Course Authors

Dr. Gray reports no commercial conflict of interest.

This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Evaluate the patient and make the diagnosis of the irritable bowel syndrome by virtue of the typical history and exclusion of other diseases that may produce similar symptoms

• Enumerate the associated conditions that commonly occur in the setting of IBS

• Discuss the emerging pathophysiologic mechanisms that appear to be important in leading to IBS

• Design a flexible approach to the individual patient, based on the predominant response and the response to therapy.

 

The irritable bowel syndrome (IBS), also called spastic colon or functional bowel syndrome, is a very common malady that may be experienced to some degree by 10 to 20 percent of adults in the Western world.(1) It is recognized, most commonly, in young adulthood and is at least twice as common in women as in men. Only 10 percent of patients have the onset of the disease after age 60. Although 60-70 percent of patients with this entity simply accept their symptoms as a nuisance and do not seek medical advice),(2) IBS is the most common gastrointestinal condition seen by family physicians and internists. Of those seen by their primary physician, only a fraction (~15 percent) are referred to specialists.(3)

Although symptoms vary and there is only a partial consensus among experts about the criteria for IBS diagnosis, two complaints are usually paramount: 1) abdominal pain, often moderate in intensity and localized to the lower abdomen, most typically in the left lower quadrant; and 2) altered bowel habits, usually marked by intermittent bouts of multiple stool passages for several days alternating with periods of constipation with failure of stool delivery, often for several days. These symptoms should be chronic, usually with a pattern established over at least several weeks before the diagnosis can be considered.

Women with IBS are more likely than men with the syndrome to complain of constipation and a sensation of abdominal bloating.(4) Patients often complain of a bloating sensation in the abdomen(5) that they commonly interpret as the presence of excess intra-colonic gas but the sensation is usually not associated with actual abdominal distention and it is not related to gas retention in the small intestine or colon. Patients with a bloating sensation do not pass excessive quantities of gas.(6)

The periods of multiple stool passages are often reported by the patient to be diarrhea because of the urgency and passage of liquid material but stools are usually small in volume and are passed, in relatively rapid succession, typically in the early morning over a period of 30 minutes to an hour or so. A mucus coating is often observed on the stool but there is no visible blood. When the total stool quantity is determined, it is usually only slightly greater than the normal of 200-300 gm per day. The physician should determine whether there is only a transient "squirt" of stool (typical of that in IBS) or a "gush" that lasts for several seconds (indicating high volume output, suggesting an infectious, inflammatory or secretory cause).

The diagnosis depends on the presence of typical symptoms and the absence of any structural abnormality of the colon or small bowel, as estimated by stool analyses for ova, parasites and bacteria and examination of the colon mucosa by contrast X-ray and endoscopy. The acute and limited nature of the infectious diarrheas usually makes these relatively easy to distinguish from IBS. Before the diagnosis of IBS can be made, a flexible sigmoidoscopy and barium enema or full colonoscopy are required to exclude the possibility of other conditions, especially the inflammatory bowel diseases (ulcerative colitis or Crohn's disease). Because a normal appearing colon may harbor only microscopic inflammation, biopsies should be taken at the time of lower bowel endoscopy to exclude microscopic colitis. In some patients, a small bowel series may also be advisable. In the setting of typical symptoms and normal structure of the colon, the diagnosis of IBS can be made.

Associations and Risk Factors for IBS

Because the diagnosis of IBS must be based on a constellation of symptoms and cannot yet be based on any established physiological or pathological test, it is important for the physician to be aware of several associated phenomena that may aid in the diagnosis and prompt the selection of a strategy for therapy.

More than one-third of patients with IBS also have symptoms typical of functional dyspepsia (non-ulcer dyspepsia).(7) Such patients have upper abdominal discomfort that is similar to that occurring in ulcer disease but the relief with food or acid lowering agents is not consistent. Further, no abnormality is detected by upper GI X-ray or endoscopy and systematic use of acid-inhibitory drugs is not beneficial. Children and adolescents with recurrent episodes of abdominal pain are at greater risk of eventually developing typical IBS.(8) Psychologically depressed patients are 10-times more likely than non-depressed controls to have symptoms of IBS.(9) Panic disorder, (10) schizophrenia (11) and physical or sexual abuse during childhood(12) may set the stage for the development of IBS. Sexual dysfunction is often found in IBS.(13)

The possible role of gastroenteritis as a precursor of IBS has recently received considerable attention. Clinical investigators have noted that patients who experience a gastroenteritis, presumably caused by an infectious agent, may be at increased risk of developing chronic symptoms compatible with the irritable bowel syndrome.(14)(15) Based on analysis of more than 500 patients experiencing an acute bacterial gastroenteritis, Neal et al(15) noted that one-quarter of them noted persistence of altered bowel habits six months after the acute episode and 7% of the total group developed a chronic syndrome compatible with IBS. A similar proportion of another group of nearly 100 patients with presumed infectious gastroenteritis developed chronic symptoms typical of IBS and a concomitant chronic inflammatory infiltrate was observed in rectal biopsies from these patients, suggesting the possibility of a chronic microscopic colitis.(14)

The Pathophysiology of Irritable Bowel Syndrome: Altered Features of Colonic Function

Altered Perception of Pain in Response to Rectal Distention

In recent years, there has been a focused interest in identifying measurable altered parameters of bowel function in IBS, particularly as these correlate with activities of the peripheral and central nervous system. When subjected to performance of mental arithmetric problems, a higher proportion of IBS patients (29%) than non-IBS control subjects (4%) display altered electroencephalo-graphic (EEG) patterns.(16) This suggests that psychological stress factors may be expressed in an altered brain response in IBS patients.

Although altered mechanisms are only beginning to be understood, Mayer(17) has noted several potential targets for sorting out the pathophysiology of IBS and for eventually identifying useful pharmacologic agents. These include function of receptors for visceral afferent nerve terminals (ligands: opiates and serotonin); ion channels and receptors on dorsal horn neurons within the spinal cord (ligands: opiates, glutamate, calcitonin gene-related peptide, neuorokinin-1, as well as receptors within the brainstem, the limbic system and the prefrontal cortex (ligands: serotonin, catecholamines, dopamine and acetylcholine).

Data are sparse that demonstrate any change in physiological functioning in IBS but there are some promising leads. IBS patients with constipation, despite having little sensation that an evacuation is eminent, often retain a prolonged sensation of incomplete evacuation. This is correlated with a hypersensitivity to the perception of pain to rectal balloon distention. Although distention is perceived at the same degree of distention as in those without IBS, patients experience pain at lower volume distention than do normal subjects.(18)(19) Thus, they have a lower pain threshold than normal, a finding that is supported by the extreme discomfort that IBS patients often experience when undergoing a colonoscopy or barium enema X-ray.

The heightened sensitivity to painful colon distention in IBS contrasts with the situation in patients with chronic ileal inflammation due to Crohn's disease where there is often an actual increase in the threshold for discomfort.(20) Whereas, the increased threshold in inflammatory bowel disease can be considered to be adaptive and perhaps beneficial to the patient with bowel inflammation and distention, the lowered threshold in IBS seems to be a possible cause of the discomfort, a seeming paradoxical or inappropriate response, rather than the expected adaptive increasing of threshold. Despite the lowered threshold for visceral perception of bowel pain, IBS patients display an enhanced tolerance for somatic cutaneous discomfort induced by electric stimulation as compared to individuals without IBS.(21)

Altered Regional Cerebral Activity in IBS

Patients with IBS have been found to have changes in regional blood flow during perception of pain generated by rectal distention. As measured by Positron Emission Tomography (PET) scanning of the brain, normal control patients respond to painful rectal distention by an enhanced regional blood flow in the anterior cingulate cortex (ACC). In contrast, IBS patients fail to increase blood flow to the ACC and, instead, display an increase in regional flow to the left prefrontal cortex.(22)

These analyses of pain perception and its reflection in altered cerebral regional blood flow have served to bring attention to the interaction of the gut and brain interaction as a basis for further studies on the our understanding of the pathogenesis of IBS.

Therapy of IBS

Diagnosis of the Syndrome of Irritable Bowel

It is important to exclude inflammatory, infectious or vascular conditions of the colon or small intestine before making a diagnosis of IBS. Routine analysis for ova, parasites and bacteria is indicated in any patient who has a change in bowel habits manifested by an increase in the number and a decrease in consistency of stools. A flexible sigmoidiocopy with biopsy, even if the mucosa appears normal, is essential to identify any microscopic inflammation. If the patient describes a high-output diarrhea, stools should be analyzed for osmolality, Na+, and K+ to determine whether the excessive output is related to an osmotic diarrhea (2 x [Na+ + K+] is insufficient to explain the osmolality, indicating that unabsorbable, solutes must be present in the stool). A barium enema should also be done in most patients to exclude a right colon source. A full colonoscopy may be preferred to flexible lower colon exam plus a barium enema in the patient who has prominent systemic symptoms (fatigue, anorexia, weight loss).

When the evaluation for other major diseases is negative and the symptoms typical of IBS, the physician should proceed with therapy of the disease, along the lines detailed below. Several modes of therapy are important in the treatment of the IBS patient.

Providing Insight and Giving Support

Because IBS manifests a myriad of symptoms in the individual patient, the physician must provide the patient with a lucid explanation of the interaction of mind and body that is so important prior to gaining an understanding of this malady prior to the institution of any nutritional or drug therapy. Explanation of the visceral hypersensitivity and of the changes identified in brain activity will provide the sort of insight that enables the patient to work closely with the physician on controlling the disturbing and, at times, debilitating, manifestations of IBS.

Because of the differing constellation of symptoms seen in IBS, it is worthwhile for the physician to identify the principal subtype of the syndrome that is affecting the patient. This can be simplified, at the outset, by determining from the patient's history whether the condition is primarily diarrhea-predominant, constipation-predominant or pain and bloating-predominant. Table 1 provides the initial and long-term approach to these categories of IBS. The rationale for the use of dietary change and drug therapy is provided below. A great deal of selection of therapy may be necessary, depending on the patient's response.

Table 1. General Medication Guidelines in IBS Treatment.

Sub-type of IBS	Primary Rx	Additional Rx	Other Measures
Diarrhea-predominant	Antidiarrheal agents1	Tincture of Opium2 Antispasmotics3	trial fiber Tricyclics4
Constipation-predominant	High fiber diet5 Physical activity	osmotic-active drugs6	Tricyclics4> Special Drugs7
Pain-predominant	Antispasmotics3	Avoid narcotics Physical activity	Pain management (with psychiatric input)

1. diphenoxylate or loperimide 1 tab q.i.d.
2. Tincture of Opium 6-10 gtts q.i.d.
3. Hyoscyamine (or equivalent) 0.125-0.250 mg q.i.d.
4. Amitryptaline (or equivalent) 25-50 mg h.s.
5. See text below; supplement with metamucil 1 teasp. t.i.d. to 1 tablespoon t.i.d.
6. Lactulose (10 gm/15 ml) 2 tablespoons b.i.d.
7. See text below under Specialized Drug Therapy

Dietary Fiber

Primary therapy of patients with IBS is based. to a considerable extent. on trial and error. Because there is a substantial positive placebo in IBS, controlled studies require large numbers of patients and there are very few definitive clinical trials. The most commonly administered therapy is the addition of non-digestible carbohydrate, the so-called fiber that is present in legumes and partially processed grains.(23) Wheat bran, raw fruits and vegetables, or those that are only partially cooked, serve as important sources and have been widely recommended, especially for the constipation-predominant form of IBS.

Most patients find it difficult to consume the recommended minimum 12 grams of fiber per day and choose to augment non-digestible fiber by taking in commercial preparations such as Metamucil^®, Citrocel^® or Fibercon^®. These are usually taken in relatively small quantities such as a teaspoon once to three times daily. But much greater amounts are usually required to provide any relief of the constipation, often three tablespoons three times daily. Although the infrequent stools are often replaced by larger volume, partially formed excreta, many patients note an increase in the bloating sensation. Patients with diarrhea-predominant IBS may respond adversely to the increase in fiber intake, particularly when bran is the source, with an increase in the bloating sensation and in the volume of stools, with little or no reduction in stool frequency.

Anti-diarrheal Agents

When the patient with the diarrhea-predominant form experiences a major bout of loose movements, a favorable response may be obtained from the use of antidiarrheal agents such as loperamide Lomotil^® or Immodium^®. In a few patients with very severe diarrhea, tincture of opium may be beneficial when other antidiarrheal drugs have failed.

Specialized Drug Therapy

No single drug has been consistently efficacious in IBS, probably because of the varying degree and types of symptoms that often occur within the individual patient passages and severe obstipation in the same patient.

IBS patients have elevated serum concentrations of 5-hydroxytryptamine (5-HT)(24) and activation of 3-HT3 receptors may induce hyperalgesia of sensory nerve receptors. Recently, drugs that inhibit the 3-HT3 receptor have been used in clinical trials. Alosetron, a 3-HT3 antagonist, inhibits the 5-hydroxytryptamine-induced skin flare response in normal individuals and increases the colonic compliance to pressure and distention in patients with IBS.(25) In a trial of nearly 400 patients with diarrhea-predominant IBS, alosetron was effective in relieving abdominal pains, increasing stool consistency and decreasing frequency in female patients but there was no benefit to male patients.(26) Activation of 5-HT4 receptors on enteric nerves enhances gut motility and the appropriate agonist of this receptor may have potential benefit in constipation-predominant IBS.

As estimated from meta-analysis, myorelaxants, such as cimetropium, pinaverium, trimebutine, octilium and mebeverine, provide relief superior to placebo for global assessment (62% drug vs. 35% placebo) and for pain relief (64% vs. 45%) but no significant effect was observed for constipation and abdominal bloating.(27)

A variety of drugs, including neurokinin-2 antagonists, gut selective agents (muscarinic antagonists and channel blockers), cholecystokinin (CCK) receptor antagonists, 5-hydroxytryptamine (5-HT4) agonists and 3-HT antagonists (see above) and octreotide all have potential beneficial effect on IBS(28) and clinical studies are being instituted with several of these agents. Otilonim, a spasmolytic agent, has shown a ~15% advantage over placebo for abdominal bloating and global assessment of improvement.(29)

Regardless of whether the patient with IBS is emotionally depressed, the monamine re-uptake inhibitors (tricyclic antidepressants: amitriptyline, desipramine, nortriptyline, doxepin) that act on adrenergic neurons via a-2 receptors, are effective in a proportion of patients with IBS in reducing abdominal pain and increasing satisfaction with bowel movements.(30)(31) The tricyclics appear to be superior to anticholinergics or placebo when given for several weeks at dosages of 25-50 mg per day.

Expectations for the Therapy of IBS in the Next Few Years

The irritable bowl syndrome is one of the most common maladies afflicting the population of the Western world. By advancing our knowledge of the molecular basis for this disease, we look forward to being able to define IBS and its subtypes with pathophysiologic tests and to designing more specific and effective therapeutic modalities in the next few years.