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Irritable Bowel Syndrome
Irritable Bowel Syndrome
Irritable bowel syndrome occurs in about15 to 20 percent of adults. The disorder is more common in women than in men. Symptoms typically begin during young adulthood. While only about one-third to one-half of symptomatic adults seek medical attention for their symptoms



Irritable bowel syndrome (IBS), in its essence, can be defined as a combination of abdominal pain or discomfort and altered bowel habit. The alteration in bowel habit can take the form of altered stool frequency (ie, diarrhea or constipation) or altered stool form in terms of thin, overly hard and firm, or soft (and even liquid) stools. Symptoms that are commonly associated with IBS include passage of clear or white mucus with a bowel movement, sensation of incomplete evacuation after having a bowel movement, and relief of abdominal pain or discomfort transiently after defecation and abdominal bloating. Patients with IBS have traditionally been described as being "constipation predominant," "diarrhea predominant," or as having an alternating pattern of constipation and diarrhea (ie, so-called "alternators)". Although the research on the exact epidemiology of these 3 variants of IBS is incomplete, our best understanding is that each type is represented approximately equally in the overall IBS population. Abdominal pain or discomfort is a sine qua non for the diagnosis of IBS. The pain or discomfort most commonly occurs in the left lower quadrant, but can be found anywhere in the abdomen; however, isolated pain or discomfort above the level of the umbilicus is uncommon in patients with pure IBS. This combination of altered bowel habits with abdominal pain or discomfort separates IBS from other functional bowel disorders, such as functional dyspepsia, functional constipation, functional diarrhea, or functional abdominal bloating, to name a few.
In addition to gastrointestinal symptoms, IBS has been associated with a number of extraintestinal conditions, such as fibromyalgia, sexual dysfunction, urinary symptoms, and certain psychiatric disorders in excess of non-IBS controls. These latter findings have implications both for further supporting the diagnosis of IBS, as well as for helping to define the level of disability of the patient who presents with IBS with extraintestinal manifestations.



Prevalence
A number of prevalence studies using standardized diagnostic criteria have been performed in the last 10 years to help determine the true prevalence of IBS. The overall prevalence of IBS is estimated to be approximately between 10% and 20% of the population.[1] Its prevalence varies by age -- it is higher in individuals in the second to fifth decades of life and declines considerably thereafter. Prevalence in individuals younger than 50 years of age has been determined to be somewhere between 15% and 20%, and in individuals older than 50 years of age, prevalence is approximately 10% to 12%.[2] This latter finding is important because IBS is generally considered a condition of "younger people." Its prevalence, although lower in elderly individuals, is not inconsiderable, however. An increasing number of transcultural and transracial population studies have been performed documenting a fairly constant prevalence across national boundaries and ethnic and racial lines for IBS. No particular country or geographic area seems to definitively stand out as having a higher or lower prevalence of IBS.
IBS does seem to be more prevalent in women. The sex ratio for individuals with IBS who chose not to seek care is 2:1 (female to male). Of interest, when individuals are studied who chose to seek care for IBS, the ratio jumps to 4:1 (female to male).[3] This may in part reflect the general tendency of females to seek medical care. However, it is reasonable to assume that most patients seen in clinical practice with IBS will be women.


Impact on Patients
IBS is not associated with excess mortality. A number of large retrospective studies have shown that patients diagnosed with IBS do not go on to develop inflammatory bowel disease, colorectal or other gastrointestinal cancers, or any other significant disorders of the cardiovascular or neurologic systems in excess of non-IBS controls. Overall life expectancy for individuals with IBS is as good as (or somewhat better than) that of the population at large. However, these favorable findings should not confuse the reader into thinking that IBS is not associated with significant morbidity.
Patients with IBS have been shown to have rates of absenteeism from work that are almost 3 times that of non-IBS controls. Likewise, studies have shown that absence from school, as well as from work; inability to participate in activities of daily living; and the need to modify one's work setting, either in terms of working fewer hours per week, shifting the work setting to home, or in some cases, actually giving up one's occupation because of IBS, are all too common. In this respect, patients with IBS differ significantly from patients with most other chronic medical illness, and they differ dramatically from normal controls. In addition to income and productivity losses associated with IBS, a number of studies also have shown that the health-related quality of life (HRQOL) of patients with IBS is significantly lower than that of population-based controls and individuals with other chronic medical conditions. Two recent medical studies used the standard QOL instrument (ie, standard form-36 [SF-36]) to measure QOL in patients with IBS and then compared them to individuals with other chronic medical conditions, as well as to historic controls. In these 2 studies, patients with IBS were found to have dramatically lower QOL than did normal controls, which seems somewhat intuitive. However, these studies also showed that compared with individuals with rheumatoid arthritis, asthma, diabetes, as well as gastroesophageal reflux disease, IBS patients showed significantly lower levels of QOL, as measured by SF-36.[4,5] It is this profound impact on QOL that makes IBS a medical condition worthy of our attention.

The essentially zero mortality rate associated with IBS is more than offset by its somewhat unique ability to induce morbidity as it impairs an individual's ability to participate effectively in society.[6]


Impact on Physicians
IBS has traditionally been viewed as a somewhat frustrating condition by physicians. The reasons for this are multifactorial. First, the lack of precise diagnostic criteria for IBS has led many patients with a variety of chronic abdominal pain syndromes to be seen as having "IBS" by physicians. These challenging patients have often made the physician-patient encounter a "painful" experience for the treating physician. The second frustration for physicians who treat IBS is the fact that disorder-specific treatments for IBS did not exist. This was further complicated by the fact that many of the proposed treatments for IBS had little evidence to support their usefulness in IBS. The final stress confronting physicians dealing with the IBS patient was how to properly diagnose the syndrome. Because IBS was considered a diagnosis of "exclusion," it was difficult for the treating physician to determine which tests should be routinely included in the evaluation of the IBS patient. Likewise, when to cease increasingly complicated and esoteric testing before finally arriving at a diagnosis of IBS has traditionally been an unclear area in the medical literature.
Fortunately for physicians, this somewhat dismal situation is rapidly evolving for the better. The development of validated diagnostic criteria for IBS has come into being (see detailed discussion below). Use of these criteria allows physicians to separate patients with IBS from patients with structural disorders of the gastrointestinal tract. The evaluation of the IBS patient is becoming increasingly rationalized. We have moved away from the concept of "diagnosis of exclusion" toward a so-called "positive approach" to diagnosis. This means that patients who fit the epidemiologic profile for IBS and have IBS-like symptoms that meet the Rome II diagnostic criteria for IBS are considered to have IBS, unless so-called "alarm factors" are present. The presence of alarm factors in turn would suggest that a disorder other than IBS was causing the patient's symptoms. Alarm factors, if present, require diagnostic evaluation on their own merit. If a patient meets Rome II criteria for IBS and does not have alarm factors, treatment for IBS should be initiated.
Subsequent failure to improve on a reasonable IBS treatment regimen or the development of other signs and symptoms inconsistent with IBS then prompt exploration of other diagnostic possibilities. This "positive diagnostic approach" has the potential of dramatically curtailing the use of scarce medical resources. Finally, the last 5 years have brought dramatic improvements in the care of IBS, from both pharmacologic and behavioral perspectives. The ability to offer patients proven treatments that offer real hope of improving IBS symptoms has greatly enhanced the role of the physician to effectively ameliorate the suffering of the IBS patient.



Pathophysiology
Irritable bowel syndrome may be caused by alterations in bowel motility and visceral hyperalgesia have been demonstrated. Stress, gut neuropeptides and neuroendocrine connections to the brain are under investigation. There is a higher frequency of psychiatric diagnoses in patients with irritable bowel syndrome who seek medical attention.


The pathophysiology of IBS is a work in progress. Roughly 200 years after its initial description by the English physician William Powell, our understanding of what causes IBS symptoms remains incompletely understood. For most of the second half of the 20th century, tremendous attention was paid to the concept of altered gut motility as a cause of IBS symptoms.[20] However, several difficulties are apparent in this approach. First, although altered motility of the colon and small bowel can be demonstrated in patients with IBS, there is a very poor correlation between IBS symptomatology and the presence of alterations in gastrointestinal motility.[21] Likewise, drugs that alter gastrointestinal motility alone, such as antispasmodic[22,23] and prokinetic drugs like metoclopramide and cisapride,[24,25] have not been shown to be of any significant benefit in relieving IBS symptoms.
The third dilemma facing investigators in this area is that no pathognomonic pattern of gut dysmotility can be identified specifically with IBS, as opposed to other functional or organic disorders of the gut.[20] Altered motility, as occurs in IBS, is currently seen as one of many epiphenomena associated with the disorder, as opposed to being a cause of the disorder itself.
In the early 1980s, it was discovered that upon balloon distention in the rectum, individuals suffering from IBS were more sensitive to distention than were individuals who did not suffer from IBS.[26] This means that IBS patients feel discomfort at lower levels of balloon inflation in the rectum and lower bowel than do normal controls. This finding has been replicated in numerous studies, and the concept of "visceral" hypersensitivity has been established.[27] A second level of investigation in this area is the fascinating finding that individuals with IBS not only have a unique local response (in the rectum) to visceral stimulation, but they also tend to process signals in the brain differently from non-IBS controls. Mertz and others[27] have shown that IBS patients have differential responses in the anterior cingulate cortex and other areas of the brain when stimulated with rectal or sigmoid colon distention, compared with controls. These findings have been replicated by other investigators.[28] These data certainly suggest the possibility of a "brain-gut axis" where peripheral symptoms are processed in the end organ (ie, the colon), and then neural signals are carried via visceral afferents to the spinal cord, and then to the brain, where they are subject to additional processing.[29] It is this brain-gut axis that has received considerable attention recently in IBS research.
The findings of enhanced visceral sensitivity in the colon and rectum, as well as altered processing of signals in the brain, have provided new insight. Regarding the pathophysiology of IBS, the altered processing of neural sensation in IBS patients logically raises the question as to which neurotransmitters play a role in this abnormal signal transmission.
A large number of neuropeptides are involved in the regulation of both gastrointestinal motility and sensation in the gut. These include motolin, gastrin, peptide Y, cholecystokinin, serotonin, and others.
Serotonin has received the most interest for a number of reasons.
The first reason is the dramatic impact that modulation of serotonin has had on psychiatric disorders.
The development of selective serotonin reuptake inhibitor (SSRI) medications in the late 1980s revolutionized the practice of psychiatry.
The ability to treat depression with far fewer side effects than seen with earlier drugs made depression treatment more acceptable both to patients and physicians.
The success of these medications led to increased interest in the role of serotonin in the nervous system.
The second reason is that almost all (ie, more than 90%) of the serotonin contained in the body is found in the gut and not in the central nervous system.[29]
This fact raises the reasonable question of whether modulation of serotonin action in the gut could influence IBS and other functional bowel symptoms.
Serotonin (5-HT) is an interesting molecule. There are at least 15 subtypes of the 5-HT molecule. 5-HT1 and 5-HT2 are contained almost exclusively in the central nervous system. These are the target neurotransmitters for the SSRIs. The subtypes of serotonin contained in the gut consist mainly of 5-HT3 and 5-HT4, which has led to the development of drugs designed specifically to act on these serotonin subtypes (see detailed discussion in the Management section below). Identifying the role of serotonin in the pathophysiology of IBS symptomatology has led to the investigation of other neurotransmitters. Cholecystokinin antagonist and various neurokinin antagonists are all actively being investigated for their potential to influence IBS symptomatology.[30] This has led to a whole new era of gastrointestinal pharmacology based on a brain-gut axis. The opportunity to develop interventions at the level of the bowel, spinal cord, and brain based on this pathophysiologic conceptual model is considerable.




Diagnosis
Irritable bowel syndrome is a functional bowel dis­order. Functional gastrointestinal disorders can present with several constellations of symptoms for which an organic cause may not be identifiable. Lactose intolerance, the use of products that contain sorbitol or fructose and the use of medications, such as laxa­tives and antacids, that affect the intestines may be easily treatable causes of diarrhea, cramps or bloating. Approximately 52 percent of patients with lactose intolerance who meet the clinical criteria for irritable bowel syndrome were unaware of the relationship between lactose-containing foods and their symptoms.
A history of verbal or sexual abuse may also be important. Up to 50 percent of individuals with symptoms of irritable bowel syndrome report such a history. Other psychosocial factors and stressors should be identified, since it has been suggested that stress can exacerbate the symptoms of irritable bowel syndrome.
Findings such as occult blood, fever, weight loss, anemia or other biochemical abnormalities should be investigated for more specific causes. The occurrence of pain or diarrhea that interferes with normal sleep patterns or awakens the patient from sleep is suggestive of organic disease.

Alarm Symptoms Suggestive of Organic Disease
History
Weight loss > 10 lbs
Nocturnal symptoms
Initial onset at age > 50 years
Significant travel history
Severe diarrhea or constipation
Rectal bleeding
Arthritis/rashes
Family History
Colon cancer
Inflammatory bowel disease
Celiac disease
Physical Findings
Fever
Oral ulcers
Palpable abdominal mass
Guaiac-positive stool
Other physical finding (eg, abdominal mass, distension)
Rectal bleeding or obstruction
Laboratory Evaluation
Increased white blood cell count
Anemia
Abnormal chemistry
Increased thyroid-stimulating hormone
Elevated erythrocyte sedimentation rate or C-reactive protein

Differential Diagnosis of IBS*
Malabsorption
Dietary Factors
Intestinal disorders
Lactose intolerance
Pancreatic insufficiency
Alcohol/caffeine
Postgastrectomy
Sorbitol/high fructose corn syrup
Gas-producing foods
Infection
High-fat foods
Bacteria
Wheat (celiac disease)
Parasites
HIV and associated infections
Psychological Disorders
Inflammatory Bowel Disease
Panic disorder
Crohn's disease
Somatization
Ulcerative colitis
Depression
Microscopic/collagenous colitis
Gynecologic Disorders
Endometriosis
Malignancies
Dysmenorrhea
Endocrine tumors
Ovarian cancer
Colon cancer
Neurologic Disorders
Parkinson's disease
Medications
Multiple sclerosis
Antibiotics
Spinal cord lesions
Nonsteroidal anti-inflammatory drugs
Chemotherapy
Endocrine/Metabolic Disorders
Opiates
Diabetes
Calcium-channel blockers
Hypo/hyperthyroidism
Antidepressants
Hypercalcemia
*Consider dominant bowel symptom
†Not an all-inclusive list


Diagnostic Criteria for Irritable Bowel Syndrome
Persistence or recurrence of the following symptoms for a period of at least three months:
1. Abdominal pain or discomfort, relieved with defecation or associated with a change in the frequency or consistency of stool
2. An irregular (varying) pattern of defecation at least 25 percent of the time, with two or more of the following:
a. Altered stool frequency
b. Altered stool form (hard stool or loose, watery stool)
c. Altered stool passage (straining or sensation of urgency, feeling of incomplete evacuation)
d. Passage of mucus
e. Bloating or a feeling of abdominal distention

Clinical evaluation and tests
Symptoms suggestive of biliary or upper gastrointestinal disease should be evaluat­ed with an appropriate barium, endoscopic, ultrasonographic or nuclear evaluation. If diarrhea is a major component, a colonic biopsy for microscopic (lymphocytic) or collagenous colitis should be performed. A relationship of symptoms to the menses may suggest endometriosis.
Studies with negative findings not only help to confirm the diagnosis of irritable bowel syndrome but also provide reassur­ance for the patient. It is important, how­ever, to avoid excessive testing and retest­ing, which may undermine the patient's confidence in the diagnosis. Further inves­tigations should be performed if the diag­nosis remains in question or the symptoms have changed or progressed.



Treatment
Stratifying patients into those with predominant constipation or diarrhea, or pain, gas and bloating can be a useful way of directing treatment. Specific foods that aggravate symptoms sometimes can be identified and eliminated from the diet. Up to 50 percent of patients with irritable bowel syndrome improved with specific dietary exclusions. A careful nutri­tional assessment is also useful for exclud­ing artificial sweeteners and food additives that may contribute to symptoms and for determining optimum daily fiber intake.
Psychologic factors, including stress, anxiety, depression and somatization, need to be identified so that treatment can be directed at the underlying problem. Special attention should be given to a history of verbal or sexual abuse.



Treatment Options for Patients With IBS: A Focus on Serotonin
Despite numerous mechanistic studies, the relationship between changes in motor function and corresponding alterations in GI symptoms remains unclear. Psychological interventions, antidepressants, CCK antagonists (eg, loxiglumide), -opioid agonists (eg, fedotozine), somatostatin analogs (eg, octreotide), muscarinic antagonists (eg, zamifenacin), and serotonin agents are current treatment options for IBS. Serotonin agents acting upon the 5-HT3 and 5-HT4 receptor subtypes will be emphasized here.
5-HT3 receptor antagonist
The 5-HT3 receptor antagonist alosetron (Lotronex®) has recently been introduced in the market. In 1998, Delvaux and colleagues[16] studied 22 patients with IBS to test the effect of alosetron (0.25 mg or 4 mg for 7 days) on the perception of colonic distention. In comparison to placebo, alosetron increased the compliance of the colon, leading to an increase in the volume required to elicit the first sensation of abdominal pain.
The various effects of 5-HT in the gut and brain are attributable to the existence of numerous receptor subtypes (as many as 14 are known to date). The 5-HT1A, 5-HT1P, 5-HT2, 5-HT3, and 5-HT4 receptor subtypes predominate in the GI tract. The 5-HT3 and 5-HT4 receptor subtypes are involved in the control of GI function and have been implicated in the pathophysiology of IBS. The following table summarizes the effect of 5-HT3 antagonists and 5-HT4 agonists on GI function.[4-7]
5-HT3 antagonists
5-HT4 agonists
Act on ligand-gated ion channel
Act on a G-protein-coupled receptor
Attenuate visceral pain due to rectal distension
Directly inhibit spinal afferent neurons
Delay colonic transit
Enhance peristalsis and colonic transit
Increase fluid absorption in small intestine
Stimulate intraluminal secretion of chloride
Relieve abdominal pain and discomfort
Improve global GI symptoms, abdominal pain and discomfort, bowel movement, and bloating





A randomized, controlled Phase III trial of female patients with D-IBS given alosetron (1 mg bid) or placebo demonstrated compelling evidence of treatment efficacy despite the fact that this GI condition is notoriously associated with a high placebo effect.[17] This study had a 2-week screening period, a 12-week treatment phase, and a 4-week follow-up. Data were obtained primarily through a telephone-based patient data collection system, using "adequate relief" as the primary endpoint. Alosetron induced adequate relief from symptoms 1 week after the beginning of treatment, and this effect was maintained during the treatment period; a return to baseline conditions was apparent shortly after alosetron treatment cessation. Similar findings were described in a separate study using mebeverine (a smooth muscle relaxant that is unavailable in the United States) as a comparator drug. Alosetron treatment facilitated significant relief from symptoms in comparison with mebeverine; however, the onset of treatment efficacy was not apparent until 4 weeks posttreatment.[8]




5-HT4 receptor agonists
Cisapride (Propulsid®), a 5-HT4 receptor agonist/5-HT3 receptor antagonist, enhances motility in the upper GI tract but does not appear to have appreciable prokinetic actions on the colon. Two novel serotonin agents with promotility actions are currently under development: tegaserod (a 5-HT4 receptor partial agonist) for IBS and prucalopride (a 5-HT4 receptor full agonist) for chronic constipation.
Scintigraphic analysis of gastric emptying, small bowel transit, and colon transit of 24 patients with C-IBS given tegaserod (Zelmac[TM]; 1 mg or 2 mg bid) or placebo indicated that tegaserod facilitates about a 20% acceleration of proximal colonic transit.[19] In a randomized, double-blind, parallel-group study, 881 patients with C-IBS were given tegaserod (4 mg or 12 mg) or placebo during 12 weeks of active treatment, following a 4-week baseline period. A subject's global assessment (SGA) of relief measure was obtained weekly, using a 5-point ordinal scale (ie, completely, considerably, somewhat, unchanged, or worse) as the primary endpoint. The SGA of relief measure encompassed relief of abdominal pain, bowel movement, and overall well-being. At week 1, a significant increase in relief was apparent among patients taking tegaserod (12 mg/d) compared with counterparts on placebo. This effect was sustained through month 3.[20] Pooled data from two Phase III trials indicated that, compared with placebo, tegaserod (12 mg/d) significantly reduced abdominal pain -- an effect that was apparent as early as day 2. Tegaserod (12 mg/d) also significantly increased stool frequency as early as day 1. A trend toward a treatment-induced reduction in bloating was apparent, but more studies are necessary to obtain definitive data.
Figure 19. Effect of Tegaserod in C-IBS Patients

Figure 20. Effect of Tegaserod on Colonic Transit in Patients With C-IBS
Prucalopride has been shown to induce HAPCs (high-amplitude propagating contractions) in a dose-dependent manner, accelerating colonic transit and causing mass movement.[21,22] A study with a crossover design showed that prucalopride (1 or 2 mg/d), when administered to healthy volunteers, increased the percentage of loose stools and the overall number of stools per week.[21]
Figure 21. Prucalopride in Healthy Volunteers: Double-Blind Crossover Study
5-HT1 receptor agonist
A subset of IBS patients experiences dyspepsia, an upper GI disorder that occurs due in part to the failure of the fundus to relax. The efficacy of sumatriptan (a 5-HT1 receptor agonist) in alleviating symptoms of meal-related dyspepsia (characterized by upper GI discomfort and bloating) suggests that 5-HT1 receptors mediate fundic relaxation.[23]

Irritable Bowel Syndrome (IBS): Examining New Findings and Treatments CME
Authors: Marvin M. Schuster, MD; Michael D. Crowell, PhD; Nicholas J. Talley, MD, PhD
medscape



Criteria for the Diagnosis of Functional Constipation
Presence of two or more of the following symptoms for at least three months:
1. Two or fewer bowel movements per week
2. Stool weight of less than 35 g per day
3. Straining on more than 25 percent of occasions
4. Hard, lumpy stools on more than 25 percent of occasions
5. Sensation of incomplete evacuation on more than 25 percent of occasions


In most patients, constipation can be managed by supplementing the amount of dietary fiber to include at least 20 to 30 g per day. Adequate supplementation often can be achieved with one-half cup to one bowl per day of wheat bran or one-half to one tablespoon of psyllium twice daily. For patients who are unable or unwilling to take fiber supplements, a detailed listing of the fiber content of various foods can be helpful. A trial of supplemen­tal fiber is reasonable in all patients, be­cause of the relative safety of this approach and because of the placebo effect of 'all treatments for this disorder. Fluid intake should be increased in patients receiving fiber supplementation, and moderate daily exercise may also be beneficial.


A bowel-training regimen may be help­ful in patients who continue to have con­stipation. A 15- to 20-minute period should be allocated every day (typically after breakfast) for sitting on the toilet without attempts at straining. Patients should be discouraged from abusing laxa­tives. If laxatives must be used, osmotic laxatives are preferred. Lactulose (30 to 60 mL) or less expensive agents such as mag­nesium hydroxide (Milk of Magnesia) or magnesium citrate, taken at bedtime, are safe and effective in patients with normal renal function and may help in bowel retraining. The use of other types of laxatives should be discouraged.


The risk of side effects is increased with chronic use of mineral oil, stimulant laxa­tives such as bisacodyl (Dulcolax), senna concentrates (Dosaflex, Senokot) and laxa­tives that cause increased intestinal secre­tion, such as docusate (Colace). The effica­cy of prokinetic agents such as cisapride (Propulsid) remains largely unproved.


For patients with predominant diarrhea, supplementation of soluble fiber intake can be helpful in "bulking" the stools to improve the quality of bowel movements. The occasional use of antidiarrheal agents such as loperamide (Imodium), 2 to 4 mg four times a day. In addition, an empiric trial of small doses of cholestyramine (Questran), 4 g per day, may be help­ful, even in patients with no evidence of bile salt malabsorption.


Patients with predominant pain or gas syndromes may benefit from the elimina­tion of gas-forming foods. One initial approach is to eliminate lactose, legumes (beans, peas and lentils) and other gas-forming vegetables, including broccoli, cauliflower, brussels sprouts, onions, cucumbers and leafy vegetables. If symp­toms improve, foods can be incrementally reintroduced.
While antispasmodic drugs have often been used to treat pain symptoms, their efficacy remains unproved, and they may be associated with anticholinergic side effects. Dicyclomine (Bentyl), 10 to 20 mg three or four times daily may have fewer side effects than nonselective anticholiner­gic agents.



Antidepressants. Several con­trolled and uncontrolled trials suggest that antidepressants help manage pain in patients with irritable bowel syndrome. Benefits of antidepressant therapy may included improve­ment in anxiety or depression, alteration of visceral nociception and stress reduction.39 Antidepressants that have been used in patients with functional gastrointestinal syndromes are listed in Table 4.



Antidepressant and Anxiolytic Drugs Used for Irritable Bowel Syndrome
Dosage
Drug (mg per day)
Tricyclic antidepressants
Amitriptyline (Elavil, Endep) 10 to 150
Doxepin (Adapin, Sinequan) 10 to 100
Protriptyline (Vivactil) 5 to 15
Imipramine (Janimine, Tofranil) 20 to 25


Anxiolytic / antidepressants
Alprazolam (Xanax) 0.25 to 2.25


Course to Follow When Initial Treatment Fails
Despite reassurance and conservative treatment, many patients with irritable bowel syndrome continue to have symp­toms. In rare cases, a reappraisal of the diagnosis may be indicated, and additional appropriate tests should be performed. This approach, which is often encouraged by patients, must be carefully balanced with the risks and expense of overtesting, as well as the possibility that patients will develop unrealistic expectations.
A consistent approach should be used, with regular, brief appointments with the patient, and the patient should be helped to accept realistic goals for treatment. These measures may assist in strengthening the physician-patient relationship and minimiz­ing the tendency toward Adoctor shopping@. Referral to a gastroenterologist or a colorectal specialist may be helpful for selected patients. Psychotherapy may be a useful adjunct to medical therapy in motivated patients.
Pelvic floor dysfunction and colonic inertia must be considered in patients withintractable constipation. Several tests may be used to assess anorectal and pelvic floor function. Delayed colonic transit can be measured in several ways. One technique uses radiolabeled resin pellets that are delivered to the ascending colon by means of a delayed-release pH-sensitive polymer that dissolves in the ileum. Another method uses radiopaque markers, with radiographs taken four days and one week after the ingestion of 20 markers on three successive days.
For patients with intractable diarrhea, repeated studies to exclude bacterial or par­asitic infection may be helpful. In the absence of infection, an assessment of small-intestine transit time can be considered. One such test, the hydrogen breath test, assesses the time it takes for a substrate (e.g., lactulose) to reach the colon, where it is metabolized by bacteria. The presence of bacterial overgrowth in the small intestine invalidates this test. While the usefulness of the hydrogen breath test remains to be proved, further efforts to reduce the rate of intestinal transit, such as increasing the dose of Ioperamide, may be helpful in patients with intractable diarrhea.