8mert.dt

The new england journal of medicine d r u g t h e r a p y
From the Department of Medicine, Division rritable bowel syndrome, a common disorder in which bowel habits are altered in association with abdominal pain or discomfort, has a preva- of Radiology and Radiological Sciences,Vanderbilt University, Nashville. Address lence of 12 percent among adults in the United States and a similar prevalence reprint requests to Dr. Mertz at Nashville worldwide.1 By definition, no mechanical, biochemical, or overt inflammatory condi- Gastrointestinal Specialists, 4230 Harding tion explains the symptoms. Validated, symptom-based criteria for the diagnosis of ir- Rd., Suite 309 W., Nashville, TN 37205.
ritable bowel syndrome are highly predictive in the absence of alarming symptoms such as weight loss, fever, and intestinal bleeding.2-4 The pain or discomfort experienced by Copyright 2003 Massachusetts Medical Society. patients with irritable bowel syndrome often leads to health care use and a decreasedquality of life.5-7 Diarrhea is a symptom that often leads to medical consultation,5 sinceit can be inconvenient and, if associated with urgency, may be accompanied by fecal in-continence, an altered lifestyle (owing to frequent trips to the bathroom), and anxiety.
Constipation may be associated with bloating, discomfort, and an altered body image.
The quality of life was reported as impaired in people with irritable bowel syndromewho sought medical care but only marginally reduced in those who did not seek medi-cal care.8,9 The therapeutic goal is both a reduction in the severity and frequency of symp-toms and an overall improvement in the quality of life.
The age at onset of irritable bowel syndrome varies, but the incidence appears to in- crease during adolescence and peaks in the third and fourth decades of life. An onsetafter the age of 50 years is unusual. Women have a higher prevalence of symptoms thanmen (2:1 ratio). Patients seen in clinics, particularly those who are referred for irritablebowel syndrome, appear to have a high frequency of psychosocial stress or dysfunctionassociated with the condition. However, persons with irritable bowel syndrome whodo not seek medical care have no more psychological symptoms than unaffected con-trols.5,10 Since psychosocial stress appears to predict both the use of health care andthe persistence of symptoms, the patient’s social history is relevant to therapy, and cli-nicians should attempt to determine what has triggered each consultation.11 The cause of irritable bowel syndrome is unknown, though associated pathophysiolo-gy includes altered gastrointestinal motility and increased gut sensitivity (Fig. 1). Somestudies,12,14 but not all,15 reported increased small-bowel and colonic contractionstemporally associated with abdominal pain. Heightened sensitivity to visceral distention,particularly that which is perceived as noxious, has been described in numerous stud-ies.13,16 Interplay between motor and sensory dysfunction appears to explain the symp-toms of irritable bowel syndrome. The gastrointestinal effects of stress in animals andhumans include increased small-bowel and colonic motility and increased visceral sensi-tivity.17,18 These effects appear to be exaggerated in patients with irritable bowel syn-drome, as well as in animals previously sensitized by either visceral inflammation or psy-chological trauma.19-21 Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. Patients with irritable bowel syndrome have been reported to have an increased colonic motor re- sponse to corticotropin-releasing factor, a stress hormone, consistent with the occurrence of an in- creased gastrointestinal stress response.22 The gas- trointestinal sensory-motor dysfunction in irritable bowel syndrome is consistent with an up-regula- tion in neural processing between the gut and the brain, termed the “brain–gut axis.” Indeed, thera- pies for irritable bowel syndrome are generally di- rected at gastrointestinal motor, gastrointestinal Motility Index (mm Hg/min)
sensory, or central nervous system processing.
n o n p h a r m a c o l o g i c t h e r a p i e s Nonpharmacologic therapies alone are adequate for many patients and should accompany pharma- cologic therapy, when it is administered. A firm di-agnosis of irritable bowel syndrome based on vali- dated symptom criteria,2,3 the absence of alarmingsymptoms, and a normal physical examination, coupled with limited relevant diagnostic testing, is reassuring to patients. Identification of psychoso-cial stressors that trigger or maintain symptoms should lead to supportive advice and lifestyle mod-ification, which often reduces the number of visits Subjects Reporting Pain (%)
to physicians.23 Patients generally seek dietary ad-vice, but specific diets or elimination diets have not been proven effective. Some studies indicate that Rectal Distention (ml)
elimination diets followed by sequential reintroduc-tion of specific foods can be useful, though in these Figure 1. Alterations in the Colonic Motility Index (Panel A) and Gut Sensitivi-
studies, patients and investigators were not blind- ty (Panel B) in Irritable Bowel Syndrome (IBS).
ed to the excluded foods. Furthermore, when no The gastrocolic reflex is augmented in patients with irritable bowel syndrome. offending foods were identified during the reintro- As indicated in Panel A, the mean (±SE) motility of the sigmoid colon is great-er after meals in patients than in control subjects as measured by manometry. duction phase of the diet, most patients neverthe- Data have been adapted from Rogers et al.12 Patients with irritable bowel syn- drome also have hypersensitivity of the gut. As a rectosigmoid balloon is pro- A reasonable approach to nonpharmacologic gressively inflated, a greater proportion of patients report pain than do con- management includes avoidance of dietary excess- trol subjects (Panel B). This distention often reproduces the pain of irritable es, caffeine, and dietary triggers the patient suspects bowel syndrome. Data have been adapted from Ritchie.
of leading to symptoms. Moderation in fat intake is
reasonable, since lipids amplify gut sensations and
motor reflexes — effects that may be heightened in
patients with irritable bowel syndrome.25 Patients studies and is reasonable as a general recommen-
with diarrhea as the predominant symptom may dation.26
have lactose intolerance or excess fruit or sorbitol
intake that may exacerbate symptoms. Patients in the placebo effect and irritable bowel
whom constipation predominates may have inad- syndrome
equate fiber intake as a contributing factor. In pa- Symptoms of irritable bowel syndrome may re-
tients with symptoms of bloating or flatulence, spond to placebos, as reported by 20 percent to
avoiding beans, cabbage, and uncooked broccoli more than 50 percent of patients in some trials.27,28
and cauliflower may help. Exercise has been asso- A salutary placebo effect appears to last at least three
ciated with improved outcomes in uncontrolled months.27,28 As a result, the findings of any stud-
Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ies of therapy for irritable bowel syndrome that are Patients with anxiety or depression appear to have anot randomized, blinded, and placebo-controlled better outcome in response to psychotherapy thanare difficult to interpret. In clinical practice, the pla- do patients without these conditions.34cebo effect makes short-term effects of therapeutic It is difficult to blind patients to psychotherapy trials difficult to interpret as well.
treatment; none of the published trials of psycho-therapy are double-blind or placebo-controlled. In f i b e r s u p p l e m e n t s
most trials patients are not representative of those Oral fiber supplementation has been widely rec- seen in general practice but, rather, are identifiedommended as therapy for irritable bowel syndrome, in tertiary practices and are willing to enroll in ther-though supporting data are lacking. Fiber is indi- apy. Furthermore, psychotherapy requires a skilledgestible plant carbohydrate (primarily cellulose, practitioner, so results from selected centers mayhemicellulose pectins, and lignins) that colonic bac- not be reproduced in general practice. Despite theseteria metabolize into gas, fluid, and short-chain fatty caveats, psychotherapy is considered useful for se-acids. Fiber supplementation results in softer, wet- lected patients with irritable bowel syndrome, par-ter, bulkier stool, which can promote colonic peri- ticularly those who have relatively severe or refrac-stalsis and ease defecation. Fiber accelerates stool tory symptoms or prominent psychosocial issues.
transit in both control subjects and patients with ir-ritable bowel syndrome and chronic constipation.29 n o n s p e c i f i c b o w e l - d i r e c t e d Controlled trials suggest that fiber supplements are effective for the constipation symptoms of irritablebowel syndrome, but not for pain or diarrhea.30-32 Initial therapy for irritable bowel syndrome shouldIn fact, many patients who take fiber, particularly include measures to reduce specific symptoms relat-those with diarrhea-predominant irritable bowel ed to constipation and diarrhea. Often in patientssyndrome, have worsening of symptoms.32,33 Since with constipation, regular passage of stool willfiber may take one to three days to traverse the gut, reduce pain and bloating. Although antidiarrhealsymptoms of constipation may get worse before agents do not reduce the pain of irritable bowel syn-they improve. Patients should be advised of this drome, they can improve the quality of life if theypossibility, and gradual introduction of fiber may decrease stool urgency and frequency.
be tried.
t r e a t m e n t o f c o n s t i p a t i o n
p s y c h o t h e r a p y
Constipation is a nonspecific symptom reported by Psychosocial stressors are important triggers for patients who have slow transit of the colon, im-the symptoms of irritable bowel syndrome, and pa- paired defecation and straining, or a sensitive co-tients who seek a consultation for irritable bowel lon that causes a bloated feeling and a desire to def-syndrome have a greater prevalence of psychologi- ecate without result.40,41 Fiber supplements suchcal diagnoses than those who do not seek medical as psyllium seed, methylcellulose, and polycarbo-care. Thus, psychotherapy is expected to be useful. phil relieve constipation by accelerating stool trans-A variety of psychotherapy techniques, including it and facilitating defecation. Fiber is unlikely tocognitive behavioral therapy (directed at maladap- offer relief for bloating in patients with normal stooltive perceptions of illness and behavior), dynamic frequency. Fiber is also less likely to work for con-psychotherapy (directed at interpersonal problems), stipation in those with very slow colonic transitrelaxation therapy, and hypnotherapy, alone or in (e.g., more than five days between movements). Incombination, are reportedly effective for symp- this situation, long-term use of an osmotic laxativetoms.34-39 A review of psychological treatments for is effective and safe. Magnesium salts, phosphateirritable bowel syndrome identified 12 randomized, salts, and polyethylene glycol–based laxatives are ef-controlled trials in which the level of symptoms fective when taken on a scheduled basis or as need-was the primary outcome38; 8 of these reported ed, and tachyphylaxis is rare.42,43 Nonabsorbed car-positive responses to psychotherapy. Two studies bohydrate laxatives such as sorbitol and lactuloseindicated that the marked improvement in symp- are effective but expensive and can promote the for-toms during initial psychotherapy lasted for up to mation of gas, which many patients find uncomfort-one year.34,36 Diarrhea and pain appear to respond able and difficult to expel.25,42 Stimulant catharticsto psychotherapy, whereas constipation does not. such as bisacodyl and senna are more likely than Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. other agents to cause cramping and are associatedwith both tachyphylaxis and dependency. In animal Table 1. Antispasmodic Agents.
models, cathartics induce swelling and fragmenta- Generic Name (Common Brand Name)
tion of enteric neurons.44 For these reasons, long- Single agents
term use of stimulant cathartics should be avoided.
a n t i d i a r r h e a l a g e n t s
The opiate and opioid analogues diphenoxylate–atropine and loperamide stimulate receptors in the enteric nervous system that inhibit peristalsis and fluid secretion. Loperamide has demonstrated ef- ficacy against diarrhea, but not pain, in patients with irritable bowel syndrome.45 Medications of the same class, such as diphenoxylate–atropine, would Combined sedative and antispasmodic agents
be expected to have similar efficacy. Loperamide may be preferable for long-term use because it is available without prescription, does not have an an- ticholinergic component, and does not induce eu- phoria at any dose. These agents can be used as Hyoscyamine, atropine, and phenobarbital needed or according to a schedule. A bile-acid bind-er such as cholestyramine may be added empirically * This agent is not available in the United States.
to control refractory diarrhea. A night-time dose ofa bile-acid binder is often very effective after chole-cystectomy in patients with diarrhea-predominantirritable bowel syndrome.46 odds ratio for global improvement with antispas-modic agents, as compared with a placebo, exceeds2.0 on the basis of these two meta-analyses (Table 2), but this apparent beneficial effect may be overes- a n t i s p a s m o d i c a g e n t s
timated, since a trial indicates that the serotonin-3– Antispasmodic agents relax the smooth muscle of receptor antagonist alosetron (discussed below) isthe gut or reduce its contractility. Anticholinergic more effective than an antispasmodic agent, evenagents, calcium-channel blockers, and opiate an- though the odds ratio for global improvement withtagonists may all act as antispasmodics, though alosetron therapy is only 1.7.56only anticholinergic agents are approved for this in- The heterogeneity of older studies and publica- dication in the United States (Table 1). Patients with tion bias may lead to an overstatement of the effec-irritable bowel syndrome typically have augmented tiveness of antispasmodic medications. The anti-colonic motility in response to meals (gastrocolic spasmodic agents available in the United Statesreflex), which can be associated with diarrhea and (Table 1) may not be the most efficacious; however,cramps47 (Fig. 1A). Anticholinergic agents can re- there are data to support the use of dicyclomine andduce this excessive postprandial contractility.48 The hyoscyamine.57 In practice, antispasmodic agentsliterature regarding various antispasmodic drugs for taken 30 minutes before meals can substantiallythe treatment of irritable bowel syndrome is large; inhibit the gastro-colic reflex, reducing postprandi-however, many trials lacked appropriate blinding, al urgency and cramps. Fast-acting sublingual anti-had small numbers of patients, were of short dura- spasmodic agents are available that are appropriatetion, and used unclear criteria to define a clinical re- for use on an as-needed basis. Long-acting formssponse.
are also available. Common but generally mild and On balance, data from randomized trials indicate rapidly reversible side effects of anticholinergic an- that antispasmodic agents decrease global symp- tispasmodic agents include dry mouth, blurred vi-toms and reduce pain. This effect is reviewed in two sion, fatigue, and urinary hesitancy. Narrow-anglerecent meta-analyses, which suggest that although glaucoma and urinary retention are contraindica-these agents decrease pain, they have no effect on tions. These drugs can be administered as neededsymptoms of diarrhea and constipation.49,50 The for cramps, before meals that are expected to cause Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Drug Therapy for Irritable Bowel Syndrome.
Serotonin-4–
Serotonin-3–
Antispasmodic
Tricyclic
Receptor
Receptor
Variable
Antidepressants*
Agonist†
Antagonist‡
Absolute increase in response rate over placebo (%) * The results are from a meta-analysis of various trials and compounds.49,50,51† The results are for constipation associated with irritable bowel syndrome and are from high-quality trials involving a sin- ‡ The results are for diarrhea associated with irritable bowel syndrome and are from high-quality trials involving a single § A direct comparison showed that this agent was superior to an antispasmodic agent.56 symptoms, or when postprandial symptoms would chest pain, and functional dyspepsia.62-64 The un-be relatively inconvenient. Because of the safety, low derlying mechanism of the benefit is unknown, butcost, and utility of antispasmodic agents given on it could be due to a reduction in the sensitivity ofan as-needed basis, these drugs are generally tried peripheral nerves or to alterations in the brain.65,66first if reassurance and nonspecific therapies fail to Although in healthy volunteers tricyclic antidepres-control symptoms.
sants raise both the threshold for and tolerance of Several formulations have combined benzodiaz- cutaneous pain,67,68 these effects have not been epine or barbiturate sedatives with anticholinergic convincingly demonstrated in the gut.67,69 In func-drugs. Data from small studies support the efficacy tional bowel disorders, data are mixed regarding theof phenobarbital and belladonna in combina- ability of tricyclic antidepressants to alter visceraltion.58-60 The combination compounds have a ra- pain thresholds.70,71 The antidepressant action oftionale for use and an extensive history. Anxiety tricyclic antidepressants does not appear to be re-increases intestinal motility as part of the stress quired for the salutary effects of these agents on theresponse, and this response can be blunted by ben- gut, since low doses are effective, benefits are seenzodiazepines.61 Sedatives may reduce the central within two weeks, patients without depression ben-nervous system component of intestinal contrac- efit, and full doses of selective serotonin-reuptaketions, whereas antispasmodic agents reduce the in- inhibitors do not provide the same benefits.64 Intestinal motor response. The risk of dependency or theory, the beneficial effects of tricyclic antidepres-recreational use of the anxiolytic component is very sants could be due to their anticholinergic proper-low, since the anticholinergic component causes ties; however, studies that controlled for this effectunpleasant side effects in higher doses. Side effects have still shown a benefit of treatment.72include those of anticholinergic components and A number of randomized, controlled trials have sedation related to anxiolytic agents. The use of al- demonstrated decreased symptoms in patients tak-cohol and other sedatives must be avoided if these ing low-dose tricyclic antidepressants such as ami-drugs are taken. Driving and other activities requir- triptyline, desipramine, clomipramine, doxepin,ing an alert state should be avoided until patients and trimipramine. A recent meta-analysis revieweddetermine whether they can tolerate these drugs. these treatments for irritable bowel syndrome andThese agents are best used as needed for more indicated an odds ratio for benefit of 4.0 as com-severe episodic symptoms when anticholinergic pared with placebo51 (Table 2). Some studies, butagents alone have failed.
not all, indicate greater benefits in patients with di-arrhea-predominant irritable bowel syndrome than t r i c y c l i c a n t i d e p r e s s a n t s
Tricyclic antidepressants in low doses appear ef- include constipation, anticipatory treatment of con-fective for irritable bowel syndrome and for a vari- stipation is suggested if tricyclic antidepressants areety of other painful conditions, including migraine, used for constipation-predominant irritable bowelneuropathic pain, pain due to cancer, noncardiac syndrome. Other side effects include fatigue, som- Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. nolence, dry mouth, and urinary retention. In anti- The clinical result of alosetron is a reduction in di-depressant doses, tricyclic antidepressants have arrhea and urgency. All these effects address thebeen associated with cardiac arrhythmia and low- known physiological abnormalities in diarrhea-pre-ered seizure thresholds. These effects appear ex- dominant irritable bowel syndrome.
ceedingly rare at low doses.
In two large, randomized, double-blind, place- Tricyclic antidepressants are recommended for bo-controlled trials, alosetron (1 mg twice daily) moderate-to-severe irritable bowel syndrome in was beneficial in women with irritable bowel syn-which pain is prominent or when other therapies drome who did not have constipation.54,55 An ear-have failed. Tricyclic antidepressants can be com- lier dose-finding study indicated that a dosage ofbined with antispasmodic agents if either treatment 1 mg twice daily was most effective and that its ben-has had partial success. Since somnolence may oc- efits were restricted to women. A response was re-cur, the drugs should be taken at bedtime. Daily ad- ported in 43 percent of subjects in one study (an ab-ministration starting at a dose of 10 to 25 mg for solute increase of 17 percent, as compared with theany of the tricyclic antidepressants, with a gradual rate in the placebo group; P<0.001) and 41 percentescalation to a dose of 25 to 100 mg, is suggested. in the other (an absolute increase of 12 percent, asAlthough benefits are often seen within a week, a compared with the rate in the placebo group;four-week trial is reasonable. Tricyclic antidepres- P<0.05). The use of alosetron is associated with im-sants may be continued for 6 to 12 months, after proved quality of life, as compared with placebo, inwhich an attempt should be made to taper the dose. the dietary, social, and physical domains.83 Consti- Selective serotonin-reuptake inhibitors and other pation was a side effect in 25 to 30 percent of sub- newer antidepressants have been widely used to jects, explaining, in part, the 10 percent dropouttreat irritable bowel syndrome, since they lack many rate. Alosetron was reported to be superior to me-of the side effects of tricyclic antidepressants and beverine, an antispasmodic agent, for pain associ-have similar efficacy for depression. These agents ated with irritable bowel syndrome (e.g., rates of ad-do not have the same antinociceptive effects as tri- equate pain relief were 10 to 13 percentage pointscyclic antidepressants and have yet to be proved ef- higher at two and three months) in a multicenterfective for irritable bowel syndrome or any other European trial.56 Although the incidence of side ef-functional gastrointestinal disorder.64 Selective se- fects was similar in each treatment group, consti-rotonin-reuptake inhibitors may be useful when ir- pation was more common in the alosetron groupritable bowel syndrome is accompanied and exac- (22 percent).
erbated by a mood disorder. Although evidence to After the introduction of alosetron, ischemic support its use is lacking, this class of drug may colitis was diagnosed in approximately 1 of 700also be tried if a tricyclic antidepressant fails.
patients who took the drug.84,85 Consequently, thedrug was withdrawn from the market by the manu- s e r o t o n i n - 3 – r e c e p t o r a n t a g o n i s t s
facturer. In part as a result of lobbying by patient- Serotonin-3 receptors are also located on enteric advocacy groups, the Food and Drug Administration
nervous system sensory neurons.74 Serotonin is (FDA) authorized the reintroduction of alosetron in
released by gastrointestinal enteroendocrine cells June 2002 under specific guidelines that require
after mucosal stimulation, diffuses to the nerve end- patients to sign a consent form and prescribing phy-
ings, and stimulates peristalsis by binding to sero- sicians to sign a certificate.86 The drug again be-
tonin-3 and serotonin-4 receptors located on enteric came available in late 2002. Given its known side
nerves.75 Activated serotonin-3 receptors stimulate effects, alosetron therapy should be limited to wom-
intestinal motility, secretion, and sensation. The en with irritable bowel syndrome without constipa-
motor effects of serotonin-3–receptor antagonists tion who have symptoms severe enough to justify
include a reduced rate of colonic transit, reduced the risk of drug-induced ischemic colitis and who
gastrocolic reflex, and increased colonic compli- have had no response to other therapy. Other drugs
ance.76-79 The antagonists appear to reduce intes- in this class are under development, although their
tinal sensitivity to distention in humans as well as in safety and efficacy are unknown.
several animal models.80-82 The serotonin-3–recep-
tor antagonist alosetron increases colonic compli- serotonin-4–receptor agonists
ance in patients with irritable bowel syndrome and Tegaserod, a drug similar to the prokinetic agent
may reduce sensitivity to balloon distention.27,79 cisapride, is a partial agonist of the serotonin-4 re-
Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine it.89 The rate of colonic transit was slightly acceler-ated 48 hours after the ingestion of radiolabeled pellets, but not at 24 hours.89 In patients with con-stipation-predominant irritable bowel syndrome, a Education, reassurance, stress management 2-mg dose of tegaserod twice daily acceleratessmall-bowel transit and cecal filling but has no ef-fect on gastric emptying or total colonic transit.90 Three large, randomized, double-blind, placebo- controlled trials of tegaserod for constipation-pre-dominant irritable bowel syndrome indicate thatit provides symptomatic benefit.28,52,53 Tegaserod(6 mg twice daily — the FDA-approved dose) for Moderate Antispasmodic agent
three months is associated with increased responserates at one and three months, as compared withplacebo, leading to reductions in the symptoms ofpain and constipation. In the last month of therapy, 52 percent of patients taking tegaserod had an im- provement in the global symptoms of irritable bow-el syndrome — a value that was 9.3 percentagepoints higher than that in the placebo group.28,52,53 Severe Tricyclic antidepressant, psychotherapy, sedative with antispasmodic agent
Available studies suggest that these benefits occurin women but not men, although the studies were underpowered from a statistical viewpoint to de- Tegaserod has been approved by the FDA for use for up to 12 weeks in women with constipation-pre- Figure 2. Treatment Strategy for Irritable Bowel Syndrome (IBS).
dominant irritable bowel syndrome. The side ef- Treatment is individualized on the basis of the type and severity of symptoms. fects of tegaserod are generally mild, with diarrhea, When bowel-directed therapies for diarrhea or constipation are inadequate or generally brief, the most prominent (occurring in when pain is a prominent finding, therapy with antispasmodic drugs is useful, 10 percent of patients). For unclear reasons chole- particularly for postprandial symptoms. These agents are effective when giv-en on an as-needed basis, allowing the patient to take an active role in man- cystectomy was performed more frequently in pa- agement. A combined anxiolytic–antispasmodic agent is helpful for use as tients who received tegaserod (0.17 percent) than needed in patients with anxiety or refractory disease. Tricyclic antidepressants in those given placebo (0.06 percent).91 Given its in a low dose are helpful for pain symptoms when antispasmodic agents fail cost and its relatively moderate advantages over or provide only partial relief. Tricyclic antidepressants can be combined with placebo, tegaserod should be reserved for female other agents such as antispasmodics. The prokinetic tegaserod is effective for women with constipation-predominant irritable bowel syndrome. It is a rea- patients with constipation-predominant irritable sonable addition when fiber or laxatives and antispasmodic agents are unsuc- bowel syndrome who have no response to fiber or cessful. When pain is the predominant symptom, tricyclic antidepressants would appear to be preferred over tegaserod on the basis of their mechanism of action, rather than clinical data. Alosetron is helpful for women with refrac- o t h e r a g e n t s
tory diarrhea-predominant symptoms in whom loperamide, antispasmodic agents, and tricyclic antidepressants have failed. Patients should be coun- A variety of other agents have been considered for seled regarding the risk of constipation and ischemic colitis with alosetron the symptoms of irritable bowel syndrome, with therapy. Pharmacologic therapy alone is likely to be ineffective for irritable some reports of benefit. Antibiotics have been sug- bowel syndrome when ongoing psychosocial problems remain undetected or gested as a treatment for irritable bowel syndrome.
Recently, small-bowel overgrowth by enteric bacte-ria has been cited as a cause of the symptoms.92 Ina subsequent randomized, double-blind trial, 111 ceptor. Peristalsis is coordinated by neurons of the patients with irritable bowel syndrome (84 percententeric nervous system that release other mediators with small-bowel overgrowth as suggested by theafter the activation of serotonin-4 receptors.87-89 In results of a lactulose hydrogen breath test) werehealthy volunteers, 6 mg of tegaserod twice daily treated with the antibiotic neomycin or placebo. Theaccelerated gastric emptying and small-bowel trans- percentage of patients with at least 50 percent im- Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. provement in the symptoms of irritable bowel syn- sensation will probably lead to novel treatments fordrome after one week of treatment was significantly irritable bowel syndrome. Compounds under inves-greater in the neomycin group (43 percent) than the tigation include cholecystokinin-A–receptor antag-placebo group (23 percent).93 However, the follow- onists, neurokinin-1– and neurokinin-3–receptorup lasted only seven days, and the durability of such antagonists, k (peripheral) opiate agonists, a -adre- a response is unknown. Studies of methods to re- nergic agonists, and muscarinic-3–receptor antag-duce small-bowel bacteria without antibiotics in pa- onists. These agents may reduce the sensitivity ortients with irritable bowel syndrome are warranted.
motility of the gut. Probiotics have also been used A double-blind, placebo-controlled 16-week trial to alter gut flora, and preliminary data indicate of herbal therapy that used a validated survey and in- that they may be beneficial in irritable bowel syn-volved 116 patients with irritable bowel syndrome drome.98indicated that gastrointestinal symptoms improvedin patients taking a mixture of herbs. Herbal mix- tures individualized for each patient by Chinesemedical practitioners were compared with a stan- Because irritable bowel syndrome is a disorder ofdardized mixture of 20 herbs and found to offer no bowel motility and sensation that is exacerbated byadvantage.94 Whether diarrhea or constipation im- psychosocial stressors, treatment is most successfulproved most was not reported. Herbal therapy might when a multicomponent, comprehensive approachbe useful but requires more robust data plus a de- is used (Fig. 2). It is important to explain and reas-termination of the substance or substances respon- sure patients about the origin of their symptomssible for the effects.
and to let patients take an active approach to man- Peppermint oil has been advocated as a treat- agement that is overseen by their physician. Bowel- ment for irritable bowel syndrome and can be ob- directed therapies should target specific types oftained without prescription. There are positive and gastrointestinal dysfunction, such as diarrhea ornegative data regarding its use in irritable bowel constipation, and prescription medication shouldsyndrome.95 Peppermint oil appears to have direct be used judiciously when symptoms do not respondrelaxing effects on gastrointestinal smooth mus- to nonprescription remedies or are severe. Finally,cle, so it might act as an antispasmodic agent. Pep- stress management or psychotherapy should bepermint oil relaxes the lower esophageal sphincter, used when such measures do not adequately re-and heartburn related to acid reflux limits its use.
lieve symptoms or when psychological factors are Leuprolide, a gonadotropin-releasing–hormone prominent.99-102 The benefits of multicomponent antagonist, may be moderately beneficial for irrita- therapy for irritable bowel syndrome have recentlyble bowel syndrome in women.96,97 The published been reviewed by both American and British gas-trials were not blinded (owing to the presence of troenterology societies.99,102 Given the psychoso-amenorrhea in the treatment group) and had vague cial factors involved and the limited benefits ofentry criteria. The medical menopause this drug in- current pharmacologic therapies, the treatment ofduces is not without risks, and leuprolide cannot irritable bowel syndrome requires physicians to at-be recommended for irritable bowel syndrome.
tend to the minds as well as the bodies of their pa-tients in order to help them find relief.
Supported by a grant (DK 57047) from the National Institutes of Increased understanding of neurotransmitters andhormones mediating gastrointestinal motility and r e f e r e n c e s
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Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on April 29, 2010 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine A new model of chronic visceral hypersensi- ticomponent behavior therapy is superior to of health care seeking for irritable bowel tivity in adult rats induced by colon irritation medical treatment alone in the therapy of ir- ritable bowel syndrome. Am J Gastroenterol 22. Fukudo S, Nomura T, Hongo M. Impact
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