DOCTOR'S VIEW ARCHIVE
Alosetron (Lotronex) was approved for marketing by the FDA in February, 2000, but was withdrawn from the market in November, 2000, because of serious, life-threatening, gastrointestinal side effects. In June 2002, it was approved again by the FDA for marketing but in a restricted manner as part of a drug company-sponsored program for managing the risks associated with treatment. Use of alosetron is allowed only among women with severe, diarrhea-predominant, irritable bowel syndrome (IBS) who have failed to respond to conventional treatment for IBS.
This article was written at the time of the first FDA approval.
--Medical Editors, MedicineNet.com
Irritable Bowel Syndrome (IBS) is a complex gastrointestinal disorder of unknown cause that afflicts approximately one out of every five adult Americans and three times as many women as men. The symptoms of IBS include abdominal pain, bloating, mucous in stools, and diarrhea and/or constipation. Commonly, more than one symptom is present. Psychological features such as depression, anxiety or stress may accompany IBS. There are no tests for IBS. In fact, the diagnosis of IBS is based on the presence of compatible symptoms and normal tests for gastrointestinal disorders (for example, x-rays and endoscopic examination of the intestines). It is theorized that the cause of IBS is dysfunction of intestinal nerves and/or muscles.
Since the underlying cause of IBS is unknown and, therefore, not treatable, the focus of treatment in IBS has been the management of symptoms. An assortment of drugs including antidepressants, anti-spasmotics (muscle-relaxers), anti-diarrheals, and laxatives have been used as well as dietary changes (e.g., high fiber, low fat). Psychiatric testing and treatment also has been employed.
Alosetron (Lotronex) is the first drug to be approved specifically for IBS. Two 12-week studies involved more than 1,200 women with IBS in whom diarrhea was a predominant symptom. The patients were treated for three months with either alosetron or placebo. Each week the patients were asked if the drug they were taking had given them adequate relief from abdominal pain and discomfort. Adequate monthly relief was defined as at least two weeks out of every four consecutive weeks with adequate relief. Forty-one percent of the patients receiving alosetron experienced adequate monthly relief for each of the three months (12 weeks) of the studies while only 30% of the patients receiving placebo experienced similar relief. Patients taking alosetron also had fewer days with a sense of urgency with their stools (decreasing from 7 out of every 10 days to 4 out of every 10 days), fewer daily stools (decreasing from three to two per day), and firmer stools. The most common side effect with alosetron, constipation, was seen in approximately one-third of patients and caused nine to ten out of every 100 patients to stop taking the drug either for a short time or indefinitely.
The exact mechanism by which alosetron relieves the symptoms of IBS is unknown. The discomfort and diarrhea of IBS are believed to be due to abnormal activity of the muscles of the intestines and/or the intestinal nerves that control the muscles. One of the chemical messengers which is important in coordinating the activity of intestinal nerves is serotonin. (Chemical messengers are chemicals produced and released by nerve cells that attach to receptors on nearby nerve cells and cause changes in the nearby nerve cells.) Alosetron belongs to a class of drugs that blocks one type of serotonin receptor called the 5-HT3 receptor. Serotonin and its receptors in the intestines are believed to control how pain is felt (sensation), contraction of intestinal muscle, and release of fluid into the intestines. These actions of serotonin can result in pain and diarrhea. The cause of IBS is unknown, but it is thought that stimuli such as food, medications, hormonal changes, or stress may trigger an excessive release of or an excessive response to serotonin. This may cause the pain and diarrhea that is seen in patients with diarrhea-predominent IBS. Alosetron, by blocking 5-HT3 receptors, reduces the actions of serotonin.
There is little question that alosetron is effective. So far it looks safe, and related drugs that have been available for years have proven safe. There are some caveats, however.
First, the studies were relatively short-term--12 weeks, but IBS is a chronic problem lasting many years. Some medications lose their effectiveness over time, and it is not clear yet whether alosetron will maintain its efficacy over the longer-term. Second, efficacy (adequate relief) was defined by the studies' investigators; however, one may reasonably ask, how adequate is relief that is present for only two weeks out of every four (50% of the time)? Third, although alosetron was more effective than placebo, the difference between alosetron and placebo was small, around 10%. (Perhaps patients with IBS should be treated with placebo first, and only if it is ineffective should they be treated with alosetron!) Finally, less than half of the patients treated with alosetron obtained adequate relief.
Alosetron is expected to be widely-used since IBS is among the ten most commonly diagnosed medical problems, and there are few if any effective treatments. Nevertheless, among women with IBS, diarrhea without constipation (as experienced by the studies' patients) is present in only a minority. Constipation is the most common form of IBS, and alosetron may make constipation worse. Therefore, alosetron is appropriate for only a minority of women with IBS. Alosetron has not been studied in large numbers of men and is not approved or recommended for men because smaller studies showed that it had no benefit among men.
Despite the caveats, alosetron represents an important step forward in the treatment of IBS. The demonstration of its efficacy is likely to spur further research with other drugs that alter the release of chemical messengers or block receptors in the intestine. Progress will come slowly, however, because of the lack of understanding of the cause of IBS.