Functional Gastrointestinal Disorders: Novel Insights and Treatments

, Mayo Clinic and Mayo Foundation, Rochester, Minn.

Disclosures

Medscape General Medicine. 1999;1(3) 

In This Article

Irritable Bowel Syndrome

Pathogenesis

IBS is a biopsychosocial disorder in which psychosocial, motility, and sensation disturbances result in abdominal pain and disorders of defecation (ie, constipation, diarrhea, or alternating bowel habits).[17,18] In community studies, the prevalence of this disorder is around 10%[13] and the incidence, is estimated at 1% to 2% per year.

A fourth possible etiologic factor that has recently received much attention is prior infection.[19,20] Thus, 25% to 33% of patients with diarrhea-predominant IBS give a positive history of a previous "enteritis" episode.[19,21] However, the persistence of symptoms seems to be more closely related to the occurrence of stressful life events and hypochondriasis than to changes in physiologic function.[20]

Motor dysfunction may, as previously indicated, also contribute to some of the symptoms in IBS.[22] In this setting, the prominent colonic response to feeding results in urgency, abdominal pain, and need to have a bowel movement in the early postprandial period. Abnormal transit profiles such as accelerated small bowel and colonic transit in diarrhea-predominant IBS[23] may require the use of medications such as opioids (loperamide, diphenoxylate) that help restore normal function. Patients with urgency and diarrhea develop high-amplitude, rapidly propagated colonic contractions (HAPCs), especially postprandially.[24]

From our improved appreciation of the role of the pelvic floor and anal sphincter muscles in the process of evacuation (Figure 2) and of disturbances in the dynamics of defecation,[10] it is clear that pelvic floor disorders may produce a syndrome virtually identical to the so-called constipation-predominant IBS. Therefore, a history of excessive straining, a sense of incomplete evacuation, or the need to digitate the rectum or vagina to facilitate emptying of the rectum are all features associated with pelvic floor or anal sphincter dysfunction.[8,10,25] In patients with constipation, it is essential to perform a careful rectal examination that includes assessments of the anal sphincter tone at rest, the ability of the puborectalis to relax during straining,[10] and the descent of the perineum during straining.[25] Simple screening tests, such as the balloon expulsion test and measurement of perineal descent, are available to confirm the clinical diagnosis.

Figure 2. Pelvic floor and anal sphincter functions involved in continence and defecation. Continence requires: contraction of puborectalis, maintenance of anorectal angle, normal rectal sensation, and contraction of sphincter. Defecation requires: relaxation of puborectalis, straightening of anorectal angle, and relaxation of sphincter. Reprinted with permission from Camilleri et al. [8]

The differentiation between evacuation disorders and IBS-constipation has important practical implications. For example, a prokinetic agent for constipation is unlikely to work in patients with evacuation disorders. Much direct and indirect expenditure attributable to IBS might be avoided then if more attention were placed on the rectal examination of these patients.

Another component of motor dysfunction that may contribute to heightened sensitivity of the colon is spasm. While this event is well appreciated by radiologists during colon radiography, it has been difficult to objectively demonstrate motor disturbances in the descending or sigmoid colon in patients with IBS. Hence, pharmacologic approaches aimed at correcting motor dysfunction have been empirically based (ie, involve use of antimuscarinic or, more recently, antiserotonergic agents[17,18]).

Colonic and rectal hypersensitivity are very relevant in IBS patients with diarrhea and urgency.[26,27,28] Hypersensitivity has been proposed as a biologic marker of the condition[28]; however, the lack of responsiveness of rectal hypersensitivity in clinical trials[29] and its poor correlation with clinical responses challenge whether this symptom can be used as a biologic marker.[30] Anxiety, psychosensory function, and limbic system activation may contribute to the increased rectocolonic sensitivity.[31,32,33] In summary, the evidence for hypersensitivity in IBS is considerable, but the proof of its clinical relevance will depend on the development of effective therapies and documentation of clinical benefit by restoring normal sensation.[34]

Treatment

Several novel approaches to treatment of IBS are based on these improved insights into motor and sensory functions of the colon and rectum (Figure 3). Thus, novel 5HT4 agonists that stimulate colonic transit and motor function (ie, prucalopride,[35] tegaserod[36]) are currently in development for constipation and pain-predominant IBS. Achieving consistent relief of pain -- without associated side effects -- has always presented a considerable challenge in the treatment of patients with IBS. In the past, anticholinergic agents have been used,[37] but these drugs tend to induce systemic effects and lose efficacy.

Figure 3. Classes of novel medications undergoing trial in functional gastrointestinal disorders. Reprinted with permission from Camilleri and Choi. [63] SSRI=selective serotonin reuptake inhibitors; S2, 3, 4=sacral roots 2, 3, and 4; serotonergic antagonists 3, 4=antagonists at type 3 and 4 serotonergic receptors

Recognition of the role of 5HT3 receptors in visceral afferents, as well as demonstration that 5HT3 antagonists can reduce the gastrocolonic motor response to meal ingestion,[38] have led to large phase II[39] and phase III[40] clinical trials with the novel 5HT3 antagonist alosetron. This agent provides adequate relief of pain and discomfort while reducing frequency and urgency and improving consistency of stool in female diarrhea-predominant IBS patients (Figure 4). To date, limited studies have not demonstrated the drug to be efficacious in male IBS patients.

Figure 4. Comparison of effects of a novel 5HT 3 antagonist, alosetron, and placebo on abdominal pain (upper panel, 1 mg bid alosetron vs placebo) and frequency of defecation (4 doses of alosetron vs placebo) in female patients with diarrhea-predominant IBS. Note that a significantly larger percentage of patients report adequate relief of pain compared with placebo. Adapted from Camilleri et al. [39]

Kappa opioid (peripheral) agonists reduce the pain sensation arising in the gut without inducing any central effects.[41] Alpha-2 adrenergic agents modulate motor and sensory functions of the bowel (Figure 5), particularly the sensation of pain arising during mechanical distention of the colon.[42] Over the next 5 to 10 years, we should witness further validation of these concepts for the purpose of treating IBS.

Figure 5. Effects of adrenergic agents on human colonic sensation during mechanical distentions (4-32 mm Hg). Note clonidine markedly reduces pain but not gas sensation, suggesting a specific antinociceptive action. Reproduced from Bharucha et al. [42]

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