serotonin receptor modulation therapy.

This program was supported by an unrestricted educational grant from Novartis.

Assessing the Scale and Socioeconomic Consequences of IBS

Quality of Life and Socioeconomic Implications
Irritable bowel syndrome (IBS) can be a debilitating chronic disease, characterized by abdominal pain, altered bowel habits, and other gastrointestinal symptoms. Emerging data suggest that 11% to 25% of the general U.S. population meet the Rome criteria for IBS, and that 28% to 50% of new gastroenterology consultations are for IBS (Thomson et al; Jones et al). Importantly, IBS has an immense impact on health-related quality of life (HRQOL) as well as on economic cost, said E. Jan Irvine, MD, FRCPC, MSc, Professor of Medicine, McMaster University, Hamilton, Ontario, Canada. Indeed, recent evidence from Gralnek and colleagues has shown that persons with IBS have an impairment in HRQOL (on most scales, SF-36), similar to or worse than that with gastroesophageal reflux disease or end-stage renal disease.

Quality of life. In research studies of IBS, HRQOL is often measured with both general and disease-specific instruments (eg, SF-36, IBS-QOL). According to Dr. Irvine, studies (Hahn et al; Lea & Whorwell) have shown an IBS-related impairment of HRQOL in terms of physical symptoms (eg, abdominal pain, altered bowel habits, fatigue), social factors (eg, inability to eat out, missed work or school), and/or emotional factors (eg, disruption in personal relationships, fear, anxiety). In addition, Drossman and colleagues have demonstrated that IBS has a significant impact on absenteeism from work or school, with one survey showing IBS sufferers missing an average of 13.4 days/year (non-IBS sufferers 4.9 days/year). The GI Sufferer Study (Lieberman research group) has shown a significant decrease in productivity and in leisure time in persons with IBS versus those without IBS, and Ricci’s group showed that this was greatest in those with severe compared to mild or moderate disease. Olden and colleagues have also reported an increase in physician and emergency room visits, number of days in bed, hospitalizations, and abdominal surgeries. Finally, a recent National IBS Awareness Registry survey has shown that approximately 66% of IBS sufferers have one or more comorbid conditions, with comorbidity correlating with poorer scores in HRQOL status.

Economic impact. In terms of the economic costs of IBS, these may be direct (eg, hospitalization, physician visits, medications), indirect (eg, missed work, out-of-pocket costs), or intangible (eg, impaired QOL). The 1998 total cost of IBS was reported at $30 billion (not including medications); however, all costs, especially intangible costs, are difficult to quantify, said Dr. Irvine.

In closing, Dr. Irvine noted that appropriate focused assessment, early diagnosis, and prompt treatment targeted to the predominant symptoms are essential steps to optimizing HRQOL and minimizing costs for persons who suffer from this disease.

Patients, Patterns, and Prevalence 
IBS is a common disorder, with an overall worldwide prevalence of up to 20%, depending upon the population and the disease criteria used. However, in the United States, many IBS sufferers do not consult a physician for their illness. “In those who do seek medical attention, recent surveys suggest that physicians may underestimate the impact of pain and altered bowel habits, particularly constipation, on patients’ lives,” said William Whitehead, PhD, FACG, Professor of Medicine, University of North Carolina, Chapel Hill.

Prevalence. IBS is most common in persons younger than 45 years, and twice as common in females as in males. While data on race differences are limited, Whitehead and colleagues found a similar incidence of IBS in African American and White students, but a greater frequency of IBS with constipation in the African American group. Studies of twins by Talley and Levy suggest a genetic predisposition. Whitehead and colleagues also showed that psychosocial factors may contribute to the clustering of IBS in families.

Healthcare utilization. Drossman and colleagues recently reported that IBS constitutes 10% to 12% of primary care visits and 28% of referrals to gastroenterologists. Importantly, two thirds of healthcare utilization by patients with IBS is for non-gastrointestinal comorbid conditions. Despite this, studies show that 25% to 50% of Americans with IBS do not consult a physician. Factors recently identified as relating to non-consultation include adequate coping styles, embarrassment about symptoms, and skepticism about potential medical benefit (Talley et al).

Finally, Lieberman and colleagues conducted interviews of persons meeting the Rome II criteria for IBS and of physicians who treat IBS. Responses differed when patients with IBS with constipation reported similar symptom severity as those with IBS with diarrhea or alternating diarrhea/constipation, while physicians rated chronic constipation as less severe. In addition, those with IBS with constipation rated their disease similarly to those with IBS with diarrhea or alternating symptoms in terms of being bothersome, while physicians rated constipation as less bothersome. Dr. Whitehead concluded that, “physicians need to be aware that patients with IBS with constipation report the same level of disease severity and distress as those with IBS with diarrhea or alternating symptoms.” 
 

Table 1. Rome II Criteria for IBS

Abdominal pain or discomfort 12 wks of past 12 months
Absence of related biochemical or structural abnormality
Two of the following three:
        – Pain relieved upon defecation
        – Change in frequency of stools
        – Change in appearance of stools
 

Pathophysiologic Modeling: Relevance to Symptoms and Management

Brain-Gut Axis Imbalance
The presence and severity of irritable bowel syndrome (IBS) are defined by gut function and symptom criteria. “However, the recent use of research techniques, such as functional brain imaging, has contributed to our understanding of the pathophysiology and target areas for treatment of this disease,” said Emeran Mayer, MD, Professor of Medicine, Physiology, and Behavioral Sciences, UCLA Comprehensive Mind-Body Center, Los Angeles, California. Using emerging evidence on the pathophysiology of IBS and other conceptual models of disease, Dr. Mayer presented one possible model of IBS, involving an imbalance in the brain-gut axis, or interaction between the brain, central nervous system, and gut.

Factors in pathogenesis. While the predominant symptoms of IBS are abdominal pain and discomfort associated with altered bowel habits, certain patient subsets have many other symptoms, such as psychiatric comorbidity, non-gastrointestinal pain or symptoms, and general symptoms such as fatigue, decreased sexual drive, and disturbance in sleep patterns. Substantial data (Mayer et al review) now support the concept of an enhanced responsiveness of central stress circuits and associated alterations in neuroimmune interactions to external (eg, anxiety, fear, psychosocial factors) or internal (eg, nutrient, inflammation, infection) stressors as part of the underlying pathogenesis of IBS. Such stress hyperresponsiveness results in altered autonomic, neuroendocrine outputs as well as alterations in endogenous pain modulation. This process in turn leads to dysregulation of gut motility, altered gut epithelial function, and enhanced perception of visceral events, ultimately altering brain-gut interactions and producing the characteristic IBS symptoms.

The model. “In this evolving model, both hyperresponsiveness of central circuits [CNS] and of peripheral elements [gut] of the brain-gut axis contribute to the overall symptoms of IBS,” said Dr. Mayer. Stressors occurring early in life may represent vulnerability factors, permanently altering the responsiveness of the brain. In patients with such vulnerability factors, internal or external stressors later in life may then prompt an increased response. Indeed, in a subset of IBS patients, the fear of symptoms itself may become a stressor to perpetuate the syndrome, said Dr. Mayer. Transducing cells within the gut mucosa (such as enterochromaffin cells or certain immune cells) encode events occurring within the gut lumen into signals that are ultimately transmitted by sensory nerves to the central nervous system or that feed into reflexes within the gut. Preliminary data indicate that subgroups of patients with IBS have an increased number of enterochromaffin cells (Spiller et al), mast cells (Sullivan et al), or other immune cells, providing a basis for hyperresponsiveness of the gut to lumenal events that are signaled back to the brain or the enteric nervous system that is regulating motility and reflex activation. “While further study is needed, preliminary evidence points to hyperresponsiveness in the brain-gut axis, both central and peripheral, as a potential target for mediating IBS symptoms,” Dr. Mayer concluded.

Psychosocial, Visceral, and Other Expressions
The underlying pathogenesis of IBS is one in which alterations in brain-gut interaction, visceral perception, autonomic and enteric nervous system function, and motility result in pain, altered bowel habits, and other symptoms. Because IBS is a heterogeneous group of disorders, its specific etiology likely varies among different patients. However, many patients with IBS have psychological comorbidity and high stress levels, which may influence both symptom frequency and severity, said William Chey, MD, FACG, FACP, Associate Professor of Medicine, University of Michigan, Ann Arbor. 

Visceral perception. Studies by Whitehead and by Mayer show that the majority of persons with IBS have visceral hypersensitivity, with lower pain thresholds but also abnormal referral patterns in response to visceral stimulation. The perception of visceral pain is primarily relayed to the brain through spinal afferent neurons. Conversely, homeostatic visceral responses, such as satiety or nausea, are relayed to the brain through parasympathetic or vagal afferent pathways. “It is important to understand the pathways of visceral perception in order to develop medical therapies that may target these pathways,” said Dr. Chey. In general, somatic hypersensitivity has not been observed in patients with IBS.

Psychological factors. Studies show some patients with IBS may have identifiable psychiatric comorbidities, and these may affect patient outcomes (Drossman). Interestingly, antidepressants are being investigated as potential treatments for IBS symptoms. Tricyclic antidepressant agents (low dose) have been used successfully to treat pain and functional bowel disorders. Whether these agents have benefits in patients without underlying depression or anxiety remains a bit unclear though this possibility has been suggested. In addition, the onset of pain relief may occur in as little as 2 weeks. Selective serotonin reuptake inhibitors are also being investigated for use in persons with functional bowel disorders, and these data are awaited (Jailwala et al; Talley et al; Clouse; Jackson). In closing, Dr. Chey also noted that, in appropriately selected patients with IBS (Table 1), psychological therapies may be beneficial. Indeed, Heymann-Monnikes and colleagues found that the combination of behavioral and medical therapy may be more effective than medical therapy alone in persons with IBS. 
 

Application of Serotonin Receptor Modulation to the Treatment of IBS

Serotonin: Therapeutic Target for IBS
Approximately 95% of serotonin, also called 5-hydroxytryptamine (5-HT), is found in the gastrointestinal tract, with the remaining 5% found in the central nervous system. 5-HT is a neurotransmitter of the enteric nervous system, playing a key role in maintaining motor, sensory, and secretory functions in the gut. Two major 5-HT receptors in the gut, 5-HT₃ and 5-HT₄, are important in mediating these intestinal functions, making these receptors prime targets for the treatment of irritable bowel syndrome (IBS), according to Arnold Wald, MD, FACG, Professor of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Serotonin. Gastrointestinal function represents an integration of intestinal motor activity, intestinal sensations, the autonomic nervous system, and the central nervous system. “Importantly, 5-HT is involved in all integrated functions of the gut. In terms of motility, 5-HT simultaneously activates the pathway causing contraction and the pathway causing relaxation of the smooth muscle in the bowel, thereby inducing peristalsis,” said Dr. Wald. Indeed, there is some evidence (Bearcroft et al; Stewart et al) that patients with IBS with diarrhea have more enterochromaffin cells present, produce more 5-HT, and have a greater response to stimuli. In contrast, in patients with IBS with constipation, Elsai and colleagues found decreased numbers of enterochromaffin cells and decreased production of 5-HT.

Receptors. The major 5-HT receptors relevant to the treatment of IBS include 5- HT₃ and 5- HT₄. 5- HT₃ receptors are found in the enteric nervous system, sensory ganglia, vagal afferents, and brain stem, and are associated with the provocation and perception of pain, emesis reflex, and gut motility and secretion. According to Dr. Wald, a 5- HT₃ antagonist agent would be expected to slow colonic transit time, alter perception of volume distension, and perhaps alter sensory function. 5 -HT₄ receptors are found primarily in the gut wall, in the primary spinal afferents, excitatory motor neurons, interneurons, and secretomotor neurons of the intestinal mucosa; 5- HT₄ receptors are associated with the emesis reflex, visceral sensation, secretion, activation of neurotransmitter release, and gut motility. A 5- HT₄ agonist agent, such as tegaserod (currently under U.S. FDA review), works to stimulate peristalsis, accelerate colonic transit time, stimulate chloride secretion, and perhaps inhibit spinal afferents. Dr. Wald concluded, “The 5- HT₃ and 5- HT₄ receptors are highly important in mediating numerous functions within the gut, and modulating these receptors may be a key step in the management of IBS.”

IBS Management: Now and in the Future
IBS represents a consortium of symptoms, with a large number of possible underlying mechanisms; therefore, a single therapy is not likely to be beneficial for every patient with this disease, said Gervais Tougas, MD, CM, FRCPC, MACG, Associate Professor of Medicine, McMaster University, Hamilton, Ontario, Canada. In addition to utilizing various non-pharmacologic approaches (eg, diet, lifestyle changes, psychological therapies) when appropriate, said Dr. Tougas, pharmacologic therapies should be targeted to the predominant symptom of IBS for each individual patient, thereby successfully controlling symptoms and enhancing quality of life.

Pain. For patients with IBS for whom abdominal pain is a primary symptom, tricyclic antidepressant agents have been shown to be beneficial. However, they may increase constipation in some patients, particularly those with IBS with constipation as a symptom. In addition, smooth muscle relaxants (calcium channel blockers, antispasmodics) have been shown to mitigate abdominal pain, but may not relieve diarrhea or constipation (Akehurst et al; Jailwala et al; Poynard et al).

Diarrhea. For patients with IBS with diarrhea, 5-HT₃ antagonists may help to slow colonic transit as well as relieve 
abdominal pain and discomfort. However, the only U.S. Food and Drug Administration (FDA)-approved 5-HT₃ antagonist agent, alosetron, was recently withdrawn from the market. Another agent, cilansetron, is currently under investigation for the treatment of IBS with diarrhea. In the meantime, anti-diarrheal agents, such as loperamide, can be used for patients with IBS and diarrhea (Balfour et al; Camilleri et al).

Constipation. While bulking agents may be effective in relieving constipation, they may also exacerbate symptoms such as bloating and distension. One 5-HT₄ agonist agent, tegaserod, is currently under FDA review for use in IBS with constipation. In three large placebo-controlled clinical trials of tegaserod, as many as 60% of patients with IBS with constipation reported that their symptoms were either completely, considerably, or somewhat relieved. Global assessment symptom scores improved, as did individual symptoms of abdominal pain, bloating, stool frequency, and stool consistency. The efficacy of tegaserod was rapid and sustained. The most common side effect was diarrhea (generally mild and transient). No QT_c interval prolongation, no induction of arrhythmia, no ischemic colitis, and no increase in abdominal surgery over placebo were reported (Camilleri; Prather et al; Scott & Perry).

In conclusion, Dr. Tougas noted that IBS remains a challenging disease to treat; however, emerging new therapies appear to hold promise for persons with IBS with pain, diarrhea, and/or constipation.  

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