Mayo Clinic College of Medicine, Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Rochester, Minnesota.
Address correspondence and reprint requests to: Prof. Michael Camilleri, Atherton and Winifred W. Bean Professor, Professor of Medicine and Physiology, Mayo Clinic College of Medicine, Charlton 8–110, 200 First Street S.W., Rochester, MN 55905; (e-mail: camilleri. firstname.lastname@example.org).
The objectives of this talk are to review the current clinical management (1) and the clinical pharmacology and clinical trials evidence for new potential therapies for irritable bowel syndrome (IBS) which include 5-HT3 antagonists, 5-HT4 agonists, κ opiates, clonidine, NK antagonists, neostigmine, antibiotics and probiotics.
Current therapy is aimed at the predominant symptom. The most frequently used medications are:
1. Fiber (in moderation, <20 g/day) and osmotic laxative for constipation (but not for pain); supplementation of 12 g per day is efficacious in the treatment of simple constipation. This is relevant to patients with constipation-predominant IBS (C-IBS) in view of the evidence that symptoms complexes transition between functional constipation and C-IBS;
2. Opioids (loperamide, diphenoxylate) for diarrhea;
3. Antispasmodics p.r.n. for severe episodes of pain;
4. Daily antidepressants (low dose tricyclics in D-IBS or conventional dose SSRIs in constipation predominant irritable bowel syndrome) for the irritable bowel syndrome itself. Pharmacodynamic studies with serotonergic psychoactive agents show that venlafaxine enhances gastric volume postprandially, buspirone reduces gastric tone postprandially and reduces satiety scores and paroxetine accelerates small bowel transit (2). These observations provide some of the rationale for the extensive clinical use of these agents.
5-HT3 Antagonists: Alosetron and Cilansetron
Alosetron, a 5-HT3 antagonist, slows colonic transit, enhances colonic compliance and reduces colonic sensation during volume distensions. In phase III clinical trials (3), it results in an increased proportion of female patients with diarrhea-predominant IBS who achieve adequate relief of pain and discomfort and improvement in bowel frequency, consistency and urgency. The effective dose is 1 mg b.i.d. Cilansetron was similarly effective in adequate relief of pain and diarrhea in phase II trials; significant beneficial effects were also observed in males.
5-HT4 Agonists: Tegaserod
Tegaserod, a partial 5-HT4 agonist, accelerates orocecal transit (without effect on gastric emptying) and tends to enhance colonic transit. In phase III trials, tegaserod, 12 mg/d, resulted in an increased proportion of IBS patients who achieved the target, “subjects’ global assessment of relief.” Secondary endpoints also improved including constipation, pain-free days and bloating (4).
Clonidine, an α2 adrenergic agonist, is an interesting agent that relaxes the bowel and reduces pain sensation through central antinociceptive actions. Clinical efficacy in IBS has been evaluated in a single center phase IIb trial (5) that showed that 0.1 mg b.i.d. clonidine improves bowel dysfunction and results in a 21 percent greater proportion of satisfactory relief responders relative to placebo and clonidine 0.05 mg b.i.d.
Fedotozine, a κ opioid agonist, reduces pain hypersensitivity in IBS without altering colonic compliance or tone. A phase II study suggested 30 mg fedotozine increased the proportion of patients reporting no or slight pain (6). A newer medication, Asimadoline, is currently being evaluated in animal and human studies. In a pharmacodynamic study in healthy volunteers, asimadoline reduced satiety and relaxed fasting tone of the descending colon.
An NK1 antagonist was tested in a 1-week study; it reduced IBS symptom ratings and the anger (but not pain thresholds) associated with rectal balloon distension.
Following some promising studies in experimental models, this class of drug is being explored in early phase II studies.
Neostigmine enhances gas clearance in an experimental model, but it increases pain in healthy subjects.
A much publicized study suggests that antibiotics given for bacterial overgrowth in IBS result in clinical improvement of patients. Several methodological questions and pitfalls in the study require reappraisal before widespread clinical use of antibiotics.
A controlled study demonstrated that probiotics reduced severity of bloating in IBS without altering other symptoms or gastrointestinal transit (7). Follow-up studies are currently under way in IBS patients with predominant bloating.
This is an exciting time for novel therapeutics that are based on a greater understanding of gut physiology: motility, compliance, tone and sensation. Pharmacodynamic studies appear to facilitate drug-development programs. Improved trial methodology is bringing novel agents to clinical practice. In most cases, it is still necessary to move from proof of efficacy to clinical effectiveness.
1. Camilleri M. Management of the irritable bowel syndrome. Gastroenterol
2. Chial HJ, Camilleri M, Ferber I, et al. Effects of venlafaxine, buspirone and placebo on colonic sensorimotor functions in healthy humans. Clin Gastroenterol Hepatol
3. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet
4. Kellow J, Lee OY, Chang FY, et al. An Asia-Pacific, double-blind, placebo-controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut
5. Camilleri M, Kim D-Y, McKinzie S, et al. A randomized, controlled exploratory study of clonidine in diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol
6. Delgado-Aros S, Chial HJ, Camilleri M, et al. Effects of a kappa opioid agonist, asimadoline, on satiation and gastrointestinal motor and sensory functions in humans. Am J Physiol
7. Kim HJ, Camilleri M, McKinzie S, et al. A randomized, controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhea-predominant irritable bowel syndrome. Aliment Pharmacol Ther