Innovations in the Treatment of Irritable Bowel Syndrome
abstract & commentary
Source: Farthing MJG. Irritable bowel syndrome: New pharmaceutical approaches to treatment. Baillieres Clin Gastroenterol 1999;13(3):461-471.
It is now 10 years since klein published a devastating analysis of randomized controlled trials in the treatment of irritable bowel syndrome (IBS), concluding that the trials were flawed and that none of the agents could be regarded as effective.1 In addition, there was little information about the epidemiology, pathophysiology, and natural history of IBS.
In a recent review, it was reported that the annual incidence of IBS is 1%-2% and the prevalence of IBS is 10%-15%, with the latter being similar in Asia, parts of Africa, the United States, and the United Kingdom.2 Most patients continue to be symptomatic over time, miss work more than asymptomatic controls per year (13.4 vs 4.9 days), and seek health care when suffering abdominal pain, psychological distress,3 or an increasing number of symptoms.4 Between 48%-60% of IBS patients have a psychiatric disorder and symptoms are correlated with severity of abdominal pain; depression (6%-38%) and anxiety (7%-41%) are most commonly comorbid, and are associated with bloating.4
The search for a single, unifying pathophysiological marker of IBS has continued unsuccessfully. Recently, though, treatments are being conceptualized in a framework that is both practical for the primary care physician and self-evident in terms of the underlying pathophysiology. Broadly, patients’ problems can be dichotomized into abnormalities of motility and visceral sensation. With regard to motility, IBS patients are prone to constipation or diarrhea. Prokinetic agents include fiber, psyllium, cisapride, and Zelmac. Fiber and psyllium products have been recommended for constipation-predominant IBS because in initial trials they accelerated oral-cecal and/or anal transit, decreased intracolonic pressure, and reduced bile salt concentrations (which could indirectly be helpful). In controlled trials, however, results have been limited, with few therapeutic effects seen and/or comparable to placebo. The same is true for cisapride, which failed in two double-blinded, controlled trials. In one trial, though, a drug with similar 5HT4 partial agonist activity (Zelmac) was better than placebo in terms of abdominal pain, constipation, and overall gastrointestinal symptoms. Hypokinetic agents include loperamide, cholestyramine, and (potentially) muscarinic antagonists. A hypokinetic agent with efficacy in controlled trials is loperamide, a synthetic opiate that is preferred to others because it does not traverse the blood-brain barrier. Loperamide improved stool frequency and reduced pain intensity. Cholestyramine is considered as a second-line treatment in diarrhea-predominant IBS, based on a rationale of bile acid malabsorption in patients with functional diarrhea that mimics IBS. Data on muscarinic antagonists (anticholinergic drugs) in open trials are limited and sometimes doses required for clinical improvement of IBS also cause untoward atropine-like effects.
Visceral sensory pathways generate the symptoms of abdominal pain and bloating that are often the most difficult to treat. Drugs that modify these pathways include the 5HT3 antagonists, 5HT4 partial agonists, opiate kappa (K) receptor agonists, somatostatin analogues, and antidepressant drugs. Clinical studies with drugs acting at the 5HT3 and 5HT4 receptors are preliminary at this point. The 5HT3 antagonist odansetron reduces rectal hypersensitivity and, in diarrhea-predominant IBS, it reduces bowel frequency and improves stool consistency; it does not appear to reduce abdominal pain in this latter set of patients. Granisetron and tropisetron, but not odansetron, reduce the pain response due to dilatation in rats. In one controlled study, olasetron was better than placebo in relieving pain/discomfort, reducing bowel frequency, and improving stool consistency. As mentioned above, 5HT4 partial agonists appear to be prokinetic while antagonists may be hypokinetic; effects on visceral sensation are as of yet indeterminant. The antinocioceptive effects of opioid agonists also reduce visceral sensation. The K receptor agonist fedotozone is thought to act on peripheral receptors and is free of the undesired central effects of morphine. K receptor agonists increase the discomfort threshold to distention in normal human volunteers and reduce visceral hypersensitivity in animal models. In a double-blind, controlled trial, fedotozone was superior to placebo in reducing abdominal pain and bloating. Somatostatin modulates neural transmission in the spinal cord, depressing excitation, perhaps by inhibitory effects on N-type calcium channels. An analogue, octreotide, increases the sensation threshold and also reduces mouth-to-cecum transit time. Tricyclic antidepressants (TCAs) have been shown to be effective for post-herpetic neuralgia, facial pain, and diabetic neuropathy. Pain reduction occurs at doses lower than those for depression and occurs more rapidly than antidepressant action; it is not dependent on a change in mood. A review of six placebo-controlled trials of TCAs for IBS reveals that they generally reduce diarrhea and abdominal pain but do not help with bloating and constipation.5 Selective serotonin reuptake inhibitors (SSRIs), which often cause diarrhea, may be useful for constipation-predominant IBS, but it is not known if they alter visceral sensory pathways in a clinically meaningful way.
Comment by Donald M. Hilty, MD
IBS and psychiatric disorders may be linked biochemically in terms of etiology and/or treatment strategies. This is yet another example of how the brain and body are integrated, similar to findings between panic disorder and IBS and depression and coronary artery disease. Thus far, SSRIs have helped IBS according to anecdotal reports, with potential mechanisms of action of 5HT antagonism and anticholinergic transmission.6 If routine psychotropic medications (e.g., SSRIs) are found to be efficacious for IBS, they may both treat and prevent depression and anxiety in IBS patients.
References
1. Klein DB. Controlled treatment trials in the irritable bowel syndrome: A critique. Gastroenterology 1988; 95:232-241.
2. Talley NJ. Irritable bowel syndrome: Definition, diagnosis and epidemiology. Baillieres Best Pract Res Clin Gastroenterol 1999;13(3):371-384.
3. Thompson WG. Gender differences in irritable bowel symptoms. Eur J Gastroenterol Hepatol 1997;9:299-302.
4. Creed F. The relationship between psychosocial parameters and outcome in irritable bowel syndrome. Am J Med 1999;107(5A):74S-80S.
5. Camilleri M. Therapeutic approach to the patient with irritable bowel syndrome. Am J Med 1999;107(5A): 27S-32S.
6. Clouse R. Antidepressants for functional gastrointestinal syndromes. Dig Dis Sci 1994;39:2352-2363.
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