Sagar R. Shroff and Gregory Sayuk
GENERAL PRINCIPLES
· Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain or discomfort associated with defecation or a change in bowel habit and features of disordered defecation (constipation and/or diarrhea).
· IBS is one of several functional GI syndromes defined by symptom-based criteria, listed in Table 32-1.1,2
TABLE 32-1 The Functional Gastrointestinal Disorders (From Rome III)
Classification
· Several historical diagnostic criteria for IBS exist, with the Rome III criteria (Table 32-2) representing the most recent and encompassing criteria.1 It should be noted that these criteria were devised primarily as a tool for devising clinical studies in the area. However, when applied to clinical practice, they have a high positive predictive value (>95%).
TABLE 32-2 The Rome III Irritable Bowel Syndrome Criteria
· Although they are not necessary for IBS diagnosis, several supporting symptoms (Table 32-3) help to solidify the diagnosis and further characterize the disorder into IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M), or unsubtyped IBS (IBS-U).
TABLE 32-3 Supportive Symptoms of Irritable Bowel Syndrome
Epidemiology
· IBS is frequently seen in both primary care and specialty care settings and is one of the most common diagnoses seen by gastroenterologists.3
o Estimates place the prevalence of IBS anywhere from 1% to 20% worldwide.
o Systematic reviews suggest that 10% to 15% of the adult US population are affected with IBS.4
o Population surveys of adults have shown IBS to be more prevalent in women than in men with a ratio of 3 to 4:1.
o Symptom onset tends to occur between the ages of 20 and 40 but can occur at any age. When considering a new diagnosis of IBS in older individuals, exclusion of other mimicking conditions is requisite (e.g., celiac disease, inflammatory bowel disease, and small intestinal bacterial overgrowth [SIBO]).
· Surveys from both the United States and United Kingdom report an average disease duration of 11 years, although about one-third of patients have symptoms for even longer periods.
· As few as one in three individuals affected with IBS in the United States actually seek medical attention, and the vast majority of these are managed by their primary care physician. Still, the cost to society is considerable, accounting for approximately 3.6 million physician visits and $1.6 billion in direct medical costs each year.
· The burden on the patient is also considerable with health-related quality-of-life (HRQOL) scores similar to patients with diabetes and worse than patients with chronic kidney disease and gastroesophageal reflux disease.5
Pathophysiology
· No single pathophysiologic abnormality has been found that adequately explains the manifestations of IBS. Given the symptomatic basis on which the diagnosis is made, more than one pathophysiologic mechanism likely plays a role. Multiple factors, including abnormalities of intestinal motility, visceral hypersensitivity, GI tract inflammatory processes, disturbances along the brain-gut axis, and psychological factors, have been examined as potentially causative in IBS.6
· A portion of patients with IBS will exhibit exaggerated motility and sensory responses to stressors, meals, and balloon inflation in the GI tract; however, these are neither uniformly identifiable in IBS patients nor consistently reproducible in the same individual.
· IBS may result from sensitization of afferent neural pathways from the gut such that normal intestinal stimuli induce pain.
· Intestinal inflammation also has been hypothesized as playing a role in the development of IBS, particularly as it relates to persistent neuroimmune interactions following infectious gastroenteritis (so-called postinfectious IBS); approximately one-third of patients with IBS report symptom onset after an episode of acute gastroenteritis.
· The role of SIBO or lower levels of bacterial colonization (intestinal dysbiosis) in the development of IBS has been a focus of recent investigations, but its role remains to be fully understood.7
· The central nervous system (and its interpretation of peripheral enteric nerve signals) is receiving increasing attention in investigational settings because of the potential mechanistic significance in IBS.
DIAGNOSIS
Clinical Presentation
· IBS is a symptom-based diagnosis. Patients should report abdominal discomfort and a temporal association with alterations in stool pattern, improvement with bowel movement, or both.
· IBS diagnosis requires an element of chronicity (per Rome criteria, ≥3 days per month over the preceding 3 months), with symptom onset at least 6 months prior to diagnosis.
· The diagnosis of IBS should be made after organic or structural causes have been considered, necessitating a careful search for alarm symptoms before establishing a diagnosis of IBS.
o Important alarm symptoms include unintentional weight loss of ≥10 pounds, recurrent fever, persistent diarrhea, hematochezia, age >50 years at onset of symptoms, male sex, and family history of GI malignancy, inflammatory bowel disease, or celiac sprue.
o A brief history of rapidly progressive symptoms suggests organic disease. The presence of any alarm features warrants a more detailed investigation before diagnosing as IBS.
· Likewise, the physical examination should be focused to exclude organic disease.
o Diffuse abdominal tenderness is commonly present because of the heightened visceral sensitivity noted in this population.
o Physical examination alarm signs include the presence of thyroid abnormalities, organomegaly, abdominal masses, lymphadenopathy, perianal disease, or heme-positive stool.
Diagnostic Testing
· Laboratory and invasive testing should be kept to a minimum in the absence of alarm symptoms, because extensive or repetitive investigations may be costly and serve only to reinforce illness behavior.
· Initial laboratory testing should include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), and fecal occult blood test (FOBT).
· Testing for celiac sprue should be considered in all IBS patients (particularly in IBS-D and IBS-M) with IgA anti–tissue transglutaminase test (anti-tTG IgA).
· Complete metabolic profile and stool for culture and Clostridium difficile toxin or PCR testing can be ordered if the pretest probability is high enough, but are likely low yield for the majority of IBS patients.
· Colonoscopy and EGD typically are unnecessary in young patients presenting with classic features of IBS without any alarm symptoms.
o Colonoscopy should be performed in all patients >50 or those with positive FOBT.
o In cases of IBS-D or IBS-M, random colonoscopic biopsies should be performed to exclude microscopic colitis.
TREATMENT
· The approach to therapy in IBS is multifaceted and should be tailored to the patient given the individual’s constellation and severity of symptoms.
· Two key factors determine therapy: dominant symptoms (diarrhea, constipation, pain, others) and symptom severity (intensity, effects on quality of life).
· Current management approaches include behavioral modification, dietary changes, peripherally acting agents, centrally acting agents, and psychological-behavioral therapy.
Medications
· Cases with mild or intermittent symptoms can be managed with symptomatic treatment using peripherally acting agents administered on an as-needed basis.
· Patients with moderate symptoms (as designated by intermittent interference with daily activities) may benefit from regular use of peripheral agents as an initial approach, with the option of introducing centrally acting agents if this approach fails.
· Patients with severe symptoms (regular interference with daily activities, and concurrent affective, personality, and psychosomatic disorders) benefit from combinations of peripheral and central agents but may also need contemporary pharmaceutical agents and psychological approaches to manage their overlapping affective, personality, and psychosomatic disorders.
· Although medical therapy is available and new drugs are currently in development, IBS is a long-term condition with exacerbations and remissions, and medications should be minimized to the extent possible.
· Opioids have no role in the management of IBS. The use of opioids actually may worsen IBS symptoms and provoke so-called narcotic bowel syndrome.8
· Given the lack of identifiable biomarkers, trials of medications are frequently part of the IBS diagnostic process. These trials should be pursued for at least 4 weeks (and ideally 12 weeks) before moving on to different therapy.
· If failure to respond to a single agent in a drug class is experienced, response to a different drug in the same class may still be observed.
· It is important to recognize the substantial (up to 50%) placebo response rates present in this patient population.
· Patient education and reassurance while establishing a therapeutic relationship are cornerstones in the management of this condition. The strength of the physician-patient relationship translates into higher rates of patient satisfaction and fewer return visits.
· Table 32-4 summarizes general management principles for patients with IBS or other functional bowel disorders.
TABLE 32-4 General Approach to Irritable Bowel Syndrome and the Functional Bowel Disorders
FODMAPS, fermentable, oligo-, di-, and monosaccharides and polyols.
Peripherally Acting Agents
Therapies for Constipation-Predominant IBS
· Increasing the amount of dietary fiber is a simple, inexpensive option in mild IBS-C and can be instituted as an early approach.
o Limited randomized controlled studies seem to show some benefit in global symptom relief with this approach.9
o Whole grains, fruits, nuts, and vegetables are natural sources of fiber.
o Supplements include psyllium, methylcellulose, and guar gum.
o Our preference is the use of soluble fiber products.
o In patients who complain of bloating or gas, fiber supplementation can be associated with an increase in those symptoms and slow titration along with the exclusion of flatulogenic foods should be encouraged.
· Osmotic laxatives such as milk of magnesia, sorbitol, lactulose, or polyethylene glycol also may be considered in patients with IBS-C.
o Currently randomized controlled trial data supporting their use are lacking.
o Nonabsorbable carbohydrates such as lactulose and sorbitol can induce abdominal pain and bloating symptoms when used chronically and are probably best reserved as second-line agents.
o Polyethylene glycol can be safely used for chronic constipation on a maintenance basis.
· Lubiprostone is a chloride channel activator indicated in the treatment of IBS-C in women at a dose of 8 mcg twice daily.
o Lubiprostone has shown benefit in reducing global IBS symptom scores and increasing spontaneous bowel movements.9,10
o Side effects include nausea, diarrhea, and headache, which can be improved by taking the medication with food.
o Women of childbearing age should have a negative pregnancy test before starting lubiprostone therapy and should be capable of complying with effective contraception while on this medication.
· Linaclotide is a guanylate cyclase-C agonist, which functions as a secretogogue, and is approved for use in IBS-C at a dose of 290 mcg per day. Phase III clinical trials suggest a potential pain benefit to this medication in addition to its effect on bowel transit. Primary side effect is diarrhea.11
· Tegaserod is a partial 5-HT-4 receptor agonist that exerts GI stimulatory effects and had been indicated for short-term treatment of women with constipation-predominant symptoms. Use is limited to prescription by gastroenterologists for women <55 years of age with IBS-C or chronic constipation due to a small, but significant increase in cardiovascular events found through clinical trial data.12
Therapies for Diarrhea-Predominant IBS (IBS-D)
· The antidiarrheal loperamide taken 2 to 4 mg up to qid, no more than 12 mg/day, is the only agent with randomized, controlled data supporting its use in IBS-D. Based on its mechanism of action, diphenoxylate-atropine 2.5 mg/0.025 mg up to qid may also be used.9 No effect on bloating or abdominal pain.
· Cholestyramine taken 4 g with meals and colesevelam 625 mg up to two times daily with meals can be considered as adjuncts or for early use in diarrheal symptoms exacerbated by cholecystectomy.
· Alosetron, a selective 5-HT3 receptor antagonist that slows colonic transit, is approved for treatment of women with IBS-D. Alosetron requires a patient use agreement and prescriber registration with the manufacturer because of rare cases of ischemic colitis and severe constipation with its use. Reserved only for those who have failed to respond to conventional therapy, but can be quite effective.13
· Anticholinergic or antispasmodic agents often are used in all classes of IBS, though are most useful in the setting of IBS-D.
o Anticholinergic medications function as antidiarrheal agents by decreasing intestinal transit and modulating bowel secretory function, but also reduce pain by relaxing the smooth muscle of the gut.
o Hyoscyamine, 0.125 to 0.25 mg PO q4h PRN, no more than 1.5 mg/day or dicyclomine 10 to 20 mg PO q6h.
o The synthetic anticholinergics glycopyrrolate 1 to 2 mg two to three times a day and methscopolamine 2.5 to 5 mg twice a day also are available and have less CNS side effect potential than other antispasmodics.
o These agents are most useful in patients with postprandial symptoms of abdominal pain, bloating, diarrhea, or fecal urgency. They should be prescribed in a way that circumvents symptoms, such as before meals.
o These agents often become less effective with chronic use.
o Limited data also exist supporting the use of several herbal preparations, including peppermint oil as an antispasmodic agent.9,14
· The use of antibiotic regimens in IBS recently has generated considerable interest.
o Gut-selective antibiotics such as rifaximin (550 mg three times daily) or neomycin (500 mg twice daily) have been proposed for use in patients with IBS for whom bacterial overgrowth is suspected, particularly in those with significant gas-bloat symptoms.15
o Studies do demonstrate significant improvement in overall symptoms and bloating, but at high cost, and therefore best used for those refractory to other therapies.
o Given the modest sensitivity and specificity of hydrogen and methane breath testing, empiric use of antibiotics in the proper clinical setting is advocated, rather than a test-and-treat approach.
· Dietary interventions have demonstrated considerable benefit and are safe, easy options to consider. Higher rates of lactose intolerance are encountered in IBS patients, and a trial of lactose withdrawal should be considered. Moderation of consumption of foods containing fermentable oligo-, di-, and monosaccharides and polyols (FODMAPS) also has proven beneficial in clinical trials.16
Centrally Acting Agents
· Antidepressant medications are most useful in patients with chronic and refractory abdominal pain symptoms.
· They are particularly helpful with those who have concomitant psychiatric and somatic complaints, although their efficacy appears to be independent of any direct influence on these comorbid conditions.
· Patient perceptions and expectations should be adequately addressed in using antidepressants in the management of IBS in order to optimize compliance.
· Tricyclic antidepressants (TCAs), such as nortriptyline or amitriptyline, are the best-studied agents.17
o TCAs are used in doses much lower than those traditionally used in depression management (starting dose, 10 to 25 mg qhs, titrate up by 25 mg every week to symptom relief as tolerated).
o The anticholinergic properties of TCAs may be beneficial in IBS-D but should not dissuade use in patients with constipation or mixed pattern presentations.
o Side effects can include weight gain, sedation, dry mouth, urinary difficulties, sexual dysfunction, and dizziness.
o Individuals experiencing such side effects may tolerate use of agents with fewer anticholinergic effects, such as desipramine.
· Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) increasingly also are being used in IBS and appear to be nearly as effective as TCAs.17
o Start at the lower range of usual psychiatric doses and titrate up to symptom relief as tolerated.
o The SNRIs venlafaxine and duloxetine are good first-line options in patients with pain-predominant symptom patterns.
o Citalopram may be a good option because of its side effect profile and its beneficial effect on colonic tone and sensitivity.
o Paroxetine may be useful in patients with IBS-D because of its greater anticholinergic effect.
o Fluoxetine may be useful in patients with IBS-C because it decreases abdominal discomfort, bloating, and increases bowel movements.
Other Nonpharmacologic Therapies
· Psychological and behavioral therapies, such as cognitive-behavioral therapy (CBT), are particularly useful in IBS management, especially in patients who correlate an increase in severity of symptoms with life stressors.18,19
· CBT and hypnotherapy both have been demonstrated to be beneficial in IBS in randomized controlled trials, particularly with respect to its positive influence on global well-being.
· Although response is sporadic, factors favoring a good response include high patient motivation, overt psychiatric symptoms, and intermittent pain exacerbated by stress and/or anxiety.
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