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IntroductionMany patients with irritable bowel syndrome (IBS) have walked into their physician's office and said, "The last doctor told me my symptoms were all in my head." Those physicians may have been right, but not in a way they anticipated.Over the past 50 years, evolving conceptual mechanisms have been proposed to explain the pathophysiology of IBS. These mechanisms have ranged from a purely psychological disorder to such physiologic conditions as a primary abnormality in gastrointestinal (GI) motility or visceral hypersensitivity. However, recent scientific data have increasingly supported that a dysregulation in brain-gut interactions resulting in alterations in GI motility, secretion, and sensation is the principal pathophysiologic mechanism underlying IBS.[1] Brain-gut interactions are mediated largely by the autonomic nervous system, which is comprised of the parasympathetic (vagal and sacral parasympathetic), sympathetic, and enteric nervous systems (ENS). Many factors (both central and peripheral) may contribute to an altered brain-gut axis, including genetic predisposition, chronic stress, inflammation/infection, and environmental parameters.[1] These alterations may subsequently lead to disturbances in intestinal motility, visceral sensitivity, and mucosal immune response and permeability. In IBS, these disturbances result in symptoms of abdominal pain or discomfort and altered bowel function, the defining characteristics of this disorder.[2]There are many neurotransmitters and hormones that mediate bidirectional brain-gut communication. Serotonin (5-hydroxytryptamine [5-HT]) is one of the key mediators of gut motility, secretion, and sensation. Most of the serotonin is localized in the GI tract and is found in enterochromaffin (EC) cells and enteric neurons.[3] EC cells sense luminal factors such as food or mechanical distension in the gut, and release serotonin; 5-HT receptors on intrinsic primary afferent neurons (IPANs) as well as extrinsic spinal or vagal afferent neurons are activated. The ENS regulates secretion and peristalsis, whereas vagal and spinal afferents modulate nonpainful and painful sensations, respectively.[4] There are at least 7 main classes of 5-HT receptors. Particularly important for lower gut function and regulation are the 5-HT1P, 5-HT3, and 5-HT4 receptors. These receptors have been the focus of research evaluating the pathophysiologic mechanisms of IBS as well as targets for the development of novel agents in the treatment of functional gastrointestinal disorders. There is also evidence to suggest that other older serotonergic agents -- that is, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) -- may modulate intestinal function as well.[3] The roles of other neuropeptides and their receptors are also currently being explored as potential molecular targets for drug development.The development of more effective treatment for IBS is crucial because it is one of the most common disorders seen by gastroenterologists and primary-care physicians, but patients are often not satisfied with traditional therapies. In addition, proper diagnosis and treatment are particularly critical for a number of reasons. Studies have demonstrated the dramatic impact of this disorder on the quality of life of patients with IBS compared with the general population and with individuals with other chronic health conditions.[5,6] In addition, patients with IBS utilize the healthcare system for both GI and non-GI complaints more than patients without IBS.[7] The latter in turn impacts the productivity of patients with IBS such that their absenteeism from work or school has been found to be 3 times higher than that of patients without IBS.[8] Not surprisingly, economic studies have demonstrated that this disorder is costly to the healthcare system and to the economic system as a whole, resulting in an annual associated cost of up to $30 billion.[9,10]The challenge for clinicians is to identify individuals with IBS despite the fact that no diagnostic biologic marker currently exists for this disorder, and to manage their symptoms despite the lack of effective treatment. Studies evaluating the utility of symptom-based criteria and medical tests in the diagnosis of IBS vs organic GI disorders have resulted in recent recommendations for a more cost-effective diagnostic approach.[11] Although many patients may respond to reassurance, life-style changes, and traditional therapies, it is important for healthcare providers to familiarize themselves with advances in the pathophysiologic mechanisms of IBS that have subsequently led to the development of novel therapeutic agents, such as the serotonergic medications. In addition, these advances have inspired a new look at older medications that affect the serotonin receptors.Diagnosis of IBSSymptom-Based Diagnostic CriteriaDue to the lack of a diagnostic biologic marker for IBS, the diagnosis is made using symptom-based criteria. A number of symptom-based criteria have been used in the past; however, the currently accepted criteria are those that have been developed by the Rome II committee, a group comprised of experts specializing in functional gastrointestinal disorders.[2] IBS is most recently defined as abdominal pain or discomfort not explained by biochemical or structural abnormalities that is present for at least 12 weeks (not necessarily consecutive) over the past 12 months and associated with at least 2 of the following features: (1) relief with defecation; (2) a change in stool consistency (eg, watery/loose or hard/lumpy); and/or (3) a change in stool frequency.The Rome II criteria are a simplification of the Rome I Criteria.[12] The Rome I criteria were similar to the above indicated features, but also stated that 2 or more of the following features must be present as least 25% of the time: (1) abnormal stool form; (2) passage of mucus; (3) bloating or distension; (4) abnormal stool passage (feeling of incomplete evacuation, straining, or urgency); and (5) altered stool frequency (> 3 bowel movements/day or < 3 bowel movements/week). These symptoms are presently used as supportive symptoms for the diagnosis of IBS.Because patients may present with diarrhea and/or constipation, patients are often subgrouped by predominant bowel habit. However, GI symptoms may fluctuate over time and, therefore, a special task force of the American College of Gastroenterology has suggested that patients with IBS be identified using the following designations: IBS associated with abdominal pain, fecal urgency, and diarrhea; IBS associated with abdominal discomfort, bloating, and constipation; and IBS associated with alternating diarrhea and constipation.[11]Diagnostic ConsiderationsOnce a dominant symptom complex is identified in the patient, it is also useful to exclude possible "red flags" that might be indicative of an organic disorder. Table 1 outlines the potential "alarm" symptoms that need to be considered when evaluating a patient with IBS.Table 1. Alarm Symptoms Suggestive of Organic DiseaseHistoryWeight loss > 10 lbs Nocturnal symptoms Initial onset at age > 50 years Significant travel history Severe diarrhea or constipation Rectal bleeding Arthritis/rashes Family HistoryColon cancer Inflammatory bowel disease Celiac disease Physical FindingsFever Oral ulcers Palpable abdominal mass Guaiac-positive stool Other physical finding (eg, abdominal mass, distension) Rectal bleeding or obstruction Laboratory EvaluationIncreased white blood cell count Anemia Abnormal chemistry Increased thyroid-stimulating hormone Elevated erythrocyte sedimentation rate or C-reactive protein Once a thorough medical history and physical examination are performed, a variety of laboratory tests that have been advocated in the literature may be considered.[1,13] These diagnostic tests include: (1) complete blood count (CBC); (2) thyroid-stimulating hormone (TSH) level; (3) erythrocyte sedimentation rate (ESR); (4) complete metabolic profile; (5) stool for ova and parasites (O&P); (6) stool culture and examination; (7) fecal occult blood testing; and (8) celiac sprue panel. Other diagnostic tests include flexible sigmoidoscopy, colonoscopy, or barium enema, and hydrogen breath tests, which should be considered on an individual basis. It is generally recommended that clinicians take an evidence-based medicine approach in their medical evaluation and consider the pretest probability of a test for diagnosing another medical condition (eg, colon cancer, inflammatory bowel disease, celiac sprue) before ordering it. The presence of alarm symptoms would suggest a higher pretest probability of an organic disorder that needs to be ruled out. The differential diagnosis of IBS often depends on the predominant symptom (eg, diarrhea or constipation), as outlined in Table 2.Table 2. Differential Diagnosis of IBS*Malabsorption Dietary Factors Intestinal disorders Lactose intolerance Pancreatic insufficiency Alcohol/caffeine Postgastrectomy Sorbitol/high fructose corn syrup Gas-producing foods Infection High-fat foods Bacteria Wheat (celiac disease) Parasites HIV and associated infections Psychological Disorders Inflammatory Bowel Disease Panic disorder Crohn's disease Somatization Ulcerative colitis Depression Microscopic/collagenous colitis Gynecologic Disorders Endometriosis Malignancies Dysmenorrhea Endocrine tumors Ovarian cancer Colon cancer Neurologic Disorders Parkinson's disease Medications†Multiple sclerosis Antibiotics Spinal cord lesions Nonsteroidal anti-inflammatory drugs Chemotherapy Endocrine/Metabolic Disorders Opiates Diabetes Calcium-channel blockers Hypo/hyperthyroidism Antidepressants Hypercalcemia *Consider dominant bowel symptom†Not an all-inclusive listStudies of reasonably good quality have suggested that the diagnostic yield associated with performing most of these tests is not very high -- for many, in fact, less than 2%.[14,15] However, there are a few exceptions. One exception is lactose intolerance, which is present in approximately 25% of the population. However, lactose intolerance is often coexistent with IBS and, when treated, the patient still has symptoms of IBS. The other exception is celiac sprue. The pretest probability in the patient with IBS is significantly higher than that found in the general population (4.67% vs 0.25% to 0.50%).[16,17] Therefore, screening with endomysial antibody, among other such screening tests, may be indicated, particularly if the patient has failed to respond to treatment. Seven percent of patients with celiac disease are IgA deficient and, therefore, the clinician may want to measure the IgA level as well when celiac disease is a diagnostic consideration.Although the pretest probability of finding an etiology for symptoms by colonoscopy is not high, most gastroenterologists would agree that patients >/= 50 years of age should undergo this examination (or, alternatively, a flexible sigmoidoscopy and barium enema) if a previous screening examination has not been done. This age threshold should be lowered to 40 years if there is a significant family history of colon cancer.Another condition to consider excluding from the differential diagnosis when managing a patient with symptoms of IBS is bacterial overgrowth. Two studies from the same research group found that 78% to 84% of patients with IBS had bacterial overgrowth.[18,19] In patients with evidence of bacterial overgrowth, those treated with neomycin had a >/= 35% reduction in clinical response (ie, improvement) compared with an 11% reduction in patients on placebo.[19] Although these data are extremely intriguing, there are some methodologic limitations in these studies and, therefore, the use of widespread hydrogen breath testing for bacterial overgrowth is still not generally advocated.The diagnosis of IBS is primarily symptom-based, and the literature suggests that once made, the clinician can be confident of his/her diagnosis. Retrospective views of patients have suggested that the diagnosis is an enduring one, with 92% to 97% of the individuals maintaining the same diagnosis over 2-13 years.[20,21]Pathophysiology of IBS and Serotonin SignalingAbnormal GI MotilityThe pathophysiology of IBS has evolved tremendously over the last 50 years. IBS was previously considered a disorder primarily due to abnormal intestinal motility. In the 1950s, a study by Thomas Almy[22] demonstrated that gut motility was increased in both normal individuals and patients with IBS when presented with a stressful situation. Subsequent research demonstrated that patients with IBS had increased motility abnormalities related to meals (ie, after eating) compared with control subjects.[23,24] Studies have also demonstrated GI motility abnormalities, such as clustered contractions, prolonged propagated contractions, and high-amplitude propagating contractions more commonly in patients with IBS compared with healthy individuals.[25-28] Although these motility abnormalities may be, but are not always, associated with IBS symptoms, there does not appear to be a consistent motility abnormality to explain the etiology of symptoms in all patients, and therefore, they are not currently used as diagnostic markers.Visceral HypersensitivityThe initial clinical observations that led to the hypothesis that patients with IBS have visceral hypersensitivity include recurring abdominal pain, tenderness during palpation of the sigmoid colon on physical examination, and excessive pain during endoscopic evaluation of the sigmoid colon. Experimental evidence suggests that a variety of perceptual alterations exist in patients with IBS: visceral hypersensitivity involving the upper and lower GI tract, as well as a heightened perception of physiologic intestinal contractions. Multiple studies using various balloon distension paradigms have reported lowered colorectal perceptual thresholds, increased sensory ratings, and viscerosomatic referral areas in patients with IBS compared with healthy individuals.[29-33] By contrast, most studies have demonstrated that patients with IBS do not exhibit generalized hypersensitivity to noxious somatic stimulation.[30,34,35] At least 2 underlying, distinct mechanisms contribute to the visceral hypersensitivity in IBS: a hypervigilance towards expected aversive events arising from the viscera, and a hyperalgesia that is inducible by sustained noxious visceral stimulation.[32]Central Nervous System ModulationIn the 1980s and 1990s, a greater appreciation for the role of the "brain-gut" axis was achieved, and it was recognized that patients with IBS had a dysregulation between these 2 areas.[36] In general, brain-gut interactions play a key role in the modulation of GI functioning in health and disease. Signals from the brain to the gut play an important role in ensuring optimal digestive function, reflex regulation of the GI tract, and modulation of mood states. Proposed alterations in the brain-gut axis in IBS are best supported by recent findings in functional neuroimaging studies. Using distal colonic stimulation, several studies have demonstrated alterations in regional brain activation in patients with IBS compared with healthy control subjects.[37,38] These brain regions include the anterior and midcingulate cortices, insula, and dorsal pons (in the region of the periaqueductal grey) -- which are some of the most consistently activated brain areas in response to visceral as well as somatic nociceptive stimuli.One area that is consistently activated to a greater degree in patients with IBS compared with control subjects is the anterior midcingulate cortex, a brain region concerned with cognitive processing of sensory input, including attentional processes and response selection. Furthermore, midcingulate activation correlates with the subjective unpleasantness of visceral and somatic pain. These observations suggest that patients with IBS may fail to use central nervous system downregulating mechanisms in response to incoming or anticipated visceral pain. They further show altered activation or deactivation of brain areas involved in the emotional or cognitive processing of visceral stimuli, ultimately resulting in the amplification of pain perception.Role of Stress and Psychological Factors in IBSStress is widely believed to play a major role in the pathophysiology and clinical presentation of IBS. It has been postulated that in the predisposed individual, sustained stress can result in permanent increased stress responsiveness of central stress circuits and vulnerability to develop functional and affective disorders.[39] Stress may be central (eg, psychological distress) or peripheral (eg, infection, surgery) in origin. Numerous studies indicate that patients with IBS report more lifetime and daily stressful events, including abuse, compared with patients with organic GI conditions or healthy individuals.[1] In addition, in patients with IBS, stress is strongly associated with symptom onset, exacerbation, and severity. Even though the effects of stress on gut function are universal, patients with IBS appear to have greater reactivity to stress compared with healthy individuals.[40]A large proportion of patients with IBS or other functional bowel disorders have concurrent psychological disturbances, particularly those with severe symptoms or those seen in tertiary care referral centers. Psychosocial factors have been recognized to modify the illness experience and influence healthcare utilization and treatment outcome. These psychosocial factors include a history of emotional, sexual, or physical abuse, stressful life events, chronic social stress, anxiety disorders, or maladaptive coping styles.[1] A current conceptual model regarding the role of psychosocial factors and stress in IBS suggests that adverse life experiences (past and present) influence stress responsiveness, physiologic responses, and susceptibility to developing and exacerbating this functional disorder via amplification of brain-gut interactions.Role of Immune or Inflammatory MediatorsIBS-like symptoms have been reported in 7% to 30% of patients who have had a recent history of proven bacterial gastroenteritis; this has been termed postinfectious IBS (PI-IBS).[41] A subset of patients with IBS can trace the development of their symptoms to an episode of infectious diarrhea, primarily bacterial[42] or amebic,[43] and possibly even viral,[44] in etiology. Risk factors for PI-IBS include female sex, duration of acute diarrheal illness, and the presence of significant life stressors occurring around the time of the infection.[41]Investigators have found that there are colonic mucosal abnormalities in PI-IBS. One study compared rectal mucosal cellularity and intestinal permeability in patients at 2, 6, and 12 weeks and 1 year after an acute infection with Campylobacter enteritis with those of patients with a history of PI-IBS and healthy controls.[45] Compared with controls, patients with a previous Campylobacter infection were found to have increased numbers of intraepithelial lymphocytes and EC cells and increased intestinal permeability, even after 1 year, as did the patients with PI-IBS. When the secretory granules of the EC cells were evaluated, patients with PI-IBS had granules containing mainly serotonin. The EC cells in healthy control subjects had granules containing primarily PYY, a peptide associated with antisecretory effects. It is conceivable that these findings play a role in the GI symptoms (eg, diarrhea, mucus in the stool) in at least a subset of patients with IBS.Role of Serotonin in GI Function and IBSThe ENS plays a key role in regulation of both gut motility and secretion. A number of neuropeptides are involved in regulation of motility and secretion, including serotonin, which can modulate both of these functions. Ninety-five percent of serotonin is found in the gut, with 90% localized within the EC cells and 10% in the enteric neurons. Serotonin is an important mediator of the peristaltic reflex. The excitatory 5-HT1P, 5-HT3, and 5-HT4 receptors have been found to be particularly important in modulating this motor activity. Following mucosal stimulation (eg, mechanical or chemical stimulation), serotonin is released from EC cells. Serotonin acts on the 5-HT1P receptor located on the terminals of IPANs within the submucosal plexus. 5-HT4 receptors are located on the presynaptic terminals of these afferent nerves and, when activated, facilitate the release of acetylcholine and calcitonin gene-related peptide (CGRP).[3] Following activation of interneurons within the ENS, acetylcholine and substance P are released from enteric motor neurons proximally (orad), which leads to a contractual response. Release of vasoactive intestinal peptide and nitric oxide distally (caudad) result in relaxation in the gut. Peristaltic activity of the gut then occurs. 5-HT3 receptors are located on enteric nerves within the myenteric plexus as well as on vagal and spinal afferents. These receptors are thought to play a role in other intestinal reflexes and modulation of nonpainful (eg, nausea) and painful sensations, respectively.Serotonin Reuptake TransporterThere is likely an evolutionary advantage to having physiologic mechanisms that regulate serotonin levels and activity, because it could be quite harmful without these regulatory mechanisms.[3] One of the primary mechanisms the body has for regulating availability of serotonin within the extracellular space is the serotonin reuptake transporter (SERT). SERT is present in the brain and gut. The amount of serotonin reuptake that occurs from the extracellular space is genetically determined and is based on whether there are long, short, or heterozygous polymorphisms in the promoter for synthesis of SERT. For instance, homozygosity for the short variant and presence of the heterozygous variant result in less transcript, less protein expression, and thus, less reuptake of serotonin. SERT activity is obviously an important factor influencing serotonin availability to act on postsynaptic receptors, and would possibly affect the response to serotonergic medications such as SSRIs, in the treatment of depression, and to the novel agents tegaserod and alosetron, for IBS.Camilleri and colleagues[46] hypothesized that differences in SERT polymorphisms in patients may influence a patient's response to the 5-HT3 antagonist alosetron. It was noted that there were both sex effects and interindividual effects in the way that the medication worked in patients, slowing intestinal transit in some with IBS more than in others. Therefore, a small study of 30 patients (15 women) with IBS with diarrhea was performed in which the patients were given alosetron 1 mg orally twice daily for 6 weeks and their colonic transit measured via scintigraphy at the end of treatment. Only 23 (12 women) of these patients actually submitted blood for analysis, but 8 long homozygous, 4 short homozygous, and 11 heterozygous SERT polymorphisms were identified. When colonic transit was measured, the patients with a long homozygous polymorphism (associated with more serotonin reuptake, ie, there is conceivably less serotonin around to stimulate the gut and peristalsis and therefore gut motility is slowed) had greater slowing of colonic transit with alosetron than heterozygotes. The importance of SERT and its effect on colonic transit response to alosetron on its clinical efficacy, as well as the vulnerability to adverse events associated with the drug, such as constipation and ischemic colitis, need to be examined.Pharmacologic Treatment of IBS: ContextAlthough there are a number of traditional and novel therapies for IBS, for contextual purposes, the scope of this review will be limited to discussion of the serotonergic agents. Excellent systematic reviews of IBS clinical treatment trials can be read for a more comprehensive discussion of available therapeutic agents.[47,48] As reiterated in these reviews, many of the traditional therapies are used to treat specific IBS symptoms because they have not been shown to significantly relieve global symptoms, which would improve an overall sense of well-being. However, the discovery of the serotonergic molecular targets has led to the development of novel medications and reevaluation of relatively older pharmacologic agents that also act on the serotonin system. In well-designed, multicenter clinical trials, these novel serotonergic agents have been shown to be effective in treating global symptoms in patients with IBS compared with placebo.
 

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Pharmacologic Treatment: 5-HT4 Receptor AgonistsTegaserodThe prototypical agonist of 5-HT4 that is currently available for patients with IBS with constipation is tegaserod. This drug is an aminoguanidine indole derivative of serotonin that is classified as a partial agonist.Effect on GI function. Activation of 5-HT4 receptors (transmembrane proteins coupled to G-protein translation), located on EC cells, enterocytes, smooth muscle cells, and the IPANs, are involved in triggering the peristaltic reflex (as discussed previously). In human and animal models,[49] tegaserod mimics serotonin in its effects when applied luminally by stimulating the IPANs via 5-HT4 receptors. By virtue of this fact, it not only stimulates the peristaltic reflex but also accelerates whole orocecal transit.[50]Another action of tegaserod is to increase intestinal chloride secretion[51] and thus, fluid into the gut lumen, the mechanism by which this agent likely improves stool consistency. Tegaserod also reduces the firing of rectal afferent neurons in rats,[52] which suggests that the drug may decrease visceral sensitivity. Furthermore, there is also a recent study that found that tegaserod reduced the inhibitory effect of rectal balloon distension on a somatic reflex (RIII) in healthy women.[53] However, the RIII somatic reflex is an indirect measurement of visceral sensitivity (eg, less inhibition of the somatic reflex suggests a reduction in visceral sensitivity). More direct mechanistic studies evaluating the effect of tegaserod on visceral sensitivity in patients with IBS are needed. Using subjective outcome measures, clinical trials have shown that tegaserod significantly reduces abdominal pain scores in patients with IBS with constipation.[54,55] Hopefully, future studies will improve our understanding of the effect and specific mechanisms of tegaserod on visceral perception in patients with functional bowel disorders.Pharmacokinetics. Tegaserod reaches peak plasma concentrations in 1 to 1.3 hours and the terminal half-life is 11±5 hours. Taking the drug with food significantly decreases its absorption, and therefore, it is recommended that this medication be taken 30 minutes before breakfast and 30 minutes before dinner. Although not specifically studied, administering the drug in this fashion may also enhance its effect by taking advantage of the meal-induced peristaltic reflex.[56]Once ingested, tegaserod undergoes acid hydrolysis in the stomach. Subsequently, it undergoes oxidation and glucoronidation with the production of inactive metabolites. Two thirds of the drug is excreted unchanged in the feces, and the remaining one third is excreted in the urine. The pharmacokinetic profile is similar despite age or sex. Therefore, the dose of the drug does not need to be adjusted in the elderly or in those individuals with mild to moderate renal or hepatic impairment. Analysis of the drug reveals no significant drug-drug interactions, and administration of the drug with digoxin, theophylline, oral contraceptives, proton-pump inhibitors, warfarin, or dextromorphan has not been associated with any ill effects or required any adjustment in dosage.With regard to embryofetal or neonatal development and hormonal or reproductive functions, animal studies have not shown any toxic effects. Fetal studies in animals showed very low levels of drug, but the drug may reach high levels in breast milk -- up to 3 times that in plasma. The medication has been given a pregnancy category B rating, but the drug is not advocated for use in pregnancy and its high levels in breast milk effectively contraindicate its use in breastfeeding.Clinical efficacy in IBS with constipation. Four large multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trials evaluating the efficacy of tegaserod in IBS patients with constipation have been published.[54,55,57,58] A fifth study was just completed in a Nordic population (tegaserod in Nordic population [TENOR study]).[59] Over 4100 patients were randomized in these trials and the treatment period lasted 12 weeks in all studies. One of these 5 trials was performed in the Asian-Pacific population,[58] and the remaining 4 in Western populations.[54,55,57,59] All 5 studies conformed to the clinical design recommendations made by the Rome Committee and were also judged by the American College of Gastroenterology task force to be of the highest quality.[47]Both primary and secondary efficacy measurements were performed in all studies. In 3 of these studies, the primary efficacy measurement was the subject's global assessment of relief of IBS symptoms.[54.55,57] Patients were asked to consider, with respect to their IBS symptoms in the past week, how they felt in terms of their overall well-being, feelings of abdominal pain or discomfort, and their altered bowel habits. Using a Likert scale (ie, a graded comparison scale), the study subjects were asked to compare this to how they felt before entering the study. A responder was defined as a subject who reported having at least some relief of symptoms 100% of the time or complete relief of their symptoms at least 50% of the time. In the other 2 trials, the primary efficacy endpoint was a binary endpoint to assess whether patients had satisfactory relief of global IBS symptoms (yes/no responses) compared with baseline.[58,59] Secondary endpoints were used in all of these trials and included assessments of changes in pain and bloating scores and stool frequency and consistency.The efficacy of tegaserod in these clinical trials is summarized in Table 3. Typically, improvement was seen within 1 week of starting therapy and maintained throughout the 12-week treatment period, suggesting that there was no significant tolerance effect. Three of the studies involved a 4-week observation period posttreatment and demonstrated a return to 30% to 40% of baseline in symptoms for both the IBS and placebo groups.[54,58,59] The TENOR study divided patients with less than 10 years duration of symptoms vs those who had had symptoms for over 10 years. The group with symptoms for less than 10 years had an average therapeutic gain of 10% to 26% for weeks 1-12.[59]With regard to secondary efficacy measurements of individual symptoms, the studies evaluated change in abdominal pain and discomfort, relief of bloating, change in bowel habits, and satisfaction with bowel habits.[54,55,57,59] All of these measures showed a statistically significant greater response in these specific symptoms in tegaserod-treated patients than in patients receiving placebo_On the basis of several of these studies,[54,55,57] the United States Food and Drug Administration (FDA) approved tegaserod at 6 mg twice daily for the treatment of female patients with IBS with constipation for a 12-week period. It is important to understand that the drug was not approved for males, but this is not related to any safety concerns -- only to the fact that efficacy of tegaserod could not be adequately measured in men due to a small sample size.Table 3. Effect of Tegaserod in IBS With ConstipationClinical Trial N Female (%) Responders for Primary Outcome (%) Therapeutic Gain Tegaserod Placebo Muller-Lissner et al[55] 881 83 38 30 8 Lefkowitz et al[57] 799 87 46 33 13 Novick et al[54] 1519 100 44 39 5 Kellow et al[58] 520 88 47 28 19 Nylin et al[59] 647 86 40 29* 11+ * Represents data from week 12 -- average effect was 22% to 29% for weeks 5-12+ Represents data from week 12 -- average therapeutic gain/week was 5% to 15% for weeks 5-12Safety profile. The safety profile of tegaserod is comparable to that of placebo. The primary side effects associated with tegaserod, compared with placebo, include diarrhea (9% vs 4%) and headache (15% vs 12%) -- effects that are mild and transient. Diarrhea was found to usually occur within the first week of treatment and, interestingly, was more common in a subset of patients who intermittently experienced diarrhea prior to the study. Tegaserod does not cross the blood-brain barrier, so migraine headaches were no more common in drug- vs placebo-treated patients. Safety data in a 12-month study did not indicate any important concerns. Chief adverse events were diarrhea (10%), headache (8%), abdominal pain (7%), and flatulence (6%). No tegaserod-related abnormalities in hematologic and biochemical laboratory tests, urinalysis, blood pressure, pulse rate, or electrocardiograms were found.[60]Another prokinetic agent, cisapride, which acts through cholinergic, serotonergic (5-HT4 agonist activity), and direct smooth muscle effects, has been found to be associated with adverse cardiac effects (ie, prolongation of the QT interval). However, in a study where over 11,000 electrocardiograms were performed in patients taking tegaserod, the drug was not found to have a significant effect on the QT interval or to cause any cardiac arrhythmias.[61] Additionally, tegaserod was not associated with the development of ischemic colitis. No deaths have been reported to be attributable to the use of this agent.The US FDA had raised concern over the number of abdominal surgeries in patients treated with tegaserod as compared with patients receiving placebo. In particular, the number of cholecystectomies in the drug-treated group was greater (5 vs1) than in the placebo group. When each of these cases was blindly evaluated by experts on an individual basis, the US FDA determined that tegaserod was not associated with an increase in the incidence of cholecystectomy or abdominal and pelvic surgeries. In addition, a recent study that measured gallbladder function in a small group of subjects found that tegaserod did not significantly affect gallbladder fasting volume, emptying dynamics, or resistance to duodenal bile flow in healthy volunteers (n = 12) or patients with IBS (n = 19).[62] Commentary. Like most therapeutic agents, tegaserod is not effective in all individuals. A number of issues are worthy of further study. It certainly would be helpful to further clarify the efficacy of this medication in men. Also, the effect of this drug for a period of more than 12 months is not yet known. Evaluating how these therapeutic agents that effectively relieve global symptoms impact quality of life and health-related economic issues, such as healthcare utilization and individual productivity, will be interesting and clinically useful. Future studies will elucidate the effect of tegaserod in treating other GI conditions such as chronic constipation, gastroesophageal reflux disease, functional dyspepsia, and gastroparesis, for which preliminary studies have shown efficacy.Prucalopride (see footnote)Another 5-HT4 receptor agonist, prucalopride, has an unclear future. This drug is a benzofuran carboxamide, which is a full agonist. This agent showed efficacy in improving symptoms[63] and accelerating GI transit[64] in patients with chronic constipation. However, animal studies have suggested possible concerns with respect to cardiac effects and carcinogenic potential,[65] and thus, further development has been suspended.The United States Food and Drug Administration has not approved this medication for the treatment of IBS.Pharmacologic Treatment: 5-HT3 AntagonistsAlosetronAlosetron is one of three 5-HT3 antagonists currently available in the United States. The other 2 such agents are ondansetron and granisetron, which are primarily used in the treatment of chemotherapy-induced nausea and vomiting and were the initial prototypical drugs in this class. Alosetron is known to be 10 times more potent than ondansetron, is a potent antagonist of the 5-HT3 receptor, and has been approved for the treatment of IBS with severe diarrhea in women.Central and peripheral effects on GI motility and sensation. Unlike the 5-HT4 receptors, the 5-HT3 receptors are not involved in the initiation of the peristaltic and secretory reflexes. They also differ in that they are ligand-gated ion channel receptors, not G-protein-coupled receptors like the 5-HT4 receptors (and all other 5-HT-receptors).[3] The 5-HT3 receptors are known to act on myenteric IPANs and postsynaptic 5-HT3 receptors, which are recognized to be present in both the submucosal and myenteric plexuses. When stimulated, they evoke fast inward currents that are responsible for mediating a subset of fast excitatory postsynaptic potentials in the ENS. Other 5-HT3 antagonists do not normally block propulsion at this receptor because propulsion is in large part mediated by acetylcholine. However, because of the potency of alosetron, it may act to inhibit propulsion to some degree.The more potent effect of the 5-HT3 receptor is to activate extrinsic sensory nerves in the gut. The release of serotonin from the EC cell can stimulate 5-HT3 receptors on vagal afferents, which can result in nausea (eg, associated with cancer chemotherapy), and possibly nonpainful GI sensations such as bloating and fullness. The 5-HT3 antagonists can thereby reduce these sensory symptoms. They are also known to block the 5-HT3-mediated depolarization of guinea pig myenteric and submucosal neurons in vitro. This occurs in a dose-dependent fashion.[66] Alosetron has been found to slow colonic transit, particularly in the left colon,[67] and decrease chloride and water secretion. The effect on visceral hypersensitivity may be due to its peripheral effects (increases colonic compliance)[68] and its central effects.[69] Measuring cerebral blood flow using positron emission tomography (PET), it was found that nonconstipated IBS patients taking alosetron (1-4 mg orally, twice daily) had a significant reduction of blood flow (deactivation) to limbic regions such as the amygdala, ventral striatum, and dorsal pons, which significantly correlated with the reduction in IBS symptoms (abdominal pain). These areas are involved in the modulation of emotional autonomic, perceptual, and neuroendocrine responses to physical and psychological stressors.[69]Pharmacokinetics. After a dose of 2 mg daily, alosetron has a bioavailability of 60% and an elimination half-life of 1.5 hours. The pharmacodynamic half-life is 6-10 hours. When taken with food, the absorption is decreased by about 25%. However, this drug can be taken with or without food. Alosetron is metabolized via the cytochrome P-450 (CYP P-450) enzymes (3A4, 1A2, and 2C9). No clinically important drug interactions are known. Approximately 75% of the drug is cleared by the kidney, and the remainder can be recovered from the stool. A small percentage (approximately 7%) is excreted as intact drug. The drug should be avoided in patients with severe hepatic and renal failure.[70]Clinical efficacy. To date, there have been 4 multicenter, double-blind, randomized, placebo-controlled, parallel-group studies published evaluating the efficacy of alosetron (Table 4).[71-74] The clinical efficacy of 1-, 2-, 4-, and 8-mg doses given orally twice daily was evaluated and compared with placebo. The optimal dose of alosetron was found to be 1 mg given orally twice daily. An additional trial,[75] which was not placebo controlled, assessed the efficacy of the drug (1 mg given orally twice daily compared with the antispasmodic agent, mebeverine. All of these studies had treatment periods of 12 weeks.Table 4 Efficacy of Alosetron in IBS With DiarrheaReference N Female (%) Responders for Primary Outcome (%) Therapeutic Gain Alosetron Placebo Camilleri et al[71] 370 53 60 33 27 Camilleri et al[72] 647 100 41 29 12 Camilleri et al[73] 626 100 43 26 17 Lembo et al[74] 801 100 73 57 16 Jones et al[75] 623 100 58 48* 10 *Represents comparison to mebeverine, not placeboOver 3000 patients were enrolled in these clinical trials. Ninety percent of the patients were white, and mean age was 45 years. Women comprised the study populations in all except 1 of these trials.[71] Three of the 4 studies used adequate relief of IBS pain and discomfort for at least 2 of the 4 weeks in the past month as their primary efficacy endpoint.[71-73] The remaining study enrolled women with IBS with diarrhea who lacked satisfactory control of urgency on at least 50% of days.[74] In this study, a 7-point Likert scale was used with the global measure of relief ranging from substantially worse to substantially improved. Patients were asked to rate the degree of relief they experienced over the previous 4 weeks compared with the 3 months prior to the trial. This study also used a yes/no response to the satisfactory control of bowel urgency as a primary endpoint.Because men were underrepresented in the initial phase 2 trials, the effectiveness of alosetron in men was not established initially. One dose-ranging clinical trial evaluated the efficacy of alosetron in 662 men with IBS with diarrhea.[76] This completed study found that alosetron at a dose of 1 mg twice daily provided significantly greater adequate relief of IBS pain and discomfort compared with placebo.Safety profile. In clinical trials, the 1-mg twice-daily dose of alosetron produced constipation as an adverse event in approximately 28% of patients, but in only 11% of those taking the 0.5-mg twice-daily dose. Constipation caused approximately 11% of patients to prematurely withdraw from the studies. The incidence of serious complications of constipation (defined as ileus, bowel obstruction, toxic megacolon, fecal impaction, or perforation) in women was approximately 1 in 1000. Patients who are elderly, debilitated, or taking additional medications that decrease GI motility may be at greater risk for complications of constipation. It is currently recommended that alosetron be discontinued immediately in patients who develop this complication (ie, constipation). Restarting treatment at a lower or similar dose can be considered when the diarrhea recurs, which typically takes about 2 days.Ischemic colitis is another adverse event associated with alosetron that has been reported during the clinical trials and postmarketing period. A total of 11,874 patients were studied in these trials, and 17 cases of ischemic colitis were reported. Nine patients were hospitalized and there were no surgeries or deaths. The postmarketing experience has demonstrated that in 275,000 patients who had taken alosetron, there were 80 (0.02%) reported cases of ischemic colitis. Seventy-four percent of these cases occurred within the first month. Fifty-five percent of these cases were considered probable, 17.5% were possible, and 27.5% had insufficient evidence. It is generally accepted in medical practice that a diagnosis of ischemic colitis is only confirmed after positive endoscopic and histologic findings. Cases of ischemic colitis have been classified as probable or possible on the basis that a diagnosis is supported by clinical evidence and endoscopic and/or biopsy findings that were suggestive of, but not necessarily consistent with, the diagnosis of ischemic colitis. Of these 80 cases, there were 48 hospitalizations, 6 surgeries, and no deaths.Restricted-use program. Subsequent discussions due to concerns from patients who were successfully treated with the drug and the physicians who treated them led the US FDA to re-review this agent and approve the restricted use of alosetron in June 2002. The drug became available again in December 2002. Under the restricted-use program, physicians who want to prescribe alosetron must fill out an attestation that they feel comfortable with the diagnosis and management of IBS. Once they complete this form, they will receive an educational binder that includes a patient-physician agreement form, a patient information sheet informing them of the signs and symptoms of constipation and ischemic colitis, and a special sticker for the prescriptions for each patient. The medication is indicated for women with IBS with severe diarrhea who have: (1) chronic IBS symptoms (generally lasting >/= 6 months); (2) anatomic or biochemical abnormalities of the GI tract that have been excluded; and (3) failed to respond to conventional therapy. IBS is considered severe if it includes diarrhea and >/= 1 of the following features: (1) frequent and severe abdominal pain/discomfort; (2) frequent bowel urgency or fecal incontinence; and (3) disability or restriction of daily activities due to IBS. The recommended starting dose of alosetron is 1 mg orally per day, to be increased to 1 mg given orally twice daily after 1 month only if symptoms are not controlled at the daily dose. If the twice-daily dose does not control the patient's symptoms after 4 weeks, it is recommended that the drug be stopped.Cilansetron (see footnote)Cilansetron is another 5-HT3 antagonist with similar properties to alosetron. Randomized, double-blind, placebo-controlled phase 2 studies in both men and women with nonconstipated IBS have been performed. Cilansetron at doses of 1 and 16 mg given 3 times daily proved to be efficacious in providing adequate relief of IBS symptoms in nonconstipated men and women.[77] This agent resulted in decreased stool frequency and consistency, as well as in a trend toward improving abdominal pain. Constipation was the most frequent side effect, but otherwise, this drug was well tolerated. Phase 3 studies for safety and efficacy are currently being completed.The United States Food and Drug Administration has not approved this medication for the treatment of IBS.Pharmacologic Treatment: Combined 5-HT3 Antagonist and 5-HT4 Agonist TherapyRenzapride (see footnote)Renzapride, a drug with both 5-HT3 and 5-HT4 receptor activity, is slated to enter phase 3 studies for IBS in mid 2004. This drug is a benzamide derivative with full 5-HT4 receptor agonist activity. It also possesses 5-HT3 receptor antagonist properties and seems to show promise for the treatment of IBS. In a phase 2B, randomized, double-blind, dose-ranging (1, 2, and 4 mg/day), placebo-controlled, parallel-group study of over 500 patients with IBS with constipation conducted in the United Kingdom, the drug demonstrated acceptable efficacy and safety. This agent demonstrated 8% global improvement over placebo for both men and women. When assessing these data for women only, the global improvement rate increased to 12.3%.[78] Renzapride is administered daily and has demonstrated improved frequency in bowel movements with the 2- and 4-mg doses. Chief adverse effects were diarrhea and headache. No clinically relevant effects on laboratory values or electrocardiographic activity were seen.AntidepressantsAntidepressants have been, and are currently being, evaluated for the treatment of IBS. Most of this research has focused on SSRIs and TCAs. The potential use of these agents is based on 3 observations.[79] First, antidepressants are assumed to have utility in this setting because of the observation that many patients seem to present with associated psychological symptoms such as depression, anxiety, or somatization. It is not clear whether this symptomatology results in more consultations for GI symptoms or if the symptoms are what caused the disorder in the first place.[80] The presence of psychological symptoms is more prevalent in patients who have severe symptoms and who are seen in tertiary referral centers. Second, these drugs may have a modulating effect either through a centrally mediated action or a local gut action that changes visceral and motor activity or both. Certainly, data in this area are currently limited. Last, both SSRIs and TCAs seem to have a central effect in modulating pain. On the basis of functional magnetic resonance imaging[37] and PET[38] studies, it appears that brain activation patterns to visceral stimuli are altered in patients with IBS compared with controls.SSRI and serotonin and noradrenaline reuptake inhibitor. Creed and colleagues[81] compared the effect of psychotherapy and paroxetine footnote on symptoms, quality of life, and healthcare costs in patients with severe IBS. Patients (n = 257, 78% women) were randomized to 1 of 3 treatments arms: (1) routine care by a gastroenterologist; (2) 8 weeks of psychotherapy; or (3) 20 mg of the SSRI antidepressant, paroxetine, daily. The primary outcome measures were abdominal pain, quality of life, and healthcare costs both at 3 months and 1 year later. Both psychotherapy and paroxetine improved physical aspects of quality of life compared with routine care, but there were no differences in the psychological component. The paroxetine group had a lower number of days of pain (but not pain scores) at 3 months, but there were no differences at 1 year. Psychotherapy compared with usual care by gastroenterologists significantly decreased healthcare costs. The paroxetine group showed a trend toward decreased healthcare costs, but the difference was not statistically significant. Although suggestive of some benefits, this study was limited by the fact that there was no placebo group and that only 50% of patients allocated to taking paroxetine were taking it at the end of 12 weeks. Another consideration is that the study was conducted in patients with "severe" disease, raising the question of whether their disease process was more advanced and therefore not as amenable to change by medication or psychotherapy than those with less severe disease. The effects of these treatment modalities on IBS symptoms, health-related quality of life, and healthcare costs in patients with less severe symptoms need further assessment.In a double-blind, placebo-controlled study, the effect of the SSRI, fluoxetine, (see footnote) on symptoms and rectal sensitivity was evaluated in 40 patients with varying subtypes of IBS and compared with controls.[82] Patients randomized to drug treatment did not show a significant difference in these outcome measures of rectal perception compared with placebo. In another study, Broeaert and colleagues[83] measured the effect of the SSRI citalopram (see footnote) in a small number of patients with IBS using a crossover design. They found that patients receiving the drug orally for 6 weeks did indeed seem to have decreased abdominal pain and bloating, but that intravenous citalopram had no effect on rectal sensitivity.Chial and colleagues[84] compared the effects of venlafaxine (see footnote), (a serotonin and noradrenaline reuptake inhibitor [SNRI]), buspirone (see footnote) (a 5-HT1A agonist), and placebo on rectal sensitivity and compliance in healthy controls. Venlafaxine appeared to reduce colonic compliance and sensation and decrease the normally increased colonic tone that occurs postprandially. Buspirone had no effect on colonic sensitivity in this study.TCAs. Results of previous treatment trials regarding the use of TCAs in IBS have suggested that these agents may be effective in relieving abdominal pain but not the global symptoms of IBS.[47] A recently published study by Drossman and colleagues[85] compared the efficacy of cognitive behavioral therapy (CBT) vs education and of a TCA (desipramine[see footnote]), vs placebo in 431 patients with moderate to severe functional bowel disorders. Their intention-to-treat and per-protocol (latter includes only patients who completed the study) analyses showed that CBT was significantly more effective than traditional education. In the intention-to-treat analysis, there was no statistically significant benefit for desipramine over placebo (responder rate of 50% vs 47%). This lack of a significant effect may be due in part to the high placebo effect. However, desipramine was shown to have a statistically significant benefit over placebo in the per-protocol analysis (responder rate 73% vs 49%). When the participants with nonsignificant blood levels of desipramine were excluded, there was a statistically significant difference between placebo and antidepressant therapy in favor of medication therapy. The study authors found that desipramine was more effective in the subgroup of patients with less severe illness (Functional Bowel Disorder Severity Index < 110) and a history of abuse.The United States Food and Drug Administration has not approved this medication for the treatment of IBS.
 

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ConclusionClearly, the scientific concepts in IBS have proved to be challenging, but certainly evolving. Serotonin is an important neuropeptide with both motility and sensory-modulating properties that is important in the pathophysiology of this disorder. The molecular targets of the 5-HT3 and 5-HT4 receptors are key factors in regulating normal gut function and also in the pathophysiology and treatment of IBS. The development of tegaserod for the treatment of IBS with constipation and alosetron for treatment of IBS with severe diarrhea in women represent important advances in the therapeutic area of IBS where few current medical interventions have been effective for relieving global symptoms. The antidepressants, SSRIs, SNRIs, and TCAs may be effective in treating IBS, particularly in those patients with severe disease, but further studies are needed. Other neuropeptides and receptors are also being actively investigated, and certainly a number of pharmacologic agents are on the horizon.The need for novel therapies is still significant. In addition, a better understanding of the pathophysiologic mechanisms in IBS, including those accounting for sex differences, are important in the future development of more effective treatments.ReferencesDrossman DA, Camilleri M, Mayer EA, et al. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131. AbstractThompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut. 1999;45(Suppl II):II43-II47.Gershon MD. Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord. 2003;3:S25-S34.Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271-293. AbstractWells NEJ, Hahn BA, Whorwell PJ. 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Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2001;96:2662-2670. AbstractJones R, Holmann G, Rodrigo L, et al. Alosetron relieves pain and improves bowel function compared with mebeverine in female non-constipated irritable bowel syndrome patients. Aliment Pharmacol Ther. 1999;13:1419-1427. AbstractEdwards EB, Heitman CK, Hall P, Hamedani AG, Dukes G, Mangel A. 12-week randomized, double-blind, placebo-controlled, parallel,-group, dose-ranging, phase II study to assess the clinical efficacy of alosetron in male subjects with IBS Am J Gastroenterol. 2001;96:S317.Caras S, Borel R, Krause G, et al. Cilansetron shows efficacy in male and female nonconstipated IBS patients in a US study. Gastroenterology. 2001;120:A217.Meyers NL, George A., Palmer RMJ, et al. 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A double-blind randomized placebo-controlled crossover trial of citalopram, a selective 5-hydroxytryptamine reuptake inhibitor in irritable bowel syndrome. Gastroenterology. 2001:120:A641.Chial HJ, Camilleri M, Ferber I, et al. Effect of venlafaxine, buspirone, and placebo on colonic sensorimotor functions in healthy humans. Clin Gastroenterol Hepatol. 2003;1:211-218.Drossman DA, Diamant NE, Toner BB, et al. Randomized trial of desipramine (DES) vs. placebo (PLA) in moderate to severe functional bowel disorder (FBD). Gastroenterology. 2003;125:249-253. Abstracthttp://www.medscape.com/viewprogram/2750
 
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