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Irritable bowel syndrome (IBS) is one of the most common conditions
that is encountered in general medical practices It has the potentialfor protean manifestations, but generally is characterized by abdominalpain, bloating, and disturbed defecation. Based upon survey data from thegeneral population, the prevalence of symptoms that are suggestive of IBSis between 14% and 24% in women and from 5% and 19% in men in theUnited States and Britain . Although it is clear that symptoms that aresuggestive of IBS are common, only a quarter of symptomatic patients seekmedical advice for their symptoms Despite this observation, it wasestimated that IBS is responsible for approximately 2.4 to 3.5 millionphysician visits per year and represents 12% of primary care visits and 28%of referrals to gastroenterologists
IBS negatively impacts upon the quality of life (QOL) of affected
individuals. Recent studies indicate that the QOL in patients who have IBSin the United States is worse than that of the general U.S. population and issimilar to that of patients who have any of several significant medicalconditions, including clinical depression Moreover, patients who haveIBS are much more likely to exhibit health care–seeking behaviors that are
From the Division of Gastroenterology, Department of Internal Medicine, National Naval
Medical Center and Uniformed Services University of the Health Sciences, Bethesda,Maryland (BDC); and the Division of Gastroenterology, Department of InternalMedicine, University of Michigan School of Medicine, Ann Arbor, Michigan (WDC)
The opinions and assertions contained herein are the sole views of the authors and should
not be construed as official or as representing the views of the U.S. Navy, Department ofDefense, or Department of Veteran Affairs.
Dr. Cash is a consultant for Novartis and is on the Speaker’s Bureau for Novartis and Wyeth.
Dr. Chey is a consultant for Glaxo Smith-Kline, Jannsen, Novartis, and Solvay, has activeresearch grants from Janssen, and is on the Speaker’s Bureau for Glaxo Smith-Kline andNovartis.
CLINICS IN FAMILY PRACTICEVolume 6 • Number 3 • September 2004
related to gastrointestinal (GI) and non-GI complaints. Consultations fornon-GI problems are four times more common in this population comparedwith patients who do not have IBS
The annual economic consequences of IBS in the United States are
substantial. A recent study found that patients who have IBS account forgreater health care expenditures than patients who do not have IBS . Itwas estimated that IBS accounts for approximately $1.7 to $10 billion inannual direct medical costs per year . In addition to costs from physicianvisits, diagnostic testing, and treatment, women who have IBS are morethan twice as likely as women who do not have IBS to undergo abdominalor pelvic surgery . These surgical procedures frequently are performedin a misguided attempt to improve symptoms that are the consequence ofIBS. Another $10 to $20 billion in indirect costs as a consequence of workabsenteeism and decreased productivity can be attributed to IBS each yearIBS represents a leading cause of work absenteeism and isequivalent to the leading cause, the common cold .
IBS likely represents the common clinical expression of multiple
potential pathophysiologic factors. Potential factors that contribute to IBSinclude a genetic predisposition to the condition, disturbed central nervoussystem pain processing and visceral hypersensitivity, mucosal inflamma-tion, abnormal colonic motility, and emotional stress. It is likely, given thedegree of variation of IBS symptoms in affected patients, that the etiologyof IBS is actually a heterogeneous combination of these factors, as well asother mechanisms that remain to be elucidated.
It is not uncommon for patients who have suspected IBS to describe
similar symptoms, if not the diagnosis, of IBS in family members. Thisobservation gave rise to several studies that evaluated the possible role of agenetic predisposition for IBS. Although these studies do seem to support agenetic contribution to IBS, the basis of this contribution remainsunknown. Some investigators hypothesized that differences in inheritedpatterns of serotonin processing at the neuronal level may play a role Studies from Olmstead County, Minnesota demonstrated that IBS is morecommon in patients who have a first degree relative who has IBSsymptoms Such observational studies, although interesting, do nothelp us to understand the relative contribution of ‘‘nature versus nurture’’.
Levy and colleagues observed that IBS was more common inmonozygotic twins than in dizygotic twins. They also observed that thepresence of a parent who had IBS was even more predictive for thesubsequent development of IBS, a finding that lends credence to the theorythat IBS may have a significant learned or behavioral component.
For many years, investigators focused on the role of abnormal motility
in the pathogenesis of IBS. Numerous motility abnormalities that affect theGI tract have been identified in patients who have IBS. For example,patients who have a predominant symptom of diarrhea seem to haveaccelerated whole gut and colonic transit times Conversely,patients who have constipation-predominant IBS demonstrate decreasedmigrating motor complexes compared with controls who did not have IBS. Whether these motility changes are primary or secondary to anotherpotential etiology of IBS remains to be proven. The degree of variability inthe observed results and the methodologic limitations of previous trials ofcolonic motility highlight the need for additional evidence in this area.
Currently, motility studies are not recommended for use as diagnosticmarkers or therapeutic guides for patients who have IBS.
Visceral Hypersensitivity and Brain-gut Interactions
Pain is a central requirement of the definition and diagnosis of IBS.
Over the past 20 years, the potential roles of heightened visceral sensation,also referred to as ‘‘visceral hypersensitivity,’’ and abnormalities in brain-gut interactions also were implicated in the pathogenesis of IBS. Severalinvestigators have reported a heightened visceral sensation in response torectal balloon distention in patients who had IBS and other functional GIdisorders. In addition, recent work using positron emission tomographyscanning and functional MRI identified abnormalities in brain activation inpatients who had IBS versus controls . Abnormalities have beenidentified consistently in the activation of the anterior cingulate cortexwhich likely plays an important role in the development of attention to apainful stimulus, the unpleasantness associated with a painful stimulus,and the attribution of an emotional response to a painful stimulus. Theanterior cingulate cortex also plays an important role in the activation ofdescending inhibitory pathways that help to gate or control the passage ofafferent information from the periphery to the brain.
Our understanding of the enteric nervous system and the role that
abnormalities in the enteric nervous system may play in patients who haveIBS continues to evolve. The enteric nervous system functions semi-autonomously but can be modulated by input from the autonomic nervoussystem. In this way, the enteric nervous system plays a critical role inmodulation of GI motility and secretory function. Evolving evidence hasimplicated several neuromodulators, including serotonin, in the normalfunction of the enteric nervous system .
Gastrointestinal infection with its consequent mucosal inflammation
seems to play a role in the etiology of IBS in a subset of patients. Several
groups have reported that up to one third of individuals who suffered witha case of bacterial enteritis go on to develop more chronic GI symptoms.
More recent observations suggest that the percentage of patients whodevelop ‘‘postinfectious’’ IBS probably is substantially less than 33% Nonetheless, there is doubt that this condition is a real entity. Recentresearch has identified abnormalities in immune function in a subset ofpatients with IBS. Most patients who develop IBS after an enteric infectionwill suffer with diarrhea-predominant symptomatology. In such patients,abnormalities in intestinal permeability, gut transit, and the numbers andfunction of immune cells have been proposed It is likely thatpostinfectious IBS is one of many disorders that leads to chronicinflammation of the GI tract and in this fashion, causes symptoms thatare suggestive of IBS.
Several groups have determined that psychosocial stress alters GI
motor function and sensation . In this way, psychosocial stressorslikely exacerbate GI symptoms in patients who have functional GI dis-orders. Anxiety disorders, somatoform disorders, or a history of physicalor sexual abuse can be identified in approximately 42% to 61% of patientswho have IBS in referral practices In particular, several studiessuggested that the presence of somatization is particularly common andlikely influences outcomes in patients who have IBS . The role ofemotional stress as an etiologic factor in the development of IBSsymptoms also may be inferred from the effects of psychologic therapieson IBS symptoms (see later discussion).
For a variety of reasons, clinicians often struggle to arrive at a
confident diagnosis of IBS. The differential diagnosis in patients who havesymptoms that are suggestive of IBS is broad and there is no reliablebiologic marker for this condition. chronicles the differentialdiagnosis for abdominal pain and disturbed defecation As such, IBS isviewed more often as a ‘‘diagnosis of exclusion’’ than as a primarydiagnosis. Over the past 30 years, several groups have attempted todevelop symptom-based criteria to guide researchers and clinicians inidentifying patients who have IBS. Multiple symptom-based criteria havebeen developed, including the Manning, Rome I, and Rome II criteria(. In particular, the Rome I and Rome II criteria, developedby multinational working groups, provide a uniform framework for theselection of patients in diagnostic and therapeutic trials of IBS.
In recent years, the application of these criteria to patients in clinical
practice has been encouraged . Studies found that the Rome IIcriteria are specific for IBS and have the advantage of being easier torecall and use than the older Rome I criteria Recent evidence
Box 1. Differential Diagnosis of Abdominal Pain
Irritable bowel syndromeCeliac diseaseInﬂammatory bowel disease
Crohn’s diseaseUlcerative colitisProctitisMicroscopic/collagenous colitis
BacterialViralProtozoalParasiticSmall intestinal bacterial overgrowth
Addison’s diseaseHyper/hypothyroidismDiabetes mellitus
Lactose intoleranceCeliac diseasePancreatic insufﬁciency
ColorectalEndocrinologic/amine precursor uptake decarboxylation (APUD)Metastatic
Postgastrectomy syndromesShort gut syndrome
Panic disorderSomatization disorderDepression
Data from Cash BD, Chey WD. Irritable bowel syndrome: an evidence-based
management approach. Journal of Clinical Outcomes Management 2002;9(7):410.
suggests, however, that the Rome II criteria may not be as sensitive as theRome I criteria, largely because of the more restrictive temporal painrequirement that is associated with Rome II For the clinician, thismeans that patients who fulfill IBS criteria are likely to suffer with IBS.
Many patients who do not fulfill the criteria still ultimately end up with adiagnosis of IBS.
Symptom-based Criteria for the Diagnosis of Irritable Bowel Syndrome
Abdominal pain relieved At least 12 weeks of
consecutive, in thepreceding 12 monthsof abdominal discomfortor pain that has twoof the three features:
Altered stool frequency, orAltered stool form, orAltered stool passage, orPassage of mucus, orBloating or feeling of
The Rome Committee on Functional Gastrointestinal Disorders and
many IBS authorities recommend that selected diagnostic tests beperformed as a part of the routine evaluation of patients who havesuspected IBS . These tests include serum and stool studies anddirect colonic visualization by way of colonoscopy in the hopes ofexcluding important organic GI diseases Recently, the necessity ofperforming a standardized series of tests in patients who have suspectedIBS was questioned .
The performance of a diagnostic test should shift the clinician’s
estimate of pretest probability of a disease so that s/he may be assuredreasonably that the disease being considered is either present or absent() . In the case of IBS, diagnostic tests are performed to excludeorganic diseases that may have similar presenting symptoms and in sodoing, to reassure the clinician and patient that the diagnosis of IBS iscorrect. Inflammatory bowel disease (IBD), colorectal cancer, systemichormonal disturbances, enteric infections, and malabsorptive diseases areof greatest concern to the clinician who is faced with a patient who hassymptoms that are suggestive of IBS.
A recent systematic review of the English language literature
regarding commonly-used diagnostic tests for IBS was performed .
This review included clinical trials that were published between 1980 and2001 that enrolled patients who fulfilled symptom-based criteria for IBSand who underwent diagnostic testing. After applying established criteriafor quality and validity of trials about diagnosis , six studies fulfilledinclusion criteria A review of these studies suggested that thepretest probability of organic disorders, including colon cancer, IBD,thyroid disease, and lactose malabsorption, was not different betweenpatients who were suspected of having IBS and the general population.
When patients fulfilled symptom-based criteria for IBS, performance ofcommonly-recommended tests, including endoscopic evaluation of thecolon, a complete blood cell count, comprehensive serum chemistrypanels, stool ova and parasite testing, fecal occult blood testing, thyroidfunction test screening, and hydrogen breath tests for lactose intolerance,were unlikely to lead to the diagnosis of organic GI diseases. One possibleexception was celiac disease, which seemed to be more common inpatients who had suspected IBS than in age- and gender-matched controls.
This single study was conducted in a referral setting with a homogeneouspopulation. Thus, the results require replication in the United States beforerecommending routine testing for celiac disease in patients who havesuspected IBS. The absence of compelling evidence to pursue a detailed
Pretest Probability of Organic Gastrointestinal Disease in Patients Who MeetSymptom-based Criteria for Irritable Bowel Syndrome
Data from Cash BD, Schoenfeld PS, Chey WD. The utility of diagnostic tests in irritable
bowel syndrome patients: a systematic review. Am J Gastroenterol 2002;97:2812–19.
diagnostic evaluation in patients who have suspected IBS does not addressthe potential ‘‘reassurance value’’ of a negative evaluation. Such a responsehas been demonstrated with other functional GI conditions, such asdyspepsia but has not been shown with IBS.
There is a broad consensus that the presence of ‘‘alarm’’ features of GI
symptomatology should prompt an appropriate, complete, and directedevaluation. Such features include the onset of new GI symptoms in patientswho are older than age 50; unexplained weight loss; progressive orunrelenting abdominal pain; symptoms that awaken the patient at night; afamily history of colon cancer; and stool characteristics, such as fastingdiarrhea or large volume diarrhea (greater than 300 mL/d).
The choice of detailed diagnostic testing in those patients with
refractory symptoms or alarm features is dictated by the patient’spredominant symptoms. Celiac disease antibody testing, with antiendo-mysial or tissue transglutaminase serum antibody tests may be useful,particularly in patients who have prominent complaints of abdominalbloating and loose stools. In most patients who have suspected IBS basedupon symptom-based criteria, the clinician can feel comfortable aboutproceeding to therapeutic interventions without performing an exhaustivemedical evaluation. These recommendations do not negate the need forcolorectal cancer screening in all individuals who are older than 50 years.
There is no single consistently successful therapeutic approach for
patients who have IBS. Because IBS typically is a chronic condition, thegoals of therapy should focus on patient reassurance, education about thesyndrome, and symptom improvement, rather than on disease cure. This isbest achieved through a well-developed patient-physician relationship witha clear delineation of realistic goals and expectations. presents ageneral therapeutic approach to IBS and specific agents, depending uponthe predominant IBS symptom subtype that is encountered.
Most patients who have IBS (ie, those who have mild symptoms and
minimal impairment) can be managed at the primary care level. Fewer than25% of patients who have IBS have more severe symptoms with significantlifestyle impairment and require management by a gastroenterologist.
Finally, approximately 5% of patients who have IBS have such severe andincapacitating symptoms that they require referral to a center withmultispecialty capability .
Supplemental dietary fiber increases stool weight and decreases
colonic transit time. For the last 20 to 25 years, fiber has been consideredwidely to be the first-line agent for treatment of IBS. Although fiber seems toameliorate constipation symptoms in some patients, the ability of dietaryfiber to alleviate abdominal pain and diarrhea has been disappointing.
Serotonergic Agents: Differences Between Alosetron and Tegaserod
Multiple randomized, controlled trials have failed to show any convincingbenefit from fiber supplementation for the multiple symptoms of IBSFor the most part, these studies reported similar degrees ofsymptomatic improvement between experimental and control populations.
In addition, symptomatic improvement did not correlate to altered colonicmotility or changes in stool weight.
Patients who have IBS frequently relate their symptoms to the ingestion
of certain foods or food groups. Multiple trials have examined the role ofdietary exclusion as a treatment for IBS. A systematic review of the availabletrials that examined dietary exclusion concluded that such an approach didnot seem to benefit most patients who had IBS . The methodology of theincluded trials varied widely as did the results of individual studies; this maydilute any true treatment effects of such an approach. Major limitations toall of the dietary exclusion trials included the failure to use formal symptomcriteria to identify patients who had IBS, serious methodologic flaws, andvariable duration of exclusion diets and food challenges. There is noconvincing evidence that the routine use of exclusion diets (eg, lactose-reduced or gluten-free diets) consistently benefits patients who have IBS.
Nonetheless, if a careful dietary history uncovers the excessive intake ofspecific foods (eg, fatty foods; caffeine; fruits or other foods that containpoorly-digestible carbohydrates, including lactose, sorbitol or fructose) or ifthere is a clear association between symptoms and certain foods, thensimple dietary advice is inexpensive and harmless and may result in areduction in symptoms in a subset of patients who have IBS.
In 2002, a systematic review and clinical practice guideline for the
management of IBS was published by the American College of Gastro-enterology (ACG) . This document largely conformed to evidence-based
medicine criteria for a systemic review and critically assessed andgraded the various treatment approaches for IBS. According to thisdocument, traditional therapies, including bulking agents, antidiarrheals,antispasmodics, and behavioral therapy, were believed to be effective forindividual IBS symptoms, but have not been shown to improve global IBSsymptoms reliably. The presence of serious methodologic flaws compli-cates the interpretation of data from most of the older studies thatevaluated these therapies. Because the quality of clinical trials in IBS hasimproved in recent years, there is emerging evidence to suggest that sometherapies are of benefit to certain subsets of patients who have IBS Based upon the results of high-quality clinical trials, the ACG documentreported that alosetron and tegaserod were the only agents that had provenefficacy for the treatment of IBS.
Commonly-used antidiarrheals in the United States include opiate
derivatives and cholestyramine. Of the opiate derivatives, loperamide isfavored over diphenoxylate in patients who have chronic symptomsbecause it penetrates the blood–brain barrier poorly and therefore, haslittle to no potential for addiction.
The only antidiarrheal agent that has been evaluated for IBS is
loperamide. Three randomized controlled trials evaluated the use ofloperamide for symptom relief in patients who had IBS All of thesetrials had significant methodologic limitations, including differences in theway patients who had IBS patients were defined, short duration of therapy,and small sample sizes. These trials indicated that although loperamidewas an effective treatment for diarrhea, it did not relieve abdominal pain orimprove global IBS symptoms consistently.
Osmotic (eg, magnesium citrate, milk of magnesia, sodium phosphate,
polyethylene glycol, lactulose, sorbitol) and stimulant (eg, senna, cascara,castor oil, diphenylmethane derivatives, docusate sodium, mineral oil)laxatives are used widely to treat patients who have constipation-predominant IBS. No randomized controlled trials have assessed theireffectiveness in these patients.
Antispasmodics (eg, anticholinergics, antimuscarinics, calcium chan-
nel blockers) are the medications that are prescribed most frequently forpatients who have IBS. The rationale for the use of these medications isbased upon their ability to relax smooth muscle in the GI tract, and, thus,reduce the contractile response that occurs as a result of stress or a meal.
Several reviews reported that antispasmodic medications were moreeffective than placebo in patients who had IBS . The meta-analysisby Poynard and colleagues included 26 studies that examined similarend points, including global assessment, pain, constipation, distention, and
adverse reactions. The investigators determined that antispasmodics weresuperior to placebo for improving patients’ global assessment and pain. Thisstudy found these benefits to hold true for medications that containedantimuscarinic, anticholinergic, and calcium channel blocker properties. The U.S. Food and Drug Administration (FDA) has not approved any ofthe medications that were demonstrated to be more efficacious thanplacebo. In addition, the investigators pointed out that the studies that wereincluded in their meta-analyses suffered from variable inclusion criteria,study end points, insufficient sample size, and other significant methodo-logic flaws.
The most commonly-prescribed antispasmodic agents in the United
States are hyoscyamine (levsin) and dicyclomine (bentyl). Three small,randomized trials compared the effectiveness of these drugs with placeboin patients who had IBS. All of the studies had significant methodologicflaws; only one study demonstrated a benefit of dicyclomine, 40 mgfour times/d, over placebo in a 2-week trial
Another meta-analysis reported that peppermint was superior to
placebo for improvements in global IBS symptoms, probably because of itscalcium channel blocker properties Although over-the-counterpreparations of peppermint are available in the United States, the use ofpeppermint oil in clinical practice is limited by the development ofsymptomatic acid reflux in up to one third of treated patients.
Because of the associations among psychologic distress, abnormal-
ities in visceral sensation, and IBS, antidepressants are a potentiallyattractive treatment option in patients who have moderate to severesymptoms. A recent meta-analysis reported that tricyclic antidepressants(TCAs) significantly reduced abdominal pain and diarrhea in patients whohad diarrhea-predominant IBS In this meta-analysis, TCAs yielded anumber-needed-to-treat (NNT) of three and were effective at dosages thatwere lower than typically are used to treat depression. The studies that areincluded in this meta-analysis contained serious methodologic flaws thatlimit the ability to generalize the results to routine community practice.
The first high-quality randomized controlled trial that compared the
efficacy of the TCA, desipramine (norpramin), with placebo sends a mixedmessage regarding the usefulness of TCAs for patients who have IBS .
The intention-to-treat analysis failed to show a statistically significantimprovement in a composite symptom scale between the groups who weregiven desipramine and placebo (60% versus 47%, P = 0.13). This was largelydue to the patients (28%) who did not complete the trial. The mostcommonly-cited reason for patient drop-out was adverse drug effects.
There also were several patients who had undetectable serum levels ofdesipramine, despite reporting medical compliance. When these patientswere excluded from the analysis, the use of desipramine resulted in astatistically significant benefit compared with placebo (73% versus 49%,
P = 0.006, NNT = 4). This trial tells us that patients who can tolerate TCAsare likely to experience symptomatic benefit; however, many patientsexperience unacceptable side effects. It also confirms previous findingsthat the risk/benefit ratio that is associated with TCAs is most favorable inpatients who have with persistent, moderate to severe symptoms
Few studies have addressed the potential role of selective serotonin
reuptake inhibitors (SSRIs) in the treatment of IBS. Despite the lack ofevidence, many clinicians routinely use SSRIs in patients who havefunctional GI complaints, presumably related to their proven efficacy forthe treatment of anxiety and depression, beneficial effects on the treatmentof somatic pain, and better tolerability when compared with TCAs. Severaluncontrolled trials reported some symptomatic benefit from SSRIs inpatients who had a variety of functional GI disorders
Recent randomized, double-blind trials reported differing effects of
venlafaxine (effexor) or fluoxetine (prozac) on colonic sensorimotorfunction and symptomatology Venlafaxine increased coloniccompliance, decreased the gastrocolonic response, and marginally reducedcolonic sensation in healthy volunteers In another trial that involved 40patients who had IBS, fluoxetine did not significantly alter rectal sensationor reduce abdominal pain or global symptoms compared with placebo
In a third study from the United Kingdom, 257 patients who had severe
IBS were randomized to 12 weeks of active treatment with paroxetine(paxil) at a dosage of 20 mg/d, psychotherapy, or usual care by theirgastroenterologists or general practitioners Individual therapies thatwere contained within the ‘‘usual care’’ were not defined by the investi-gators, but antidepressant agents and psychotherapy were prohibited inthis group during the active treatment part (initial 12 weeks) of the study.
At the end of 12 weeks of treatment, the group that was given paroxetineexperienced a small, but significant, reduction in the number of days withabdominal pain compared with baseline (P = 0.014). Paroxetine also led tosmall improvements in QOL, that predominantly were related to effects onpsychologic distress and social disability due to emotional problems andfatigue. Only 50% of patients in the group that received SSRIs completedthe 12-week treatment.
The available data do not send a clear mandate for the use of SSRIs in
the treatment of patients who have IBS. It makes intuitive sense that SSRIsare likely to be of most benefit in patients who have comorbid psychiatricillness, but it remains unclear as to whether these agents offer any benefit inthe absence of concomitant psychiatric conditions. Further appropriately-designed and adequately-powered studies are necessary to settle thisimportant issue.
Over the past decade, our understanding of the enteric nervous
system, the afferent pathways that are responsible for the sensation ofvisceral pain, and the cortical centers that are responsible for the pro-cessing and perception of peripheral stimuli has expanded rapidly. There is
complex bidirectional communication between the cerebral cortex and theenteric nervous system (so-called ‘‘brain–gut interactions’’) that influencesGI function and sensation. In recent years, serotonin was found to be animportant neurotransmitter in the enteric nervous system, spinal cord, andbrain. Specifically, serotonin type-3 (5-HT3) receptors and serotonin type-4(5-HT4) receptors that are found on visceral sensory neurons and withinthe enteric nervous system play an important, integrated role in thereflexes that control GI sensation, motility, and secretion
The expanding recognition of the role of serotonin in the GI tract led
to the development of specific 5-HT3 receptor antagonists for the treatmentof IBS. Several 5-HT3 receptor antagonists, including ondansetron (zofran),granisetron (kytril), and alosetron (lotronex), are commercially availablein the United States. Of the available 5-HT3 receptor antagonists, alosetronis the most potent antagonist; it is 10 times more potent than ondansetronand is the only agent that is FDA-approved for the treatment of women whohave severe IBS and a predominant complaint of diarrhea. Another 5-HT3receptor antagonist, cilansetron, is currently in phase III trials within theUnited States.
Alosetron was developed to address specifically several pathophysio-
logic factors that are important to IBS. Alosetron has effects on visceralsensation, slows colonic transit, and decreases chloride and watersecretion, all of which are potentially attractive features in patients whohave IBS and diarrhea.
Several large, high-quality, randomized, parallel-group, double-blind
12-week trials assessed the efficacy of alosetron versus placebo in patientswho had IBS and a predominant symptom of diarrhea (see .
Alosetron, 1 mg twice daily, improved the primary outcome measures ofabdominal pain or discomfort and fecal urgency Stoolconsistency and frequency also significantly improved with alosetron.
The one trial that assessed global IBS symptoms reported a significantlygreater improvement with alosetron than with placebo (76% versus 44%,P < 0.001) . A fifth randomized trial from Europe compared alosetron tothe antispasmodic mebeverine (colofac); alosetron was superior for IBSsymptom relief Another study reported that overall satisfaction withtherapy was significantly greater with alosetron than placebo (69% versus46%, P < 0.001)
Between 22% and 39% of patients who had IBS and were randomized to
alosetron reported constipation as an adverse event. In the clinical trials,constipation was severe enough to cause the discontinuation of alosetron in10% of patients. Approximately 1 in 1000 patients who reported constipationdeveloped a serious complication, such as obstruction, perforation,impaction, toxic megacolon, or in a few rare instances, death Inaddition, several cases of possible ischemic colitis were reported in theclinical trials. It was estimated that 3 per 1000 patients (95% confidence
interval, 1–4) who were treated with alosetron for 6 months developedischemic colitis. During the brief time that alosetron was commerciallyavailable, the FDA recorded 113 cases of severe constipation and 80 cases ofpossible ischemic colitis. An explanation for the association betweenalosetron and ischemic colitis remains elusive. Elderly patients may bemore susceptible to adverse events in association with alosetron. To whatdegree improper patient selection played a role in the development of theseserious adverse events remains unclear.
Alosetron was withdrawn voluntarily from the United States market-
place in December 2000; as a result of the public outcry that followedwithdrawal of this drug, the availability of further safety data, anddevelopment of a detailed risk management plan with the manufacturer,the FDA reapproved alosetron for use in female patients who had severediarrhea-predominant IBS who failed to respond to conventional therapy.
Alosetron should not be used in patients who have any degree ofconstipation. Health care providers who prescribe alosetron must completean educational module, use special identifying stickers on prescriptions,fully inform patients of the potential risks that are associated with the use ofthis medication, and obtain a signed patient-physician agreement statingthat the patient understands the risks of taking this medication.
The selective, partial 5-HT4 agonist, tegaserod (zelnorm), is one of a
new class of compounds called the aminoguanidine indoles. Structurally,tegaserod is similar to serotonin, which accounts for its agonist, orstimulatory activity, at the 5-HT4 receptor. Tegaserod stimulates the releaseof calcitonin gene-related peptide from enteric neurons and promotesincreases in GI peristalsis. It induces chloride and water secretion into thecolonic lumen and may exert effects on visceral sensation . Related tothese physiologic effects, tegaserod is an attractive candidate medicationfor patients who have IBS and constipation. highlights a comparisonof mechanism of action, indication, dosage, side effects, and potentialtherapeutic gain versus placebo between alosetron and tegaserod.
In several large, well-designed, randomized, parallel-group, placebo-
controlled 12-week clinical trials, tegaserod was shown to improve globalIBS symptoms and the specific abdominal symptoms, such as pain,bloating, and constipation, that are found in female patients who have IBSand constipation As a consequence of these trials, tegaserod wasapproved by the FDA for use in women who have IBS and a predominantbowel complaint of constipation.
Largely because of safety concerns with other drugs that affect sero-
tonin receptors, multiple trials that examined the safety of tegaserod wereperformed. Tegaserod has not been associated with any serious adverseeffects or drug interactions. The most common adverse events that areassociated with tegaserod are diarrhea and headache. The discontinuationrate because of diarrhea in the large, randomized, controlled trials rangedfrom 1% to 3%. Tegaserod-associated diarrhea usually occurs within the
Box 2. Symptom-Directed Therapies for Irritable Bowel
Education and reassuranceEstablishment of a therapeutic patient-physician relationshipDietary exclusion/modiﬁcation aided by dietary and activity diaries
Fiber supplementation (psyllium/ispaghula husk)Antispasmodic agents (dicyclomine/hyoscamine)Antidepressants (TCA or SSRI)Psychologic therapies/relaxation therapyAlternative medicine
Fiber supplementation (psyllium/ispaghula husk)Osmotic laxatives (magnesium citrate, milk of magnesia, sodium
phosphate, polyethylene glycol, lactulose, sorbitol)
Stimulant laxatives (senna, cascara, diphenylmethane derivatives,
Psychologic therapies/relaxation therapyAlternative medicine
Opiate derivatives (diphenoxylate/loperamide)TCAs5-HT3 antagonist (alosetron)
Bile acid binding resins (cholestyramine)Psychologic therapies/relaxation therapyAlternative medicine
first week of initiating therapy and typically is self-limited. A recentlycompleted trial in 579 patients who had IBS and constipation assessed thesafety of tegaserod for 12 months and confirmed results from the 12-weekclinical trials . The most common adverse events reported in this trialincluded diarrhea (10%), headache (8%), abdominal pain (7%), andflatulence (6%).
Several behavioral-based therapies have been investigated as poten-
tial treatment options for IBS. Examples include cognitive-behavioraltherapy, interpersonal psychotherapy, group therapy, biofeedback, andhypnosis. Most of these therapies have their basis in relaxation therapy andare directed toward correcting maladaptive coping skills that are believedto engender emotional stress, which may manifest as GI symptoms. Much
like the clinical trials of pharmacologic agents, significant methodologicflaws limited early behavioral therapy research. It was observed, however,that certain subgroups of patients who had IBS responded to behavioraltherapy to a greater degree than others. These groups include patients whohave intermittent abdominal pain, short symptom duration, personalinsight as to the presence of depression or anxiety, and those who have apredominant symptom pattern of pain or diarrhea .
Several recent publications that evaluated the use of psychologic
therapies in IBS represent significant advances in this body of literature.
Palsson and colleagues reported the results of studies that evaluatedthe role of hypnosis for IBS. These trials found that weekly hypnosissessions, in combination with self-hypnosis techniques for 12 weeks,improved the symptoms of abdominal pain, bloating, and disturbeddefecation, and psychologic parameters by way of somatization andanxiety scores, but did not alter rectal tone and pain threshold. Anotherstudy from the United Kingdom confirmed the effectiveness of hypnother-apy in 250 unselected patients who had IBS This study suggested thatmale patients who had diarrhea-predominant symptoms may not respondas well to hypnotherapy as other subgroups of patients who have IBS.
Another study reported significant improvements in individual IBSsymptoms after meditation and relaxation for a period of 3 months .
In a recently reported well-designed, randomized clinical trial, Dross-
man and colleagues reported that cognitive behavioral therapy (CBT)significantly improved symptoms in patients who had moderate to severeIBS compared with education alone. In the intention-to-treat analysis, 70%of the group that underwent CBT responded compared with 37% in theeducation group (P < 0.001, NNT = 3). In this trial, current or recent depres-sion predicted a worse response to CBT or therapy with desipramine.
The aforementioned trial by Creed and colleagues also included a
cost-effectiveness analysis that compared individual psychodynamicinterpersonal therapy or paroxetine to usual care (not defined) for IBS.
At 3 months, no difference in pain severity was observed between thegroups that received psychotherapy or usual care. Psychotherapy led to asignificant improvement in QOL that predominantly was related to effectson psychologic distress and social disability that were due to emotionalproblems and fatigue. Over a year, health care costs were less withpsychotherapy; this was related largely to a reduction in the number ofphysician visits. Only patients from tertiary care centers were enrolled inthe study; therefore, these patients may not be representative of the overallIBS population.
Although these trials support a role for behavioral therapies in IBS, the
real-world effectiveness of such interventions depends upon motivatedpatients who can see beyond the stigma of pursuing psychotherapy andaccess to an appropriately-trained therapist. Of equal importance, coveragefor mental health care services remains inconsistent among insurancecarriers. Finally, most clinicians use antidepressants in combination withpsychologic therapies. Trials that are designed to assess the incrementalbenefit of combined medical and psychologic therapies are awaited eagerly.
Alternative medicine techniques, including acupuncture, probiotic
therapy and Chinese herbal medicine, are becoming increasingly popular.
Among GI diseases, IBS is the most common reason for the use of thesealternative strategies . A recent study from Australia reported thatmore than 20% of patients who had IBS or functional dyspepsia reportedusing alternative strategies for their GI complaints .
Previous reviews indicate that acupuncture affects the enteric
nervous system and can alter GI motility, electrical activity, gastricsecretion, and cytoprotection in animals and humans The proposedmechanism of action in IBS, similar to the pain-modifying qualities ofacupuncture, is by way of afferent neural stimulation with consequenteffects on the autonomic nervous system through opioid-dependentpathways. A recent study in patients who had IBS found that acupunctureresulted in small, but statistically significant, improvements in the patients’sense of well-being and bloating, but not in stool frequency or pain
Probiotic bacteria may have anti-inflammatory effects on the GI
mucosa. Small studies of 4 weeks’ duration reported that Lactobacillusplantarum was superior to placebo for controlling abdominal pain andflatulence in patients who had IBS . More recently, a randomized,controlled trial found that the probiotic supplement, VSL #3 (a powdercontaining multiple strains of live, freeze-dried lactic acid bacteria madeand distributed by VSL Pharmaceuticals), improved bloating, but not globalsymptoms, pain, urgency, or transit in patients who had diarrhea-predom-inant IBS .
In a well-designed, randomized, controlled trial in Australian patients
who had IBS, Chinese herbal medicine (either standardized or individu-alized) was more effective than placebo in improving GI symptoms andseveral QOL parameters however, the active ingredients that wereresponsible for these observed improvements are unknown. In addition,questions regarding product quality and purity remain. For these and otherreasons, despite these promising preliminary results, more carefullydesigned and rigorously controlled human studies are needed beforealternative therapies can be recommended routinely.
IBS is a prevalent GI disorder of diverse pathophysiology. Recent
guidelines have assessed and graded the evidence that supports variousdiagnostic approaches and therapeutic options for IBS. IBS can bediagnosed confidently through the identification of the appropriate symp-toms and the exclusion of alarm features. Younger patients who fulfillsymptom-based criteria for IBS and have no alarm features do not need toundergo exhaustive testing to exclude organic diseases. Preliminary evi-dence suggests that celiac disease may be more prevalent in patients whohave suspected IBS, although this needs to be validated in appropriately
designed trials from North America before routine screening can berecommended. After the diagnosis of IBS has been established, manage-ment should focus on patient reassurance, education, and amelioration ofsymptoms. This is best achieved through a well-developed patient-physician relationship with a clear delineation of realistic goals andexpectations. Medical therapies that target the predominant symptoms ofdiarrhea and constipation are appropriate first-line agents. Frequently,multiple therapies need to be tried in a stepwise manner before therapeuticsuccess is achieved. More recently-developed therapies, including theserotonergic agents, that affect function of the enteric nervous system andvisceral sensation, offer the possibility of addressing multiple symptoms inpatients who have IBS. Psychologic therapies seem to offer benefit inappropriately-selected patients who have IBS. Alternative medicinetechniques also may offer benefit to a subset of patients who have IBS;however, additional, adequately powered, well-designed studies in this areaare needed.
Diagnosis• In the absence of alarm features, symptom-based criteria are sufﬁcient to
make a presumptive diagnosis of IBS—Evidence Level C.
• Serologic evaluations (complete blood counts, routine electrolytes and
chemistries, thyroid function studies) cannot be recommended in theabsence of alarm features conﬁdently—Evidence Level C.
• Routine use of structural colonic evaluations (barium enema, sigmoid-
oscopy, colonoscopy, rectal biopsies) cannot be recommended in theabsence of alarm features conﬁdently—Evidence Level C.
• Among patients who have IBS with diarrhea, testing for celiac sprue may
be considered conﬁdently—Evidence Level C.
Therapy• Bulking agents and antispasmodics are not more effective than placebo at
relieving global IBS symptoms—Evidence Level B.
• Loperamide is not more effective than placebo at relieving global IBS
• Tricyclic antidepressants are superior to placebo for abdominal pain and
global IBS symptom relief—Evidence Level B.
• SSRIs are not more effective than placebo for abdominal pain and global
IBS symptom relief—Evidence Level C.
• Tegaserod is more effective than placebo at relieving global IBS symptoms
in female patients who have constipation-predominant IBS—EvidenceLevel A.
• Alosetron is more effective than placebo at relieving global IBS symptoms
in female patients who have diarrhea-predominant IBS—Evidence LevelA.
• Behavioral therapy is more effective than placebo at relieving global IBS
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Molecular Pathology of these pathways could be used clinically, we conducted a randomized phase II trial based on letrozole (LET arm) with or Laboratory without ‘metronomic’ oral cyclophosphamide. PI3K, AKT, and mTOR were assessed on tumour specimens collected before and after treatment in patients randomized in this trial. The primary aim was to explore the changes of these molecu
Appointment to the Board of Trustees BUSINESS TRUSTEE ABOUT IWM The Imperial War Museum (IWM) was founded in 1917 to record the story of the Great War. Its remit was subsequently extended to cover the Second World War and today, IWM is the world’s leading authority on conflict and its impact focusing on Britain, its former Empire and the Commonwealth, from the First World War to the