Irritable Bowel Syndrome Message Boards | Update on Treatment of Functional Gastrointestinal Disorders

Digestive Disease Week 2003
IBS/Other Functional GI Disorders CME
May 18 - 21, 2003, Orlando; Florida

The Brain, the Gut, the Food, and the Bacteria? Update on Treatment of Functional Gastrointestinal Disorders

Yehuda Ringel, MD Douglas A. Drossman, MD

Introduction
Despite 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 Brain
Antidepressants 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 Approach
In 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 Approach
The 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 Gut
Very 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 Gastroparesis
Tougas 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 Constipation
Johansen 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 Food
Nutritional 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 Bacteria
Several studies have suggested a potential beneficial effect of certain probiotics in reducing some of the symptoms of IBS.[7]

Probiotics vs Antibiotics
In 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 Probiotics
Although 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.

Concluding Remarks
The above discussion is intended to bring to the fore the current state of knowledge regarding the multifactorial nature of FGIDs. Within this context, new insight may be gained with respect to the clinical and therapeutic implications for patients with these disorders, with a view toward the effect and effectiveness of available and commonly used treatment options.

* The United States Food and Drug Administration has not approved this medication for this use.

References
Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131.
Drossman DA, Diamant N, Toner B, et al. A multi-center randomized trial of despiramine (DES) vs placebo (PLA) in moderate to severe functional bowel disorder (FBD). Gastroenterology. 2003;124:A-30. [Abstract #199]
Drossman DA, Toner B, Whitehead W, et al. A mutli-center randomized trial of cognitive-behavioral treatment (CBT) vs education (EDU) in moderate to severe functiona; bowel disorder. Gastroenterology. 2003;124:A-530. [Poster #T1422]
Tougas G, Chen Y, Luo D, et al. Tegaserod improves gastric emptying in patients with gastroparesis and dyspeptic symptoms. Gastroenterology. 2003;124:A-54. [Abstract #432]
Johansen JF, Tougas G, Chey WD, et al. Tegaserod provides rapid and sustained relief of constipation, abdominal bloating/distension, and abdominal discomfort/pain in patients with chronic constipation. Gastroenterology. 2003;124:A-47. [Abstract #371]
Atkinson W, Gurney R, Sheldon TA, Whorwell PJ. Do food elimination diets improve irritable bowel syndrome? A double blind trial based on IgG antibodies to food. Gastroenterology. 2003;124:A-29. [Abstract #198]
Kim HJ, Camilleri M, McKinzie S, et al.A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17:895-904.
Faber S. Comparison of probiotics with antibiotics alone in treatment of diarrhea-predominant IBS (D-IBS), alternating (A-IBS), and constipation (C-IBS) patients. Gastroenterology. 2003;124:A-687. [Poster #W1523]
Lamine F, Cauquil E, Eutamene H, et al. Lactobacillus farciminis reduces sensitivity to rectal distension in rats: Involvement of nitric oxide. Gastroenterology. 2003;124:A-476. [Poster #T1060]
Lamine F, Cauquil E, Nepveu F, et al. Nitric oxide released by Lactobacillus farciminis protects rat colon against TNBS-induced inflammation. Gastroenterology, 2003;124:A-113. [Abstract #828]
Verdu EF, Bercik P, Blennerhassett P, et al. Strain-dependent effects of probiotics on intestinal muscle dysfunction in an animal model of post-infective irritable bowel syndrome. Gastroenterology. 2003;124:A-29. [Abstract # 197]
Ringel Y, Drossman DA. Inflammation, infection, and irritable bowel syndrome. Medscape Conference Coverage based on selected sessions at Digestive Disease Week, 2002. Medscape Gastroenterology 2002. Available at:
http://www.medscape.com/viewarticle/434527 Accessed June 3, 2003.
Drisko JA, Bischoff B, Giles C, et al. Evaluation of 5 probiotic products for bacteria by PCR. Gastroenterology. 2003;124:A-687. [Poster #W1522]

Copyright � 2003 Medscape.

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