Treatment of Irritable Bowel Syndrome and Functional Constipation: New Insights
Nicholas J. Talley, MD, PhD
Management of irritable bowel syndrome (IBS) and functional constipation remains a challenge in clinical practice. On Sunday afternoon a topic forum session was devoted to novel treatment approaches ranging from psychological therapy and centrally acting drugs to new peripherally acting neuroenteric modulators. The results suggest unparalleled new optimism regarding the management of these difficult yet common problems. A summary of the presentations and an overview of their clinical implications follows.
Therapeutic Target: The Central Nervous System
There is increasing interest in the potential role of the new antidepressants in the treatment of IBS and related functional gastrointestinal disorders. Randomized, controlled trials in general support the use of tricyclic antidepressants, although the quality of these studies has been criticized.[2,3] The selective serotonin reuptake inhibitors (SSRIs) anecdotally appear useful, although randomized, controlled trial data are sorely needed. Furthermore, if SSRIs are indeed efficacious, the potential mechanisms will need to be explored.
Dr. Jan Tack from the University Hospitals in Leuven, Belgium, evaluated the physiological effects of citalopram, an SSRI, on the physiology of the colon. It is well established that patients with IBS as a group have an increased sensitivity to balloon distension in the rectum and colon. There is also evidence that some patients with IBS, particularly those with postprandial symptoms, have an increased gastrocolonic response. In a well-conducted, albeit small, study of 9 healthy subjects, a barostat balloon was placed in the colon, and a distension procedure was performed at baseline. This was followed by placebo or citalopram 20 mg intravenously, when the baseline distensions (after a liquid meal) were repeated and then postprandial distensions were performed. Of interest, citalopram induced a small relaxation of the colon that was not observed with placebo. This was associated with a reduction of discomfort induced by increasing volumes but not pressures. There was a decrease in balloon volume, indicating increased colonic tone, after ingestion of a meal with placebo; this response was also inhibited by citalopram. Therefore, this SSRI appears to potentially reduce visceral hypersensitivity by relaxing the colon as well as blunting the gastrocolonic response. However, as citalopram has some anticholinergic actions, this may explain the colonic changes observed, at least in part.
Whether citalopram will be efficacious in IBS remains to be established, but these results strongly support the need for adequate placebo-controlled trials with this class of drugs. Indeed, the cost-effectiveness of antidepressants early in the management of IBS may be advantageous, considering the relative high cost of new agents that are or soon will be available. However, randomized, placebo-controlled trials will be needed to establish this hypothesis.
Promising placebo-controlled results have been reported in the United Kingdom with hypnotherapy for IBS, and these findings have been confirmed elsewhere. Other psychological treatments are also promising, especially psychotherapy. The potential mechanisms by which hypnotherapy may lead to symptom improvement remain unknown. It has also been documented that patients with IBS have abnormalities in the autonomic nervous system. In particular, sympathetic overactivity has been reported in diarrhea-predominant IBS.
A study by Dr. Olafur S. Palsson and colleagues from the Eastern Virginia Medical School in Norfolk, Virginia, investigated the relationship between hypnotherapy and the autonomic nervous system in 24 patients with IBS. Autonomic nervous system function testing was based on cardiovascular reflexes. Results were obtained before and after 7 sessions of standardized hypnosis treatment. Although not a controlled trial, patients, as expected, did significantly improve after treatment, with reduction in pain and bloating and improvement of bowel habits. The authors also observed that finger sweat-gland activity, which is a measure of skin conductance, was reduced after treatment, but all other autonomic nervous system measures were unchanged.
The authors therefore suggest that hypnotherapy may contribute to symptom relief via sympathetic autonomic nervous system alterations. While plausible, one of the potential limitations of this study is a lack of placebo control. It is therefore unclear whether similar sympathetic nervous system changes would have been observed in a standard-care group not treated with hypnotherapy. Moreover, subgroups of IBS (diarrhea vs constipation) were not considered, and the number of patients was small. The study also raises the interesting issue of whether the placebo response may be modulated via the sympathetic nervous system. It is conceivable that a caring physician's attitude may promote reduced sympathetic outflow and therefore symptom improvement. These intriguing issues will require careful controlled studies to test their plausibility.
Tegaserod, a Partial 5HT4 Agonist
Recently, the 5-HT3 antagonist alosetron was approved by the FDA for the treatment of IBS. This drug slows colonic transit and is indicated for diarrhea-predominant IBS. For unknown reasons, the drug is thought to be efficacious only in women, although further studies in men are awaited with interest.[11,12] While the availability of alosetron is an advance, there remains a large group of patients with IBS who have constipation-predominant symptoms, and the availability of therapy for this group has remained very limited. Bulking agents are useful but not optimal. Laxatives also have proven to be suboptimal in this subgroup. Cisapride, which acts mainly in the proximal gut, is also disappointing.
Therefore, the results of a large randomized controlled trial of a new partial 5-HT4 receptor agonist -- tegaserod -- in the treatment of IBS reported by Dr. Mueller-Lissner and colleagues were received with interest. Tegaserod accelerates colonic transit and appears not to have the cardiac toxicity associated with cisapride.[15,16] In a large multicenter study, 881 patients with constipation-predominant IBS were randomized to 4 mg or 12 mg of tegaserod vs identical placebo. The trial was well designed and fulfilled the quality criteria recently outlined by the Rome II Committees. Both 4 mg and 12 mg of tegaserod were efficacious vs placebo at the second and third month, based on a global assessment that was the main outcome variable. Tegaserod appeared to have an onset of action by week 1, and was generally well tolerated. Predominantly women were enrolled in the study, and, therefore, the results in men remain uncertain, particularly in view of the negative findings in men treated with alosetron.
These results with tegaserod are convincingly positive. The actual effect is modest but clinically significant compared with placebo. The results are consistent with recent physiological studies. It is likely that tegaserod will become available for clinical use soon and will be a welcome addition to the armamentarium of drugs for IBS.
Prucalopride, a Potent 5-HT4 Agonist
Chronic constipation due to slow transit constipation remains difficult to manage in practice. Patients with this condition often abuse stimulant laxatives, largely because therapeutic gains with other compounds are so limited. Osmotic laxatives are usually poorly tolerated, and bulking agents may actually aggravate the symptoms in this subgroup. A potential new therapeutic approach is to use a 5HT4 receptor agonist which is highly selective for the colon. Prucalopride appears to be a promising compound. Dr. Nicolaas H. Prins and colleagues from Utrecht determined possible mechanisms for the colokinetic actions of prucalopride. In particular, they wished to determine whether 5HT4 receptors are present on longitudinal muscle. It has already been demonstrated that activation of 5HT4 receptors relaxes circular muscle. Prins and colleagues performed an in vitro study evaluating human colonic longitudinal muscle strips. Contraction was induced by electrical field stimulation. Prucalopride increased electrical field stimulation, inducing contractions despite blockage of other serotonin receptors. These experiments provide direct evidence that prucalopride stimulates 5HT4 receptors on cholinergic nerves in longitudinal muscle in humans.
Dr. John F. Johanson and colleagues next reported the efficacy of prucalopride in chronic constipation from 2 large phase III clinical trials. The results are important. There were 1246 patients randomized who had 2 or fewer spontaneous bowel movements plus at least 1 other symptom of functional constipation. At a dose of both 2 mg and 4 mg, prucalopride significantly increased the number of bowel movements compared with placebo. Overall, 33% of patients in the first trial on 2 mg of prucalopride and 37% on 4 mg of prucalopride increased their bowel movement frequency to 3 or more per week by 4 weeks, compared with 10% on placebo. Similar results were obtained in the second trial. This response was sustained over the 12 weeks of study. Furthermore, other symptoms associated with constipation, including pain and bloating, as well as need for laxatives, significantly decreased in the active arms. The results provide new hope for the medical therapy of severe constipation, but why only a subset of patients responded remains to be clarified.
Chronic Anal Fissure: Treatment Approaches
Fissures are relatively common in young and middle-aged adults and tend to occur after the trauma of passing a hard, large stool. Manometric studies have shown that there is usually resting anal hypertonia with chronic fissures. Treatment options currently include conservative management (bulking agents, sitz baths, and emollient suppositories), topical 0.5% nitroglycerin ointment, and, in chronic cases who fail medical management, surgery (usually lateral subcutaneous sphincterotomy). A "temporary sphincterotomy" may be produced by injection of botulinum toxin.
A previous controlled trial suggested that botulinum toxin healed fissures in 96% of cases compared with 60% in a nitroglycerin comparison group. Dr. Laurent Siproudhis and colleagues from Lille, France, investigated the value of botulinum toxin in a randomized, multicenter, prospective, placebo-controlled ,double-blinded trial. In 44 patients with an anal fissure for at least 1 month, no difference in outcome was observed after a single injection of botulinum toxin into both sides of the internal anal sphincter vs saline (active and placebo groups improved). Technically, the trial (including injector method) appears to have been adequate. These results are disappointing. However the results may be due to patient selection; many of the patients may have had an acute rather than a chronic fissure, and this may explain the placebo response.
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