IRRITABLE BOWEL SYNDROME IN CHILDREN

Introduction

Background

Irritable bowel syndrome (IBS) is defined as chronic or recurrent abdominal pain, altered bowel habits, and bloating, with the absence of structural or biochemical abnormalities to explain these symptoms. Irritable bowel syndrome is part of a broader group of disorders known as functional GI disorders. It is the most common GI diagnosis among gastroenterology practices in the United States and is one of the top 10 reasons for visits to primary care physicians. Irritable bowel syndrome is recognized in children, and many patients trace the onset of their symptoms to childhood. Children who have a history of recurrent abdominal pain are at increased risk of irritable bowel syndrome during adolescence and young adulthood.

Pathophysiology

Irritable bowel syndrome has no identifiable cause, and laboratory testing is unrevealing. Over the last 5 decades, the understanding of irritable bowel syndrome has evolved from a disorder of motor activities in the upper and lower GI tracts to a more integrated understanding of visceral hypersensitivity and brain-gut interaction.

GI motility abnormalities

Studies evaluating the motor response of the colon to meals, pain, and stress suggest a difference between control subjects and patients with irritable bowel syndrome. Pretreatment with anticholinergic medication in irritable bowel syndrome was demonstrated to reduce meal-stimulated pain and diarrhea. The finding of an abnormal, 3-cycle-per-minute, slow-wave activity in the colon of patients with irritable bowel syndrome was not confirmed by other studies and was noted in some individuals without irritable bowel syndrome.

Abnormal small-bowel motility has also been reported by some investigators. Intestinal transit has been demonstrated to be delayed in patients with constipation-predominant irritable bowel syndrome. In contrast, the transit was accelerated in patients with diarrhea-predominant irritable bowel syndrome. Clustered contractions in the duodenum and jejunum and prolonged propagated contractions in the ileum were noted more frequently in patients with irritable bowel syndrome. Small-bowel motility studies have demonstrated more abnormal findings in patients with irritable bowel syndrome in conscious states than during sleep, suggesting that the condition may result in part from CNS input.

Non-GI smooth-muscle abnormalities

Bladder dysfunction was identified in 50% of patients with irritable bowel syndrome and in only 13% of control subjects. One study found patients with irritable bowel syndrome to have a higher incidence of orthostatic hypotension. A clinical study demonstrated a greater reduction of forced expiratory volumes in 1 second (FEV1) induced by methacholine in patients with irritable bowel syndrome than in control subjects.

Visceral hypersensitivity

Most patients with functional disorders appear to have inappropriate perception of physiologic events and altered reflex responses in different gut regions. Patients with irritable bowel syndrome undergoing balloon distension studies of the colorectum demonstrated awareness of distension and pain at pressures and volumes that were significantly lower than in control subjects. The development of chronic hyperalgesia within the GI tract can be explained by the development of hyperexcitability of neurons in the dorsal horn in response to peripheral tissue irritation or to descending influences from the brain stem. Multiple factors are proposed to alter neuroreceptors and afferent spinal neuron functions. These factors include genetic, inflammatory, local nerve mechanical irritation, motility, and psychological factors.

Brain-gut interaction

The brain-gut axis is a bidirectional pathway that links higher cortical centers with visceral afferent sensation and intestinal motor function. Regulation of these connections occurs via numerous neurotransmitters found in the brain and gut, including cholecystokinin, vasoactive intestinal peptide, substance P, serotonin (5-hydroxytryptamine [5-HT]), and many others. These transmitters act at different sites in the brain and gut and lead to varied effects on gastrointestinal motility, pain control, emotional behavior, and immunity.

Serotonin plays a critical role in the regulation of GI motility, secretion, and sensation. In the GI tract, 5-HT is synthesized by the enterochromaffin cells (EC) located within the mucosa of the intestine. 5-HT released by EC cells initiates peristaltic and secretory reflexes by acting on its receptors. Several subclasses of 5-HT receptors are differentiated on the basis of structure, molecular mechanism, and function. Excess serotonin is removed by the serotonin transporter (SERT) expressed by intestinal epithelial cells. Studies have shown that irritable bowel syndrome symptoms may be related to imbalance in mucosal 5-HT availability caused by defects in 5-HT production, serotonin receptors, or SERT.

Dysregulation of the brain-gut system is becoming an acceptable theory to explain the functional GI disorders. Furthermore, several studies have hypothesized that specific 5-HT receptor antagonists may be beneficial in irritable bowel syndrome. Numerous newer noninvasive imaging techniques (eg, positron emission tomography, functional MRI) have been applied to assess brain-gut interactions in healthy patients and in those with irritable bowel syndrome.

Genetics

Several studies suggest that irritable bowel syndrome may have a genetic basis. The genetic theory is based on twin studies as well as familial aggregation of irritable bowel syndrome. Several twin studies have shown a higher concordance rate for irritable bowel syndrome in monozygotic twins than in dizygotic twins.^1,2,3,4 Studies on familial aggregation have found that patients with irritable bowel syndrome are more likely than controls to present positive family history.^5,6,7 However, familial and twin aggregation studies cannot exclude the influence of environmental and social learning in the development of irritable bowel syndrome.

In a twin study conducted by Levy et al, the proportion of dizygotic twins with irritable bowel syndrome who have mothers with irritable bowel syndrome was greater than the proportion of dizygotic twins with irritable bowel syndrome who have co-twins with irritable bowel syndrome. The data also revealed that having a mother or a father with irritable bowel syndrome are independent predictors of irritable bowel syndrome status and both are stronger predictors than having a twin with irritable bowel syndrome.²

Several investigators have proposed that irritable bowel syndrome may be associated with select gene polymorphisms, including SERT, alpha-adrenergic receptors, interleukin-10, transforming growth factor, tumor necrosis factor-alpha, and sodium channel. However, the data are limited, and studies have failed to identify a specific irritable bowel syndrome gene.^8,9

Psychosocial factors in irritable bowel syndrome

Numerous studies have found an increased prevalence of abnormal psychiatric disorders, including anxiety, major depression, personality disorders, and hysteria, in adult patients with irritable bowel syndrome, especially patients referred to medical facilities. These psychological disturbances are not believed to cause or induce the symptoms of irritable bowel syndrome but are thought to influence the patient's perception of the symptoms and affect the clinical outcome. Stressful events are known to affect GI functions and may lead to exacerbation of symptoms in patients with irritable bowel syndrome.

In addition, antidepressant or antipsychotic therapy is helpful in some patients with irritable bowel syndrome. A meta-analysis has confirmed the relative efficacy of antidepressant medications in irritable bowel syndrome, particularly in predominantly diarrheic patients experiencing severe pain.¹⁰ Studies have reported an increased frequency of prior sexual or physical abuse in patients with irritable bowel syndrome and other functional GI disorders.

Dietary factors

Some studies have proposed that carbohydrate intolerance may produce significant symptoms in patients with irritable bowel syndrome. Ingestion of lactose, sorbitol, or fructose is associated with increased GI symptoms. Likewise, a food allergy may play a minor role in triggering or exacerbating symptoms in some patients with irritable bowel syndrome. A study by Atkinson et al has shown that immunoglobulin (Ig)G food antibodies may have a role in irritable bowel syndrome and food elimination based on IgG antibodies may be effective in reducing irritable bowel syndrome symptoms.¹¹

GI infection and irritable bowel syndrome

Some investigations found a correlation between the development of irritable bowel syndrome and a prior severe GI infection, especially in patients with higher scores for anxiety. Symptoms compatible with irritable bowel syndrome affect 10-15% of adult patients after acute infectious gastroenteritis. Factors that increase risk to develop post infectious irritable bowel syndrome include severe and prolonged infection, female sex, younger age, antibiotic treatment for this infection, and concomitant presence of anxiety.

In one pediatric study, 36% of children with prior history of acute bacterial gastroenteritis developed abdominal pain symptoms that were consistent with functional GI disorders. Symptoms were compatible with irritable bowel syndrome in 87% and with dyspepsia in 24%.¹²

Studies have demonstrated low-grade lymphocytic infiltration in the intestinal mucosa, increased permeability, and increases in inflammatory components including EC and mast cells.

Some studies have shown that small intestinal bacterial overgrowth is common in subjects with irritable bowel syndrome. A double-blind placebo-controlled study by Pimentel et al (2003) showed that normalization of lactulose breath testing with neomycin correlated with symptom improvement in patients with irritable bowel syndrome.¹³

Frequency

United States

Symptoms consistent with irritable bowel syndrome are present in 10-20% of adolescents and adults. Less than one third of patients seek medical advice. In the pediatric population, irritable bowel syndrome symptoms are reported in 14% of high-school students and 6% of middle-school students. One third of patients with irritable bowel syndrome trace their symptoms to childhood.

International

Prevalence in developing countries is probably lower than in Western countries, but this may be explained by a combination of reduced availability of medical care and different cultural approaches to illness.

Mortality/Morbidity

Irritable bowel syndrome is not a life-threatening condition but can have a serious impact on a patient's daily activities and quality of life. Greater impairments in quality of life are reported in patients with irritable bowel syndrome who sought medical care compared with those who did not consult their physicians for irritable bowel syndrome symptoms. It is a major cause of absenteeism at the workplace and at school. Abdominal pain in patients with irritable bowel syndrome is responsible for significant school absences in 4-5% of middle and high-school students.

Race

Irritable bowel syndrome is not well characterized outside Western countries. According to reported studies, the disease prevalence is lower in Hispanic and Asian populations than in Caucasian populations, and whites are more likely to have irritable bowel syndrome than blacks.

Sex

Women are 2-3 times more likely than men to have irritable bowel syndrome. In pediatric patients, both sexes are equally affected.

Age

Irritable bowel syndrome is a disorder of young people. One half of patients experience symptom onset when younger than 35 years, and 40% of patients are aged 35-50 years when symptoms begin. Irritable bowel syndrome is recognized in children. Symptoms consistent with irritable bowel syndrome are reported in 16% of students aged 11-17 years. Irritable bowel syndrome is not described in preschool-aged and younger children because the diagnosis depends on the child's ability to report detailed symptoms.

Clinical

History

Irritable bowel syndrome (IBS) has a broad range of symptoms; the most common are abdominal pain and altered bowel movements. Although symptoms may vary among patients, a pattern usually develops for each patient. The presence of characteristic symptoms in an otherwise healthy individual is sufficient to make a diagnosis of irritable bowel syndrome in most individuals.

• The characteristics of abdominal pain vary between patients and even within an individual patient.
• The pain can be dull, achy, colicky, or sharp.
• Pain can occur anywhere in the abdomen but is commonly located in the hypogastric or periumbilical regions.
• The pain has no specific pattern but may be aggravated by stress and food and partially relieved after defecation.
• Altered bowel habits include constipation, diarrhea, or alternating constipation with diarrhea.
• Stools are usually of small volume and pasty. Constipation is associated with small, hard, pelletlike stools. Diarrhea characteristically occurs during waking hours and often is precipitated by meals.
• Mucus can be a component of the stool in as many as 50% of patients with irritable bowel syndrome.
• In some patients, defecation is associated with a sense of incomplete evacuation that can lead to repeated trips to the bathroom and prolonged straining.
• Symptoms of abdominal distension (ie, bloating, increased belching, flatulence) are frequently reported by patients with irritable bowel syndrome. They are less common in children than adults.
• Other GI symptoms (ie, heartburn, dyspepsia, nausea, vomiting) are reported in 25-50% of adult patients with irritable bowel syndrome. Dyspeptic symptoms are present in as many as 30% of pediatric patients with irritable bowel syndrome.
• Extraintestinal symptoms are also reported. Patients with irritable bowel syndrome frequently report dysmenorrhea, urinary frequency, incomplete bladder emptying, back pain, and headache. These complaints are common in adults but rare in children.
• Patients may relate a history of inciting events.
• Exacerbation of irritable bowel syndrome symptoms is sometimes reported to follow stressful experiences, ingestion of specific foods, or consumption of alcohol or caffeine.
• Menses may exacerbate irritable bowel syndrome symptoms in women.
• In children, symptom precipitants include school-related problems, overeating, or eating problems.
• The following clinical features should alert the physician to the possibility of a disorder other than irritable bowel syndrome:
• Frequent awakening by symptoms
• Steady progressive course
• Fever
• Weight loss
• Arthritis
• Rectal bleeding
• Persistent vomiting
• The diagnosis of irritable bowel syndrome requires the identification of the symptoms characteristic of irritable bowel syndrome and the exclusion of other medical conditions with similar clinical presentations. Symptom-based criteria have been established for the diagnosis of irritable bowel syndrome, which includes the Manning or, more recently, the Rome criteria. The pediatric working team adopted the Rome II criteria in the adult population because these criteria seemed to apply equally well to children. Rome II criteria apply to children old enough to provide an accurate pain history of at least 12 weeks, which need not to be consecutive, in the preceding 12 months. The history can include the following:
• The abdominal discomfort or pain has 2 out of the following 3 features: (1) relief with defecation, (2) onset associated with a change in frequency of stool, and (3) onset associated with a change in the form of stool.
• No structural or metabolic abnormalities exist to explain the symptoms.

Physical

• Physical examination findings generally are unremarkable. The patient may appear tense and anxious with sweaty palms. Abdominal tenderness may be present. Tender and palpable sigmoid is found in some patients.
• Findings against the diagnosis of irritable bowel syndrome include the following:
• Abdominal rigidity
• Rebound tenderness
• Lymphadenopathy
• Hepatosplenomegaly
• Positive fecal bleeding test result

Causes

• Irritable bowel syndrome has no identifiable cause (see Pathophysiology).

Differential Diagnoses

Crohn Disease	Malabsorption Syndromes
Endometriosis	Sprue
Giardiasis	Ulcerative Colitis
Human Immunodeficiency Virus Infection	Zollinger-Ellison Syndrome
Lactose Intolerance

Other Problems to Be Considered

Antibiotic-associated diarrhea

Workup

Laboratory Studies

• No specific laboratory markers are noted for irritable bowel syndrome (IBS). Patients who have characteristic symptoms and meet the Rome criteria for irritable bowel syndrome (see History) do not require a thorough diagnostic evaluation. A more aggressive approach is recommended for individuals with atypical symptoms, those with a rapidly progressive course, or when the index of suspicion for an organic disease is high.
• In classic cases, a limited screen for organic disease is reassuring and should consist of the following:
• CBC count
• Erythrocyte sedimentation rate
• Stool studies for ova and parasites
• Stool cultures and stool Clostridium difficile toxin assay, if clinically indicated
• A breath hydrogen test or a trial of dietary lactose restriction to exclude lactose intolerance
• The following laboratory tests are indicated in special instances:
• Lead level assessment
• Celiac serologic tests
• Serum immune markers for inflammatory bowel disease
• Thyroid function tests
• Tests for Helicobacter pylori (ie, serum antibody titers, urea breath test)

Imaging Studies

• Plain abdominal radiography is recommended for patients with pain-predominant symptoms. Perform plain abdominal radiography during a pain episode to exclude intermittent obstruction.
• Upper GI study with small-bowel follow through is a useful study if Crohn disease or celiac sprue is suggested.
• Barium enema can be useful for patients in whom Hirschsprung disease or congenital structural anomalies of the colon are suspected. Barium enema is also indicated in older patients (>50 y) because of the increased likelihood of colonic neoplasms.
• Gastric scintigraphy is indicated for selected patients to evaluate for gastroparesis.
• Abdominal ultrasonography is suggested for patients in whom biliary disease is suspected. It has high sensitivity and specificity for gallstones. It can also detect gallbladder wall thickening.

Other Tests

• GI manometry can assist in evaluating patients in whom gastroparesis or intestinal pseudoobstruction is suspected.
• Anorectal manometry is useful to screen patients in whom Hirschsprung disease is suspected.

Procedures

• Sigmoidoscopy or complete colonoscopy is useful to evaluate for inflammatory conditions such as ulcerative colitis and microscopic colitis. Severe colitis noted during colonoscopy is shown in the image below.

Severe colitis noted during colonoscopy. The mucosa is grossly denuded, with active bleeding noted. This patient had her colon resected very shortly after this view was obtained.

• Upper endoscopy with small-intestinal biopsies is recommended in patients in whom peptic ulcer disease, Helicobacter pylori infection, Crohn disease, celiac disease, or other malabsorption conditions are suspected.

Treatment

Medical Care

Irritable bowel syndrome (IBS) is a chronic illness and has no cure.
Treatment may be challenging and even frustrating to the physician, the patient, and the patient's family. The most important component of treatment is to establish an effective and therapeutic relationship with the patient and his or her family.
Educate the child and parents that irritable bowel syndrome is a chronic illness that cannot be cured. At the same time, reassure them that it is not a life-threatening condition and it does not lead to physical impairment. Tell the patient and the family that the symptoms are real and respond to their worries and concerns. Reassurance is more effective if offered after a careful history and physical examination and a conservative diagnostic evaluation.
Most patients have mild symptoms and maintain normal daily activities and regular school attendance. Address the possible dietary and psychosocial triggering factors. Counseling, dietary modifications, and lifestyle changes are usually effective and sufficient for treatment.
A smaller proportion of patients have moderate-to-severe symptoms with some disruption of their activities and school performance. This group of patients may benefit from pharmacotherapy and behavioral treatment. Referral to a psychologist may be required.

A recognized association exists between the development of irritable bowel syndrome (functional abdominal pain) and prior severe gastrointestinal infection. One study has shown that the administration of lactobacillus rhamnosus GG (LGG) significantly reduced the frequency and severity of abdominal pain in children with irritable bowel syndrome.¹⁴

Consultations

Consider further evaluation and a referral to a pediatric gastroenterologist if findings from the patient's history, physical examination, or screening laboratory tests are suggestive of organic disease.

Diet

• Dietary modification
• Some patients with irritable bowel syndrome report exacerbation of their symptoms after ingestion of certain foods. Elimination of certain foods, such as sorbitol, fructose, and gas-forming legumes, achieves relief in some patients with irritable bowel syndrome, especially those with excess gas. Attempt lactose restriction in patients with documented lactose malabsorption.
• Foods associated with increased flatulence include onions, beans, celery, carrots, prunes, bananas, raisins, brussel sprouts, wheat germ, and bagels.
• Fiber supplements
• A high-fiber diet or supplement is useful in patients with constipation-predominant irritable bowel syndrome. Several studies have demonstrated that fiber enhances water-retentive properties of stool, increases stool weight, and accelerates colonic transit.
• In general, dietary fibers are less soluble and more effective as bulking agents, whereas synthetic fibers are more soluble and increase water retention.
• The recommended daily intake of fiber (in grams) for children is estimated by adding 5 to their age in years.

Medication

Pharmacotherapy is recommended for patients with moderate-to-severe irritable bowel syndrome (IBS) symptoms that cause disruptions in activity. Treatment is symptomatic and is directed at the most predominant symptom (eg, dietary fiber supplementation and stool softeners for constipation, antidiarrheals for diarrhea, smooth muscle relaxants for pain). A better understanding of the pathophysiology of irritable bowel syndrome and the role of neurotransmitters and receptors involved in the GI sensory and motor functions have provided opportunities for the development of newer therapeutic agents. The role of serotonin in the pathophysiology of irritable bowel syndrome has drawn much attention, and agonists and antagonists at 5-hydroxytryptamine (5-HT) receptors have been approved for the treatment of subgroups of patients with irritable bowel syndrome.
Saps et al conducted a double-blind, placebo-controlled trial examining amitriptyline efficacy in treating children (n=83) with pain-predominant functional GI disorders (eg, irritable bowel syndrome, functional abdominal pain, functional dyspepsia).¹⁵ Participants were randomized to receive 4 weeks of either placebo or amitriptyline (weight <35 kg = 10 mg/d, weight >35 kg = 20 mg/d). The primary outcome, overall response to treatment (ie, child’s pain assessment and sense of improvement), indicated no difference between placebo and amitriptyline (57.5% improvement and 2.5% worsening with placebo compared with 63% improvement and 5% worsening with amitriptyline; P=0.63). Children with severe baseline pain in both groups had poorer response to treatment. Although placebo and amitriptyline both produced a therapeutic response of pain reduction, this study showed no significant difference between placebo and amitriptyline.

Antispasmodic and anticholinergic agents

These are the most frequently used medications (ie, hyoscyamine, dicyclomine) in the United States for the treatment of pain episodes in patients with irritable bowel syndrome. Results from adult studies on the efficacy of these medications have provided conflicting data. The meta-analysis of the use of smooth muscle relaxants (eg, cimetropium, otilonium bromide, pinaverium, mebeverine, trimebutine) by Poynard et al showed efficacy over placebo in irritable bowel syndrome.¹⁶ These drugs have calcium channel–blocking properties or antimuscarinic activities. No pediatric data are available with which to evaluate their efficacy or adverse effects.

Hyoscyamine (Levsin, Levbid)

Blocks action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and CNS, which in turn has antispasmodic effects.

Adult

Levsin: 0.125-0.25 mg (1-2 tab) PO/SL q4h prn; not to exceed 12 tab per d
Levbid: 0.375-0.75 mg PO bid

Pediatric

<2 years: 0.125-mg/mL gtt; repeat q4h PO prn
The following is an approximate dosage guide:
2.3 kg (5 lb): 3 gtt; not to exceed 18 gtt per d
3.4 kg (7.5 lb): 4 gtt; not to exceed 24 gtt per d
5 kg (11 lb): 5 gtt; not to exceed 30 gtt per d
7 kg (15 lb): 6 gtt; not to exceed 36 gtt per d
10 kg (22 lb): 8 gtt; not to exceed 48 gtt per d
15 kg (33 lb): 11 gtt; not to exceed 66 gtt per d
2-12 years: Use 1.25-5 mL of elixir (0.03125-0.125 mg) PO q4h prn; not to exceed 30 mL/d
The following is an approximate dosage guide:
10 kg (22 lb): 1.25 mL
20 kg (44 lb): 2.5 mL
40 kg (88 lb): 3.75 mL
50 kg (110 lb): 5 mL
>12 years: Administer as in adults
Effects decrease when used concurrently with antacids; toxicity increases when used concurrently with phenothiazines, amantadine, haloperidol, MAOIs, or TCAs
Documented hypersensitivity; obstructive uropathy; narrow-angle glaucoma; myasthenia gravis; obstructive GI tract disease

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly patients; some products contain sodium metabisulfite, which can cause allergic reactions

Dicyclomine (Bentyl)

Treats GI motility disturbances. Blocks action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and CNS.
Reports show that administration of dicyclomine syrup in infants has been followed by serious respiratory symptoms, seizures, syncope, pulse rate fluctuations, and coma. Death has been reported.

Adult

20-40 mg PO qid; discontinue if not effective within 2 wk or if 80 mg qd is associated with adverse effects

Pediatric

<6 months: Contraindicated
>6 months to 2 years: 5-10 mg PO tid/qid 15 min ac; not to exceed 40 mg/d
>2 years to 12 years: 10 mg PO tid
>12 years: Administer as in adults
Effects decrease when used concurrently with antacids; coadministration with anticholinergic drugs (eg, antihistamines, TCAs) may increase toxicity
Documented hypersensitivity; obstructive uropathy; obstructive disease of GI tract; severe ulcerative colitis; toxic megacolon; reflux esophagitis; glaucoma; myasthenia gravis; infants <6 mo

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause blurred vision or change in vision, severe constipation, urinary retention, and psychosis
Caution with hepatic or renal insufficiency, cardiovascular disease, urinary tract obstruction, ulcerative colitis, GI obstruction, hyperthyroidism, and hypertension

Antidiarrheal agents

These agents are used to treat diarrhea adjunctly with rehydration therapy to correct fluid and electrolyte depletion. They are usually helpful when diarrhea is the predominant symptom. Studies of the opiate agent loperamide show that it improves stool consistency, decreases stool frequency, and reduces abdominal pain. Cholestyramine acts by binding bile acids and can be helpful in some patients with irritable bowel syndrome. Alosetron and tegaserod are 5-HT4 receptor partial agonists that bind with high affinity at human 5-HT4 receptors. The activation of 5-HT4 receptors in the GI tract stimulates the peristaltic reflex and intestinal secretion and inhibits visceral sensitivity. In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the GI tract. In addition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals.

Tegaserod was temporarily withdrawn from the US market in March 2007; however, as of July 27, 2007, restricted use of tegaserod is now permitted via a treatment IND protocol. The treatment IND allows tegaserod treatment of irritable bowel syndrome with constipation or chronic idiopathic constipation (CIC) in women younger than 55 years who meet specific guidelines. Its use is further restricted to those in critical need who have no known or preexisting heart disease.

Earlier this year, tegaserod marketing was suspended because of a meta-analysis of safety data pooled from 29 clinical trials that involved more than 18,000 patients. The results showed an excess number of serious cardiovascular adverse events, including angina, myocardial infarction, and stroke, in those taking tegaserod compared with placebo. In each study, patients were assigned at random to either tegaserod or placebo. Tegaserod was taken by 11,614 patients, and placebo was taken by 7,031 patients. The average age of patients in these studies was 43 years, and most patients (ie, 88%) were women. Serious and life-threatening cardiovascular adverse effects occurred in 13 patients (0.1%) treated with tegaserod; among these, 4 patients had a heart attack (1 died), 6 had unstable angina, and 3 had a stroke. Among the patients taking placebo, only 1 (0.01%) had symptoms suggesting the beginning of a stroke that went away without complication.

For more information, see the FDA MedWatch Product Safety Alert.

Loperamide (Imodium)

Synthetic opioid; does not have central nervous action in therapeutic doses. Acts by slowing intestinal motility and enhancing water and electrolyte absorption. Reduces diarrhea and pain in patients with diarrhea-predominant IBS.

Adult

2-12 mg/d PO divided bid/tid; necessary doses differ greatly between individuals

Pediatric

<2 years: Not recommended
>2 years: 0.08-0.24 mg/kg/d PO divided bid/tid; not to exceed 2 mg/dose
Phenothiazines, TCAs, and CNS depressants may increase toxicity
Documented hypersensitivity; diarrhea resulting from infections; pseudomembranous colitis

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in severe ulcerative colitis or antibiotic-induced pseudomembranous colitis; monitor for CNS toxicity in patients with hepatic insufficiency because of decreased clearance

Cholestyramine (Prevalite, Questran)

Binds endogenous bile acids and can improve diarrhea in patients with unexplained diarrhea or idiopathic bile acid malabsorption.

Adult

3-4 g PO bid/qid mixed with fluid or food

Pediatric

240 mg/kg/d PO divided tid ac as slurry in water, juice, or milk
Inhibits absorption of numerous drugs including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G
Documented hypersensitivity; complete biliary obstruction

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in constipation and phenylketonuria

Alosetron (Lotronex)

Potent and selective antagonist of serotonin 5-HT3 receptor type. 5-HT3 receptors are extensively located on enteric neurons of GI tract, and stimulation causes hypersensitivity and hyperactivity of intestine. Alosetron blocks these receptors and, thus, is effective in controlling IBS symptoms.
Only approved for treatment in women with severe, chronic, diarrhea-predominant IBS that has failed to respond to conventional IBS therapy. Less than 5% of IBS is considered severe, and only a fraction of severe cases are diarrhea-predominant IBS. Limiting use to this severely affected population is intended to maximize the benefit-to-risk ratio. Previously removed from US market but reintroduced with new restrictions approved by FDA on June 7, 2002. Restricted because serious and unpredictable GI adverse events (some of which resulted in death) were reported in association with its use following original approval in February 2000.

Adult

Women: 0.5 mg PO bid for 4 wk initially; may increase to 1 mg PO bid if qd dose inadequate for controlling symptoms; discontinue if inadequate response to 1 mg bid after 4 wk
Men: Not established

Pediatric

Not established
Substrate of CYP450 isoenzymes 2C9, 3A4 (minor), and 1A2 (minor); coadministration with isoenzyme inhibitors (eg, cimetidine, fluvoxamine, fluoxetine, sertraline, metronidazole, omeprazole, co-trimoxazole) may decrease elimination and increase risk of toxicity; coadministration with isoenzyme inducers (eg, phenobarbital, fluconazole, carbamazepine, phenytoin) may increase clearance
Documented hypersensitivity; history of constipation, intestinal obstruction, stricture, toxic megacolon, GI perforation, adhesions, ischemic colitis, impaired intestinal circulation, thrombophlebitis, hypercoagulable state, Crohn disease, ulcerative colitis, or diverticulitis

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Discontinue immediately if serious GI adverse events occur (eg, ischemic colitis, serious complications of constipation); these adverse effects have resulted in hospitalization, blood transfusion, surgery, and death
Constipation is a dose-related adverse effect; elderly patients are more prone to GI risks; caution in hepatic insufficiency (decrease dose); pharmacists may only dispense prescriptions that display a prescribing program sticker affixed by an enrolled physician, and they must distribute a copy of the FDA-approved medication guide with each prescription; to enroll in the prescribing program call GlaxoSmithKline at 1-888-825-5249 or visit www.lotronex.com

Tegaserod hydrogen maleate (Zelnorm)

As of April 2008, no longer available in US. Previously available in US by restricted treatment IND for irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) in women younger than 55 years who meet specific guidelines. Indicated for the short-term treatment of women with irritable bowel syndrome in which constipation is the predominant symptom. Serotonin type 4 receptor partial agonist with no affinity for 5-HT3 receptors. May trigger peristaltic reflex via 5-HT4 activation, which enhances basal motor activity and normalizes impaired GI motility. Research studies have shown inhibitory activity of drug on visceral activity in GI tract.

Adult

Women: 6 mg PO bid 30 min ac for 4-6 wk; in patients who respond to treatment, an additional 4-6 wk of therapy may be considered
Men: Not established

Pediatric

Not established
None reported
Documented hypersensitivity; severe renal impairment; moderate or severe renal impairment; history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Diarrhea may occur; do not give to patients with diarrhea; discontinue if new or sudden worsening of abdominal pain or diarrhea occurs; ischemic colitis and other forms of intestinal ischemia have been rarely reported (causality has not been established); discontinue immediately if symptoms of ischemic colitis (eg, rectal bleeding, bloody diarrhea, new or worsening abdominal pain) occur and evaluate immediately; do not resume treatment if findings consistent with ischemic colitis

Antidepressant drugs

Numerous studies have shown that TCAs (ie, imipramine, amitriptyline) can be useful in the treatment of irritable bowel syndrome in some patients. In addition to their antidepressant effects, TCAs have neuromodulatory and analgesic properties, which can be achieved at lower doses than those required for treatment of depression. Because of their inhibitory effect on gut motor function, TCAs may benefit patients with irritable bowel syndrome with predominant diarrhea or pain. TCAs particularly benefit patients with irritable bowel syndrome who have well-defined depression or panic attacks.

Amitriptyline (Elavil)

Inhibits reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases concentration in CNS.

Adult

10-50 mg/d PO qhs; administered at lower doses than required for depression

Pediatric

0.2-0.4 mg/kg/d PO qhs
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Documented hypersensitivity; MAOIs within 14 d; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Cardiovascular disease; seizure disorder; urinary retention; adverse effects include sedation, urinary retention, constipation, dry mouth, dizziness, and arrhythmias; monitor ECG and BP at start of therapy and with dose changes

Imipramine (Tofranil)

Inhibits reuptake of norepinephrine or serotonin (5-HT) at presynaptic neuron.

Adult

10-50 mg/d PO qhs; administered at lower doses than required for depression

Pediatric

0.2-0.4 mg/kg/d PO qhs
Increases toxicity of sympathomimetic agents such as isoproterenol and epinephrine by potentiating effects and inhibiting antihypertensive effects of clonidine
Documented hypersensitivity; narrow-angle glaucoma; in acute recovery phase following myocardial infarction; MAOIs within 14 d

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May impair mental or physical abilities required for performance of potentially hazardous tasks; caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, or concurrent thyroid replacement therapy
Monitor ECG and BP at start of therapy and with dose changes

Laxatives and stool softeners

These agents can be useful in patients with constipation-predominant irritable bowel syndrome. Osmotic laxatives (eg, magnesium hydroxide, lactulose, sorbitol) or stool lubricants (eg, mineral oil) are usually required for long-term therapy for children with moderate-to-severe constipation. Long-term studies have shown that these medications are safe and equally effective. Stimulant laxatives may be necessary intermittently and for short periods, but avoid prolonged use.

Mineral oil (Milkinol)

An emollient laxative that does not appear to have any pharmacologic action on the GI tract. Acts by lubrication. When taken for 2-3 d, penetrates and softens stool and may interfere with absorption of water. Generally is well tolerated and without major adverse effects. Onset of action is approximately 6-8 h. Indigestible; limited absorption.

Adult

15-45 mL PO qd or divided tid
60-150 mL PR as single dose

Pediatric

5-20 mL PO qd or divided tid
For chronic functional constipation: Up to 1.5-5 mL/kg/d
For disimpaction: Up to 30 mL per y of age bid; not to exceed 240 mL/d
30-60 mL PR as single dose

Follow-up

Prognosis

Irritable bowel syndrome (IBS) is a chronic disorder that cannot be cured and usually persists in a waxing and waning fashion. Many children and adolescents who are diagnosed with irritable bowel syndrome continue to experience symptoms into adulthood, and many adult patients with irritable bowel syndrome trace their symptoms to childhood. The intensity of pain for a particular patient may vary with time, but the nature of symptoms usually remains unchanged.

The quality of life for many patients with irritable bowel syndrome can be enhanced with ongoing education, reassurance, psychosocial support, and appropriate pharmacotherapy when indicated.

Patient Education

Educate patients and their families about the pathophysiology, diagnosis, and treatment of irritable bowel syndrome symptoms. Patients who were given detailed discussions about their diagnosis and treatment were found to have reduced symptom intensity and fewer return visits to physicians.

For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article, Irritable Bowel Syndrome.