Irritable Bowel Syndrome
IntroductionThe management of irritable bowel syndrome (IBS) remains challenging, as presumably a number of different mechanisms can lead to similar symptom presentations. Furthermore, a number of environmental and genetic factors likely modify the treatment response, although these factors remain poorly defined. Lack of recognition of IBS in clinical practice may also complicate management. Lea and colleagues[1] reported the results from a United Kingdom survey that showed that while all specialist gastroenterologists were aware of 1 or more of the currently used diagnostic criteria for IBS (ROME I and II), the majority of primary care physicians were not. It was also apparent that management in primary and secondary care settings is very different; primary care physicians more often used antispasmodics and dietary approaches, whereas gastroenterologists were more likely to use laxatives, antidepressants, and antidiarrheal agents. Some of these differences in management will reflect more severe disease presenting to secondary care, but the impact of such disparate management strategies in IBS remains very poorly described and deserves additional study. Diagnostic Markers in IBSThe search continues for objective diagnostic markers in IBS, although at this time, symptom-based criteria remain the "gold standard." Minor inflammatory change seems to persist in a subset of patients with IBS.[2,3] Simren and colleagues[4] evaluated stool samples from 17 healthy controls, 18 patients with IBS with diarrhea, and 7 patients with IBS with constipation, based on the ROME II criteria. They found small increases in eosinophil protein X in patients with IBS with diarrhea. These investigators also surprisingly found higher levels of myeloperoxidase in healthy controls than in patients with IBS and constipation. There were no group differences observed in tryptase levels. Thus, although low-grade inflammation may be involved in the pathogenesis of a subset of patients with IBS, this initial study did not demonstrate any convincing alterations in eosinophil, neutrophil, or mast-cell markers in feces. More careful selection of patient subsets (eg, postinfectious vs not postinfectious) may yield different results; additional work in this area may be productive. Another approach to identifying new diagnostic tests involves searching for potential genetic markers in IBS. Kim and colleagues[5] postulated that polymorphisms of the alpha-2 adrenoreceptors, norepinephrine transporter, and serotonin transporter promoter would be associated with IBS. Genetic variation in these mechanisms may in turn alter lower gastrointestinal tract function and hence promote the expression of IBS. The investigators applied a validated bowel disease questionnaire and selected a number of candidate genes to test for polymorphisms by PCR-based restriction fragment length polymorphisms that were confirmed by direct sequencing. The results of this study, however, were largely negative. There was no association of polymorphisms of the serotonin transporter or of the norepinephrine transporter with functional bowel disease overall. One of the alpha-2 adrenergic receptor polymorphisms (Nci1) was associated with an increased risk of IBS with constipation compared with controls, and there was a trend for another alpha-2 adrenergic receptor polymorphism (Msp1) to also be associated with IBS and constipation -- but these results require validation in another, larger sample. It has yet to be shown that polymorphisms of the serotonergic or adrenergic pathways are relevant to the pathophysiology of IBS, and at this stage, no genetic markers have been convincingly demonstrated to be linked to IBS. Such studies are difficult because defining the phenotype remains crucial, and in a heterogeneous syndrome such as IBS, associations may be overlooked unless rigorous attention is applied. Lifestyle and Dietary Interventions in IBSMost clinicians believe that explanation, education, and support are important components of management for the successful care of patients with IBS.[3] An extension of this approach is reflected by the development of IBS educational classes that provide group training for people with this disease. It was hoped that such classes would help these individuals better cope with their symptoms. Uncontrolled data have suggested that an educational class on IBS can improve outcomes, but controlled data have been lacking.[6] Mayer and colleagues[7] reported the results of a small controlled trial testing a 5-week IBS class in Los Angeles, California. They studied 31 patients with IBS in a tertiary referral center who were randomized either to an IBS class or to a waiting-list control. The IBS class comprised 2-hour sessions over 5 weeks, with 5-8 patients per class; the classes reviewed diet, medications, and coping styles, and introduced simple relaxation techniques. Outcomes were measured at baseline and 12 weeks later. The treated and untreated patients were comparable at baseline after randomization. Those patients who attended the IBS psychoeducational class had improvement in their disability attitudes, better coping skills, increased work productivity, less activity impairment, better quality of life, less symptom severity, and improved cognitions relevant to IBS. These results suggest that sending patients to an IBS class should be strongly considered if their symptoms have been persistent. However, some of the apparent effect of the IBS class may be related to contact time with a person interested in the condition or to the social interaction between patients, rather than to the specific interventions presented in the class per se. This latter possibility cannot be dissected out from these overall data. Still, these findings represent an advance in the field and are worthy of replication in a larger randomized study. Serotonin-Type 4 Agonist TherapyTegaserodThere are very few prokinetic options currently available for treatment of patients with IBS in the United States. Tegaserod, a 5-HT4 agonist, is approved by the US Food and Drug Administration for the treatment of women with IBS with constipation.[3] The therapeutic application of this agent raises the issue of what is the exact biological function and distribution of 5-HT4 receptors in health and disease. Because the role of 5-HT4 receptors in normal enteric nervous system functioning remains poorly understood, Fiorica-Howells and colleagues[8] studied transgenic mice who lacked 5-HT4 receptors. It was interesting to note that colorectal motility was significantly slower in mice who lacked 5-HT4 receptors compared with their wild-type litter mates, although gastric emptying and small bowel motility were not different. These observations suggest that 5-HT4 receptors may be most important in maintaining health in the setting of amplifying the release of neurotransmitters in the enteric nervous system, at least in the colon. The latter may also help explain the promising results with tegaserod in constipation. New trial data presented at this year's Digestive Disease Week meeting confirm previous reports that tegaserod improves symptoms in patients with IBS and constipation.[3,9] Lin and colleagues[10] conducted a randomized, controlled trial in 510 Chinese patients and reported significant improvement in the severity of constipation, abdominal discomfort/pain, and bloating -- findings consistent with the published results found by Kellow and coworkers[9] in Asia. In a study from Scandinavia, Nyhlin and colleagues[11] randomized 647 patients to tegaserod or placebo in a 12-week double-blind trial. They found that the gain in satisfactory relief weekly ranged from 5% to 15% over the 12-week study period. It was interesting to note that those patients with less than 10 years' duration of IBS symptoms had the greatest therapeutic gain, which has not previously been prospectively evaluated. Additionally, Johansen and colleagues[12] evaluated the safety, efficacy, and tolerability of this 5-HT4 agonist in the treatment of patients with chronic constipation. They found that tegaserod, administered as 2 mg twice daily and 6 mg twice daily, effectively decreased abdominal discomfort/pain, bloating/distension, and related symptoms -- an effect that was rapid in onset and sustained for at least 3 months' duration. In another study presented during this year's meeting proceedings, Mueller-Lissner and colleagues[13] assessed the utility of this agent in the retreatment of patients with IBS with constipation to address the issue of the episodic nature of IBS symptoms. They found that upon discontinuation of the drug, there was a high rate (84% of patients) of recurrence of symptoms. Wald and associates[14] examined the tolerability and safety of tegaserod in patients with chronic constipation in a 12-week, double-blind, placebo-controlled study. These investigators found that tegaserod 2 mg given twice daily, and tegaserod 6 mg given twice daily, was well tolerated throughout the duration of the study period and was associated with no significant adverse events (most frequent adverse events were headache and nasopharyngitis, both more commonly occurring with placebo). Accumulating evidence supports the view that tegaserod is efficacious in IBS with constipation, but the mechanisms underlying the symptom complex remain elusive. Greenwood-Van Meerveld and colleagues[15] examined colorectal distension in rats, and reported in an oral presentation that tegaserod significantly inhibited a pressure dependent increase in abdominal contractions, an indirect measure of pain in both normal and sensitized (by acetic acid) rat colon. Wang and colleagues[16] also showed that tegaserod reduced inferior splanchnic afferents in vitro in rats. Another obvious question is whether serotonin release in this subgroup of patients may be abnormal. Dunlop and colleagues[17] measured serial plasma serotonin levels (after a standard 520-kilocalorie meal) for 3 hours in 15 patients with constipation and IBS, 15 patients with postinfectious IBS and diarrhea, and in 15 healthy volunteers. Both platelet-poor plasma and platelet-rich plasma serotonin was assessed using high-pressure liquid chromatography. They observed an increase in platelet serotonin in constipation with IBS compared with the other groups, but the postprandial release of serotonin (immediately after the meal) was lower in patients with IBS with constipation compared with the other patient groups. These investigators concluded that reduced serotonin release could contribute to slower intestinal transit in patients with constipation and IBS. However, the relationship of serotonin release with symptoms remains unclear at this stage, as the exact timing of serotonin release with changes in motor function remains poorly documented. Serotonin-Type 3 Receptor Antagonist TherapyAlosetron and CilansetronOne of the concerns regarding the use of the 5-HT3 receptor antagonists in IBS has been the development of ischemic colitis associated with the use of alosetron in patients presumed to be otherwise at low risk for the disease.[3] However, a mechanism for 5-HT3 receptor-induced ischemic colitis has been very elusive. Holzer and colleagues[18] evaluated the effects of alosetron and cilansetron,* both 5-HT3 receptor antagonists, compared with tegaserod, a 5-HT4 receptor agonist, on mesenteric hemodynamics in the rat. They found that both alosetron and cilansetron significantly attenuated mesenteric blood flow as well as mesenteric vascular conductance in phenobarbital-anesthetized rats over an observation period of 35-50 minutes; this was not observed with the 5-HT4 receptor agonist. Whether this apparent mesenteric vasoconstrictor action of the 5HT3 drug class has a direct clinical correlate in humans, however, is unclear. Alosetron is efficacious in women with IBS with diarrhea.[3,19] Ameen and colleagues[20] analyzed data from a 12-week randomized, double-blind, placebo-controlled multicenter US study regarding the efficacy of alosetron in fecal urgency. They reported that alosetron-treated patients had 69% of days with satisfactory control of urgency during the 12-week period compared with 56% satisfactory control in patients on placebo -- a difference that was statistically significant. Furthermore, fecal urgency was positively associated with a global improvement in IBS symptoms, suggesting that this is an important symptom target for the drug class. However, subgroup analyses of clinical trials, such as that presented here, can be misleading because the randomization is not considered and unrecognized bias can influence the results. Other Agents Targeting Visceral HypersensitivityVisceral hypersensitivity is considered one of the key mechanisms linked to IBS symptoms.[3] Abdominal distension is often experienced by patients with IBS, but the mechanisms remain poorly understood. Lea and coworkers[21] studied patients who had rectal hypersensitivity, rectal hyposensitivity, or normal rectal sensitivity and were experiencing IBS. Forty-four percent of their patients had hypersensitivity, 26% had hyposensitivity, and 30% had normal rectal sensitivity. Abdominal girth was recorded for 24 hours using ambulatory Abdominal Inductance Plethysmography (an objective measure of belly swelling). They found that abdominal girth was greater at the end of the day in patients with either rectal hypersensitivity or hyposensitivity. Furthermore, the increase in girth was greatest in patients who had rectal hyposensitivity. The study authors suggested that visceral sensitivity may therefore be linked to abdominal distension. Whether visceral sensitivity increases the expression of symptoms in individuals with distension cannot be directly established from these studies; the mechanisms may be quite distinct but still be correlated. Moreover, abdominal muscle tone may influence such readings and was not considered in these experiments. A number of new agents have targeted the modulation of visceral hypersensitivity in IBS. One of these promising drugs is asimadoline,* a peripheral kappa opioid agonist.[3] Delvaux and colleagues[22] studied the effect of asimadoline on perception of colonic distension using a barostat in 20 women with IBS. Those patients who had a specific pain threshold identified (32 mmHg or less) were randomized in a double-blind, cross-over trial to either a single oral dose of asimadoline 0.5 mg or placebo on 2 separate days. Compliance of the colon was not altered by the drug. They found that pressure thresholds for pain were higher with the kappa opioid agonists compared with placebo, but the difference was not significant. However, mean pain scores were significantly lower for patients on asimadoline at distensions of 20 mmHg and tended to be lower at higher distensions of 25 mmHg and 30 mmHg compared with placebo. Overall, asimadoline had modest effects on colonic distension-induced painful sensations; its effects are consistent with other visceral analgesics that have been tested in similar human models.[3] The efficacy of the newer kappa opioid agonists in IBS trials is awaited with interest. Another approach to the treatment of visceral pain has been the use of N-methyl-D-aspartate (NMDA) receptor antagonists. Kuiken and colleagues[23] evaluated a noncompetitive NMDA receptor antagonist, S ketamine,* in 12 healthy volunteers undergoing gastric barostat studies. These investigators found that S ketamine increased visceral sensitivity in the healthy volunteers, similar to dextromethorphan, suggesting that NMDA receptors may prove to be useful drug targets for reducing abdominal pain in IBS. Modulating StressIn the setting of IBS, stress has been postulated to be an important mechanism modulating symptoms.[3] However, a cause-and-effect relationship between stress and IBS remains to be convincingly demonstrated. Fitzgerald and colleagues[24] evaluated the cerebrospinal fluid (CSF) concentrations of potential stress mediators in 13 women with IBS with diarrhea and 12 healthy controls. Important to note is that patients with anxiety and depression were excluded, as were patients with fibromyalgia. The investigators observed that 54%, 23%, and 62% of IBS patients had increased CSF levels of corticotropin-releasing factor (CRF), norepinephrine, and substance P, respectively. However, clinical characteristics were not associated with these elevations, and hence, the clinical relevance of the findings are uncertain. In a complementary study, Kilkens and coworkers[25] asked whether inserting a rectal barostat induced greater stress in patients with IBS compared with healthy controls. The latter could be important because it may confound the interpretation of barostat studies in patients with IBS. The study authors used salivary cortisol measurements to indirectly assess the hypothalamic pituitary stress axis. They noted that in IBS patients undergoing distension studies, there was a significant increase in salivary cortisol levels, and thus greater activation of the central stress pathway compared with controls. Whether controlling for underlying psychological distress or testing in consulters vs nonconsulters would have altered the results is not known. In view of the fact that corticotropin-releasing hormone (CRH) may be a major mediator of the stress-induced response in IBS, theoretically the use of an antagonist to CRH could improve IBS symptoms.[3] Sagami and coworkers[26] studied 10 healthy individuals and 10 patients with IBS and measured colonic tone and pressure under baseline conditions and with rectal electrical stimulation, before and after administration of alpha-helical CRH9-41* (a CRF antagonist) at a dose of 10 mg/kg. Visceral stimulation induced increased motility indices in patients with IBS compared with controls; the response was suppressed by the administration of the CRH antagonist. Plasma adrenocorticotropic hormone and serum cortisol levels were not affected by CRH9-41. The CRH antagonist also reduced abdominal pain and anxiety evoked by electrical stimulation in IBS subjects. Additional work with peripheral modulators of the stress response may therefore be warranted. AntidepressantsThere has been continuing controversy regarding the efficacy of tricyclic antidepressants* in IBS despite the publication of a recent positive meta-analysis.[27] Drossman and colleagues[28] presented the results of an important 12-week trial that evaluated desipramine* vs placebo in patients with functional bowel disease (mostly IBS) who reported moderate-to-severe symptoms. The dose of desipramine was titrated in a blinded fashion and patients received up to 150 mg (an antidepressant dose) of the drug. By the intention-to-treat analysis, desipramine induced a response (defined as an average satisfaction with treatment score > 3.5 on a scale of 0-5) of 60% compared with 47% with placebo; this difference was not significant. A per protocol analysis showed that 69% of patients responded to the desipramine compared with 49% on placebo, which was a statistically significant difference. Desipramine was more effective for patients with moderate-to-severe symptoms, individuals who had a history of abuse, and those without depression, as well as patients with predominant diarrhea. The finding of greater benefit in patients without depression remains surprising. Therefore, in patients who comply with therapy, desipramine may have some benefit. However, it was rather disappointing that the intention-to-treat analysis (the "gold standard" for assessment of efficacy) was not significant, and indeed, one cannot state that this study shows unequivocally that antidepressants truly work. In a secondary analysis of the same trial, Halpert and colleagues[29] reanalyzed these data to evaluate the clinical response to desipramine and the relationship to dose among patients who were part of the per protocol analysis. They concluded that the clinical response was not determined by the desipramine dose or plasma level, suggesting that even a low-dose tricyclic antidepressant drug may be of value in IBS. An even more controversial issue is the efficacy of selective serotonin reuptake inhibitor (SSRI)* therapy in IBS.[3] Creed and associates[30] recently reported that paroxetine* improved quality of life but not abdominal pain in severe IBS, but this study was not an efficacy trial and the lack of a placebo arm confounds its interpretation. Furthermore, the mechanisms by which antidepressant agents in IBS may work remain to be adequately defined. Chial and associates[31] looked at colonic sensory motor function in healthy volunteers treated with venlafaxine,* buspirone,* or placebo. They noted that venlafaxine (a serotonin- and weak noradrenaline reuptake inhibitor) increased colonic compliance and decreased fasting tone. There was also a reduction in colonic sensation with venlafaxine compared with placebo overall, although there was a borderline statistical significance for pain scores during the phasic distensions. Buspirone did not alter colonic compliance, tone, or sensation compared with placebo. These results provide a rationale for the testing of venlafaxine and other SSRIs in IBS. However, buspirone, even though it has antianxiety properties, appears not to alter colonic function and seems an unlikely drug to consider in the setting of IBS. Psychological and Alternative Medicine Therapies in IBSPsychological ApproachesDrossman and colleagues[32] reported the results of a large and successful multicenter, randomized trial comparing cognitive behavioral therapy with education in moderate-to-severe functional bowel disorder. These investigators randomized 215 patients to either cognitive behavioral therapy or education. They found that cognitive behavioral therapy was significantly more effective than education, with a response rate of 70% compared with 37%, respectively. These results were significant and were confirmed in the per protocol analysis (in contrast to the tricyclic antidepressant results discussed above). The study authors concluded that 12-week cognitive behavioral therapy was more effective than education therapy -- regardless of symptom severity or abuse status, and this is a reasonable and defendable conclusion. However, patients with severe depression did not do significantly better with cognitive behavioral therapy vs education, suggesting that other approaches are required for this subgroup of patients. These results strengthen the evidence that psychological treatments are of value in IBS,[30] although the time-intensive nature of the interventions and their associated costs continue to limit their use in clinical practice in the United States. Other Novel ApproachesOther novel approaches to therapy of IBS include the treatment of suspected small bowel bacterial overgrowth with antibiotics.* Pimentel and colleagues[33] recently reported that neomycin* was more effective than placebo in managing patients with IBS; they postulated that this effect was due to unrecognized small bowel bacterial overgrowth, as based on breath testing. Neomycin is not a drug that should be widely used in patients with IBS because of associated ototoxicity. Simren and colleagues[34] further evaluated the bacterial overgrowth hypothesis in 33 patients with IBS, the majority of whom had diarrhea as the predominant symptom. They obtained a jejunal aspirate and quantitative culture. These investigators found that small bowel bacterial overgrowth was present in only a small subset of IBS patients (2 with diarrhea and 2 who were alternators); treatment, however, only improved symptom severity in 1 of these patients. This study involved a highly selected IBS population, 45% of whom had neuropathic-like abnormalities, as based on manometry, thus, the generalizability of these results remains questionable. Another very interesting approach to the management of IBS is to consider an elimination diet.[3] Atkinson and colleagues[35] conducted a double-blind, randomized, controlled trial in 150 patients with IBS who received either a diet excluding all foods to which they had IgG antibodies, or a sham diet excluding the same number of foods, but not those to which they were potentially sensitive (based on IgG food antibody levels). The results were most intriguing; they found that the exclusion diet was significantly more effective than the sham diet in reducing severity of symptom scores. Hence, the approach of prescribing an elimination diet may be worth considering, although any benefit may be limited to a subset of patients and likely impaired by lack of dietary compliance. Finally, additional novel approaches to the treatment of IBS using alternative medicine* were also reported during this meeting. Bortolotti and colleagues[36] treated 10 patients with IBS with a red pepper powder and found that it decreased the intensity of pain and bloating. However, there was no control group and the number of patients studied was too small to reach any definitive conclusion. The approach of desensitizing nociceptive C-fibers may be worth reviewing in IBS, but controlled trials are needed to test the concept. Ducrotte and associates[37] evaluated a purified clay (beidellitic montmorillonite) in the treatment of IBS, although why such a compound may be of utility in this setting is somewhat enigmatic. These investigators conducted a randomized, controlled trial with 524 patients and found a higher success rate with the clay compound (52%) compared with placebo (45%) -- although this difference was not significant. There was significant improvement in a subgroup analysis among subjects with IBS with constipation (49%) vs placebo (32%). Patients were allowed to take antispasmodics or polyethylene glycol if needed, but the intake was not different between patients receiving the clay and those receiving placebo. However, the value of this approach remains to be convincingly demonstrated and the lack of a clear pathophysiologic rationale remains of concern. The Brain, the Gut, the Food, and the Bacteria-- Update on Treatment of Functional Gastrointestinal Disorders
IntroductionDespite being the most prevalent gastrointestinal (GI) disorders seen in gastroenterology practice, functional gastrointestinal disorders (FGIDs) continue to be difficult conditions to understand and manage, for both clinicians and patients. The latter relates to the complex, multifactorial nature of these disorders, the limited understanding of the pathophysiologic mechanisms that underlie them, and the lack of effective comprehensive treatments. Given these circumstances, it has not been surprising to note the ongoing increase in interest in FGIDs, as reflected by the number of high-quality abstracts submitted and presented at this year's Digestive Disease Week (DDW) meeting, as well as by the number of attendees at sessions focusing on these disorders. Presentations during this year's meeting proceedings covered the wide spectrum of intensive research that is ongoing in the field, and provided interesting new data about various aspects of these disorders. The latter included discussion of new data on the epidemiology, clinical characteristics, possible pathophysiologic mechanisms, diagnosis, and management of FGIDs. This overview focuses on those key presentations that provided updates and new information about the effect and efficacy of available and commonly used treatment options for functional GI and motility disorders. The BrainAntidepressants have been commonly used for the treatment of irritable bowel syndrome (IBS) and other FGIDs, and recently published American Gastroenterological Association guidelines recommended their use for the pain associated with FGIDs, particularly when first-line therapies fail.[1] However, despite this recommendation and their long-standing availability and use in clinical settings, the evidence for efficacy of antidepressants in the treatment of FGIDs has been relatively weak. This has been, in part, due to the quality of the trials and the small sample sizes. During DDW 2003, Drossman and colleagues[2,3] presented the results of a 7-year, 2-site, randomized, double-blind, placebo-controlled, treatment trial in patients with moderate-to-severe functional bowel disorders (FBDs; ie, chronic functional abdominal pain, IBS, painful constipation, and unspecified FBD). The investigators from the University of North Carolina and the University of Toronto randomized 431 patients into 2 treatment arms: medication (antidepressants vs placebo)[2] and psychological (cognitive behavioral therapy vs education).[3] Medication ApproachIn the medication arm,[2] 216 patients were randomized to receive either desipramine* up to 150 mg/day, and averaging 100 mg/day (dosage adjustment was based on side effects), or placebo. Responders were determined by an averaged satisfaction with treatment score of > 3.5 on a 0-5 scale range. The results on the intention-to-treat analysis (includes all patients who started the medication treatment) showed no statistically significant difference between the active and placebo groups (response rate of 60% vs 47%, respectively; P = .128). However, in the per protocol analysis of study completers (excluding 25% [30% desipramine, 17% placebo] drop outs and 12 subjects with nondetectable desipramine blood levels), there was a significant effect (response rate of 73% vs 49%, respectively; P = .006) and a number needed to treat of 4.3. It is interesting to note that desipramine was found to be more effective in nondepressed patients, as well as in those with moderate disease severity, predominant diarrhea, and a history of abuse. Psychological ApproachThe other arm of this study was presented in poster form. In this psychological treatment arm,[3] 215 patients were randomized to receive either cognitive behavioral treatment (CBT) or education for 12 weeks. Responder rates were determined, similar to the medication arm, by an averaged satisfaction with treatment score of > 3.5 on a 0-5 scale range. In the intention-to-treat analysis, CBT was found to be more effective than education (P = .0001), with a response rate of 70% vs 37% (P < .0001) and a number needed to treat of 3.1. These results held also in per protocol analysis after 21% (18% on CBT, 29% on education) dropped out. CBT was found to be effective for patients with moderate or severe FBD and for individuals with or without abuse history, but was not different from EDU in efficacy for patients with severe depression. Commentary. The study authors concluded that CBT is statistically and clinically effective for treatment of FBD (including IBS) and that desipramine, although not significant in the intention-to-treat analysis, appears effective for patients who stay on treatment and who can tolerate the side effects (if present). However, certain clinically meaningful subgroups (eg, patients with depression, patients who appear less responsive) may be amenable to combination treatments using both modalities. The GutVery few medications have been specifically approved for treatment of FGIDs. Therefore, it is not surprising that the US Food and Drug Administration-approved serotonin active agent, tegaserod, has gained noticeable interest during this year's meeting. Tegaserod, a 5-HT4 partial agonist, has been shown to be more effective than placebo in alleviating IBS global and associated symptoms in women with IBS with constipation. Because of its promotility/prokinetic effects on various parts of the GI tract, clinicians have been prompted to use this medication for various non-IBS-related GI motility disorders as well. Several studies were presented during DDW 2003 that offered new information about the use of tegaserod in these settings. Dyspepsia and GastroparesisTougas and colleagues[4] investigated the effect of different doses of tegaserod* in 163 patients with dyspeptic symptoms who also had delayed gastric emptying. Subjects were randomized to receive tegaserod at 6 mg twice daily (n = 38), 6 mg thrice daily (n = 24), 12 mg twice daily (n = 38), or placebo (n = 63), and gastric emptying was quantitated by scintigraphy before and after treatment. The investigators reported statistically significant improvement in gastric emptying with the 18 mg and 24 mg per day dosages of tegaserod. Commentary. Several limitations of this study make it difficult to assess the clinical significance and relevance of these findings, such as that the currently approved dose of 12 mg daily did not show a significant effect; the patient population did not meet criteria for dyspepsia or other defined disorders; and information was not available about the symptom response or patients' quality of life (QOL) with this treatment. This is particularly important since it is well known that the correlation between dyspeptic symptoms and gastroparesis is poor. Therefore, at this time, the role of tegaserod in the treatment of dyspepsia and gastroparesis is not yet defined and additional investigation is warranted. Chronic ConstipationJohansen and colleagues[5] reported the results of a double-blind, placebo-controlled multicenter study that examined the efficacy of tegaserod* 2 mg twice daily (n = 450), 6 mg twice daily (n = 451), or placebo (n = 447) in patients with chronic constipation. They found that tegaserod, 2 mg twice daily and 6 mg twice daily, given for 12 weeks, was superior to placebo in increasing spontaneous bowel movements per week (response was defined as an increase of > 1 spontaneous bowel movements/week compared with baseline), either after 4 weeks (response rate, 41.4%, 43.2%, and 24.9%, respectively; P < .0001 vs placebo) and 12 weeks (40.3%, 44.8%, and 26.9%, respectively; P < .0001 vs placebo). This response was also associated with improvement in other functional GI symptoms. Commentary. The study authors concluded that tegaserod (2 mg twice daily and 6 mg twice daily) is effective in the treatment of chronic constipation and its related symptoms. However, it should be noted that patients with IBS whose predominant symptom was constipation were not excluded from this study. Patients with IBS with constipation are already known to benefit from tegaserod; therefore, not identifying this subgroup in the study population may have made it difficult to assess the efficacy of this agent in this setting. It would have been helpful to divide the patients in this study into 2 treatment groups -- those with chronic constipation with IBS and those with chronic constipation without IBS -- and to have looked at the treatment response rate in each subgroup. Thus, although these data are encouraging, additional investigation is warranted to assess the efficacy of tegaserod in treating chronic functional constipation. The FoodNutritional factors have been suspected to contribute to the symptoms and clinical presentation of FGIDs. Exacerbation of symptoms such as diarrhea, dyspepsia, and nausea are commonly reported postprandially. Many patients attribute some of their symptoms to certain types of food, and therefore avoid those food items. However, recommendations for elimination of specific food items in FGIDs is usually done in variable ways. That is, there are no available guidelines' evidence for the efficacy of this approach to managing these disorders. Atkinson and colleagues[6] presented an interesting approach to this issue by assessing the efficacy of an exclusion diet based on testing for the presence of IgG food antibodies in unselected (all subtypes) patients with IBS. Patients (n = 150) were tested for the presence of IgG antibodies in a variety of food items and were then blindly randomized to receive either a diet excluding all foods to which they were found to be sensitive (IgG antibody titers >/= 3:1) or a sham diet excluding the same number of foods, but not those to which they were sensitive. They found that the true diet was significantly more effective than the sham diet in reducing symptom severity scores (average reduction, 34; 95% confidence interval [CI]: 17.3, 68.6; P = .049) in the intention-to-treat analysis (considering all patients who were offered the treatment). When accounting for the patients' adherence to the number of foods to which they were sensitive, the reduction in symptom scores was even higher (average reduction, 89; 95% CI: 41, 137; P < .001). The adherence to the diet affected the response observed in patients on the true diet, but not patients on the sham diet (P = .038). These findings further supported the potential clinical benefit of food-elimination diets based on IgG food antibodies in patients with IBS. The BacteriaSeveral studies have suggested a potential beneficial effect of certain probiotics in reducing some of the symptoms of IBS.[7] Probiotics vs AntibioticsIn a small (n = 44) study, Faber[8] examined the effect of probiotics* alone (n = 20) and in combination with antibiotics (n = 24) on GI symptoms and QOL in an uncontrolled trial of unselected (all subtypes) patients with IBS. Antibiotic treatment included ciprofloxacin* 500 mg twice daily per week, and probiotic treatment included Lactobacillus acidophilus NCFM (10 billion/g) and Bifidobacteria infantis (10 billion/g) daily for 4 weeks. Both groups showed significant improvement following treatment: In the probiotic/antibiotic group, a decrease in symptom frequency index scores from 35 to 18 (P < .001) and an increase in IBS-QOL scores from 67.6 to 87.8 (P < .001) were seen; in the probiotic-only group, a decrease in symptom frequency index scores from 39 to 17 (P < .001) and an increase in IBS-QOL scores from 69.3 to 86.4 (P < .001) were seen. The predominant IBS type did not alter the response to therapy. Commentary. As a small uncontrolled study, these results may reflect, at least in part, a placebo response. Nevertheless, the findings emphasize the need for additional clinical studies to evaluate the role of probiotics and antibiotics in IBS patients. Mechanisms of ProbioticsAlthough the efficacy and role of probiotics in the treatment of IBS remain uncertain and require confirmation, several studies presented during this year's meeting examined possible mechanisms for their effects on GI motor, sensory, and immune function. Lamine and colleagues[9] investigated the effect of treatment with Lactobacillus farciminis bacteria on the nociceptive response to colorectal distension in basal conditions and after TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colonic inflammation in rats. They found that L farciminis treatment significantly reduced (P < .05) abdominal nociceptive response for all distending pressures in both the noninflamed-treated group compared with the noninflamed controls and in the TNBS-induced inflamed hypersensitivity treated group compared with the nontreated group. These researchers attributed this antinociceptive effect to the known ability of L farciminis to produce nitric oxide (NO). Indeed, hemoglobin (an NO scavenger) infusion resulted in reversing this organism's antinociceptive effect. These investigators concluded that a 3-week treatment with L farciminis can reduce visceral pain induced by colorectal distension in basal and inflammatory conditions, and that this effect depends on the NO released by these bacterial strains into the colonic lumen. In another study, the same group of investigators reported a protective effect of the NO producing-L farciminis against TNBS-induced colitis in rats.[10] Rats that were treated with this organism for 3 weeks prior to induction of colitis showed significantly lower inflammation, as expressed by reduction in macroscopic damage score, MPO (myeloperoxidase) activity, and inducible NO synthase activities. As with the previous study, hemoglobin reversed the beneficial effect of L farciminis on the inflammation activity in the colitic rats. Commentary. These studies suggest a role for NO-producing bacteria in protecting against inflammatory and hypersensitivity conditions. However, these findings in animal models deserve additional investigation in humans in order to confirm beneficial effects. Another possible mechanism mediating the effects of probiotic bacteria on GI function has been proposed by Verdu and colleagues.[11] They investigated the effects of probiotics on intestinal muscle dysfunction in a mouse model of postinfective Trichinella spiralis IBS. Study mice groups were treated with Lactobacillus paracasei, Lactobacillus johnsonii, Bifidobacterium longum, or B lactis. Additional mice received heat-inactivated L paracasei or bacteria-free L paracasei spent culture medium (SCM). At 21 days post infection, L paracasei, but not L johnsonii, showed significant attenuation of hypercontractility to carbachol stimulation, compared with the control group (P = .01). The 2 bifidobacteria strains tended to decrease the hypercontractility; however, this trend did not reach statistical significance (P = .09). The attenuation of muscle hypercontractility was paralleled by a 2-fold decrease in the secretion of interleukin-4 (P < .0001), mRNA for transforming growth factor-beta (P = .0001), and cyclooxygenase-2 (P = .001) in longitudinal myenteric plexus preparation and by modulation of genes involved in innate defenses such as RANTES and cryptdin, as evaluated by gene array analysis. Commentary. It is interesting that the normalization of the postinfection contractility was independent of L paracasei presence in the mucosa-associated flora -- thus indicating that the improvement in intestinal muscle dysfunction by L paracasei and free-L paracasei SCM is likely due to attenuation of cytokine and inflammatory mediator production in the muscularis externa and modulation of innate defense genes in the small intestine. In addition, this effect is strain-dependent. The importance of the strain-specific effect has also been suggested by findings from other studies.[12] The clinical implication for this strain-specific effect has been shown in an interesting abstract presented by Drisko and colleagues.[13] These investigators examined 5 commercially, commonly available probiotic products. They used polymerase chain reaction (PCR) gel electrophoresis and amplicon excision with DNA sequencing to determine the bacterial strain content of these 5 products and compared their findings against what was reported in the respective product labeling information. These investigators found that with a single exception, all bacterial species that were tested were detected in the probiotic samples by PCR analysis and confirmed by DNA sequencing. Bifidobacterium bifidum was not detected in 2 of the 5 samples reporting its presence. In contrast, Lactobacillus spp. were detected in 2 of the 5 product samples for which the species was not listed as an "ingredient." Commentary. Although cultures of commercially available probiotics closely resemble their labeling information overall, there are some differences. Because emerging data suggest that the beneficial effect of probiotics is strain-dependent, a better regulation of dietary supplements may be necessary to ensure proper preparation and marketing standards. * The United States Food and Drug Administration has not approved this medication for this use. References
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