Gut-acting therapies are common therapies for irritable bowel syndrome (IBS). Most of these peripheral acting agents are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in treating symptoms of IBS. The clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 antagonist alosetron in the treatment of women with severe IBS with diarrhea refractory to traditional therapy.
The irritable bowel syndrome (IBS) is a chronic, relapsing, and variably disabling bowel disorder characterized by the presence of abdominal pain or discomfort in association with altered bowel habits. IBS is further subtyped based on the predominant stool pattern into one of IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), or mixed IBS (IBS-M). Given the nature of symptoms related to IBS, gut-acting therapies have been traditionally used and remain among the most common therapies for this chronic condition. Most of these peripheral acting agents, including fiber supplements, laxatives, antidiarrheals, and antispasmodics, are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal, based on dated studies of marginal methodological quality because high-quality clinical trials are generally lacking. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in global as well as various individual symptoms of IBS. Moreover, the clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 (5-HT 3 ) antagonist alosetron in the treatment of women with severe IBS-D refractory to traditional therapy.
Fiber supplements and laxatives
The use of fiber supplements and laxatives in the treatment of IBS has evolved from the perception of altered gastrointestinal motility as a cause of the abnormal bowel symptoms associated with this heterogeneous condition. Specifically, several clinical observations have reported a decrease in bowel motility and a prolonged transit time in patients with IBS-C compared with controls. Furthermore, given the proven efficacy of fiber supplements and other laxatives in regulating bowel habits and alleviating constipation, clinicians have traditionally turned to these agents to address the bowel symptoms associated with IBS-C and IBS-M. However, the clinical evidence for this practice is based on limited data because high-quality clinical trials assessing these agents in the treatment of IBS are nearly nonexistent.
Dietary fiber supplements represent a heterogeneous group of complex carbohydrates that are resistant to hydrolysis during digestion. These nondigested products result in increased stool bulk and water content, effectively decreasing stool consistency and increasing stool frequency. Of the various commercially available fiber supplements including psyllium, ispaghula husk, bran (wheat and corn), methylcellulose, calcium polycarbophil, and partially hydrolyzed guar gum; psyllium and bran are the best studied in the treatment of IBS. The results of the 6 trials comparing psyllium and ispaghula husk (the husk of psyllium seed) with placebo were pooled, yielding a total of 321 patients with IBS, with 161 in the treatment arm. In this pooled analysis, 52% of patients treated with psyllium had persistent IBS symptoms after treatment compared with 64% of those receiving placebo. Although significant heterogeneity existed amongst the studies, the relative risk (RR) of symptoms not improving with psyllium was 0.78 (95% confidence interval [CI] 0.63–0.96) compared with placebo with a number needed to treat (NNT) of 6 (95% CI 3–50). The investigators noted that limiting this analysis to the 5 higher-quality trials resulted in a loss of this significant difference between psyllium and placebo. The pooled analysis of the 5 trials comparing bran with placebo or a low-fiber diet found no difference in treatment outcomes with bran. Guar gum has been assessed (daily dose of 5–10 g) in 2 open trials involving patients with constipation-predominant and diarrhea-predominant IBS, suggesting short-term benefits in gastrointestinal symptoms as well as in quality-of-life (QOL) measures. The effects of calcium polycarbophil on IBS have been assessed in 2 clinical trials. The first study was a 6-month, placebo-controlled, randomized, double-blind crossover trial in 23 patients with either constipation-predominant IBS or IBS with alternating diarrhea and constipation. Polycarbophil (6 g/d) was preferred over placebo in 71% of patients for treatment of their IBS symptoms. Compared with placebo, polycarbophil was reported to improve ease of bowel movements and relieve symptoms of nausea, pain, and bloating. In the second trial, calcium polycarbophil was given to 26 patients with IBS (14 with IBS-D and 12 with IBS-C). Compared with baseline there was significant improvement in frequency of bowel movement, stool form, and abdominal pain in both IBS subgroups ( P <.05). There are no clinical trials assessing the efficacy of methylcellulose in the treatment of IBS.
The clinical trials assessing fiber supplements have been evaluated collectively in several systematic reviews, with varying conclusions. The American College of Gastroenterology (ACG) Task Force recently reported on their findings from an evidence-based systematic review on the effectiveness of fiber supplements in the management of IBS, concluding that “Psyllium hydrophilic mucilliod (ispaghula husk) is moderately effective and can be given a conditional recommendation (Grade 2C) ( Table 1 ). Wheat bran or corn bran is no more effective than placebo in the relief of global symptoms of IBS and cannot be recommended for routine use (Grade 2C). A single study reported improvement with calcium polycarbophil.” Using dichotomous outcomes for relief of abdominal pain, improvement in global assessment of IBS symptoms, and improvement in symptom scores, a Cochrane review of 11 studies did not find fiber supplements effective in the treatment of IBS. These investigators cautioned that considerable heterogeneity of patients with IBS existed in the included trials and the effectiveness of fiber supplements have not been completely defined in specific IBS subtypes. In an earlier systematic review performed by the ACG Functional Gastrointestinal Disorders Task Force, this panel of experts concluded that bulking agents were not more effective than placebo at relieving the global symptoms of IBS.
| Grade of Recommendation | Description of Recommendation | Methodological Quality of Supporting Evidence | Benefit Versus Risk |
|---|---|---|---|
| 1A | Strong recommendation based on high-quality evidence | RCTs without important limitations or overwhelming evidence from observational studies | Benefits clearly outweigh risk |
| 1B | Strong recommendation based on moderate-quality evidence | RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies | Benefits clearly outweigh risk |
| 1C | Strong recommendation based on low- or very-low-quality evidence | Observational or case studies only | Benefits clearly outweigh risk |
| 2A | Weak recommendation based on high-quality evidence | RCTs without important limitations or overwhelming evidence from observational studies | Benefits closely balanced with risk |
| 2B | Weak recommendation based on moderate-quality evidence | RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies | Benefits closely balanced with risk |
| 2C | Strong recommendation based on low- or very-low-quality evidence | Observational or case studies only | Uncertainty in the estimates of benefits and risk |
The use of laxatives in the treatment of IBS-C has evolved from their known effect on the symptoms of constipation. Only 1 laxative, polyethylene glycol (PEG), has been assessed in the treatment of IBS. This was a sequential study assessing the effects of PEG 3350 on 27 postpubertal adolescents (59% female) with IBS-C (based on Rome II criteria). After 4 weeks of therapy, the group treated with 17 g of PEG 3350 once daily experienced a significant increase in mean bowel movement frequency from 2.07 to 5.04 bowel movements a week ( P <.05). However, there was no change in mean pain level for the group with the PEG therapy. Regarding laxatives, the ACG Task Force concluded that “PEG laxative was shown to improve stool frequency–but not abdominal pain–in one small sequential study in adolescents with IBS-C.”
The fiber supplement psyllium may have some beneficial effects on the symptoms of constipation and alternating bowel habits in patients with IBS-C and IBS-M, respectively. Bran does not seem to offer symptomatic benefit in IBS and the effect of other available fiber supplements remains largely unknown. Potential adverse effects including bloating, abdominal distention, and flatulence may limit use of these agents. Their widespread availability, relative inexpense, and perceived safety make them an attractive treatment options in IBS-C and IBS-M. There are virtually no evidence-based data evaluating traditional laxatives in the treatment of IBS. However, the relative safety, universal availability, and low cost of laxatives make them an attractive therapeutic option for constipation-related complaints in patients with IBS.
Antidiarrheals
As already noted, there is a general perception that the alterations in bowel habits experienced in IBS are in part a result of altered gastrointestinal motility. Studies around the world have reported accelerated small bowel and colon transit times as well as exaggerated motility patterns in those with IBS-D compared with controls. It is largely a result of these observations that antidiarrheals remain among the more commonly used gut-acting agents used in the treatment of patients with IBS-D.
Of the 2 most commonly used antidiarrheals in the United States, including loperamide and diphenoxylate, only loperamide has been evaluated in randomized controlled trials (RCTs) for the treatment of IBS. A total of 4 studies have been published, all European, none recent, and all containing methodological limitations. The first study, from England and published in 1984, was a crossover, placebo-controlled trial involving 28 patients with IBS (75% female). Compared with placebo, 5 weeks of loperamide (dose range of 2–12 mg/d) reduced small bowel ( P >.01) and whole gut transit time ( P <.01) and was superior at improving diarrhea ( P <.01), urgency ( P <.01), and boborygmi ( P <.05). There was no improvement in pain with loperamide. Eighteen patients (62%) reported an overall improvement and 9 of them continued therapy for 12 months. The first of 2 Norwegian studies was 1 of 2 double-blind, placebo-controlled trials published in 1987. This study assessed a total of 58 patients with IBS divided into 4 categories: painless diarrhea (n = 16), pain with alternating bowels (n = 21), alternating bowels without pain (n = 12), and constipation with pain (n = 9). Three weeks of loperamide 4 mg once nightly was significantly better than placebo at improving stool frequency and stool consistency in those with painless diarrhea and in those with alternating bowel habits and pain. Loperamide led to significantly fewer days of pain in those with alternating bowel habits and pain. Those with alternating bowel habits and no pain experienced no benefit from loperamide, whereas those with constipation experienced worsening symptoms with loperamide. The other double-blind, placebo-controlled study published in 1987 enrolled 25 Swedish patients with IBS with diarrhea as the predominant symptom. In the 21 patients completing the 13-week treatment period, loperamide (titrated dose ranging from 2 to 8 mg nightly) was superior to placebo at improving stool consistency ( P <.001), pain ( P <.02), urgency ( P <.05), and overall response ( P <.03). The most recently published study was a double-blind, placebo-controlled trial enrolling 90 Norwegian patients with IBS. Although IBS was not subtyped in this study and 21 patients were not included in the analysis, 5 weeks of loperamide (dose range of 2–6 mg nightly) was superior to placebo at improving stool frequency ( P <.05), and stool consistency ( P <.05). Those receiving loperamide reported an increase in nocturnal abdominal pain compared with placebo ( P <.05).
The ACG Task Force recently performed a systematic review of antidiarrheals in the treatment of IBS and concluded that “The antidiarrheal agent loperamide is not more effective than placebo at reducing abdominal pain or global symptoms of IBS, but is an effective agent for treatment of diarrhea, improving stool frequency and stool consistency (Grade 2C). RCTs with other antidiarrheal agents have not been performed. Safety and tolerability data on loperamide are lacking.” An earlier systematic review by the ACG Functional Disorders Task Force in 2002 concluded that although none of the trials reported high-quality data, loperamide was an effective treatment of diarrhea, but no more effective than placebo for the treatment of global IBS symptoms or abdominal pain. The investigators further concluded that adverse event data on loperamide were limited and it was safest for use in IBS-D.
Antidiarrheals
As already noted, there is a general perception that the alterations in bowel habits experienced in IBS are in part a result of altered gastrointestinal motility. Studies around the world have reported accelerated small bowel and colon transit times as well as exaggerated motility patterns in those with IBS-D compared with controls. It is largely a result of these observations that antidiarrheals remain among the more commonly used gut-acting agents used in the treatment of patients with IBS-D.
Of the 2 most commonly used antidiarrheals in the United States, including loperamide and diphenoxylate, only loperamide has been evaluated in randomized controlled trials (RCTs) for the treatment of IBS. A total of 4 studies have been published, all European, none recent, and all containing methodological limitations. The first study, from England and published in 1984, was a crossover, placebo-controlled trial involving 28 patients with IBS (75% female). Compared with placebo, 5 weeks of loperamide (dose range of 2–12 mg/d) reduced small bowel ( P >.01) and whole gut transit time ( P <.01) and was superior at improving diarrhea ( P <.01), urgency ( P <.01), and boborygmi ( P <.05). There was no improvement in pain with loperamide. Eighteen patients (62%) reported an overall improvement and 9 of them continued therapy for 12 months. The first of 2 Norwegian studies was 1 of 2 double-blind, placebo-controlled trials published in 1987. This study assessed a total of 58 patients with IBS divided into 4 categories: painless diarrhea (n = 16), pain with alternating bowels (n = 21), alternating bowels without pain (n = 12), and constipation with pain (n = 9). Three weeks of loperamide 4 mg once nightly was significantly better than placebo at improving stool frequency and stool consistency in those with painless diarrhea and in those with alternating bowel habits and pain. Loperamide led to significantly fewer days of pain in those with alternating bowel habits and pain. Those with alternating bowel habits and no pain experienced no benefit from loperamide, whereas those with constipation experienced worsening symptoms with loperamide. The other double-blind, placebo-controlled study published in 1987 enrolled 25 Swedish patients with IBS with diarrhea as the predominant symptom. In the 21 patients completing the 13-week treatment period, loperamide (titrated dose ranging from 2 to 8 mg nightly) was superior to placebo at improving stool consistency ( P <.001), pain ( P <.02), urgency ( P <.05), and overall response ( P <.03). The most recently published study was a double-blind, placebo-controlled trial enrolling 90 Norwegian patients with IBS. Although IBS was not subtyped in this study and 21 patients were not included in the analysis, 5 weeks of loperamide (dose range of 2–6 mg nightly) was superior to placebo at improving stool frequency ( P <.05), and stool consistency ( P <.05). Those receiving loperamide reported an increase in nocturnal abdominal pain compared with placebo ( P <.05).
The ACG Task Force recently performed a systematic review of antidiarrheals in the treatment of IBS and concluded that “The antidiarrheal agent loperamide is not more effective than placebo at reducing abdominal pain or global symptoms of IBS, but is an effective agent for treatment of diarrhea, improving stool frequency and stool consistency (Grade 2C). RCTs with other antidiarrheal agents have not been performed. Safety and tolerability data on loperamide are lacking.” An earlier systematic review by the ACG Functional Disorders Task Force in 2002 concluded that although none of the trials reported high-quality data, loperamide was an effective treatment of diarrhea, but no more effective than placebo for the treatment of global IBS symptoms or abdominal pain. The investigators further concluded that adverse event data on loperamide were limited and it was safest for use in IBS-D.
Antispasmodics
Abdominal pain or discomfort is a cardinal feature of IBS, a symptom that has been traditionally ascribed to intestinal smooth-muscle spasm. Observation and clinical studies have suggested that an exaggerated motility response of the small bowel and colon to environmental stimuli may be responsible for the symptoms experienced in IBS. For this reason antispasmodics have been and remain a mainstay of therapy for the symptoms of IBS. Antispasmodics encompass several different drug classes, including antimuscarinics, smooth-muscle relaxants, anticholinergics, and unique agents such as pinaverium, an ammonium derivative with calcium channel blocking action, and trimebutine, a peripheral opiate agonist. Of these various antispasmodics, only 4 specific anticholinergic agents are currently available in the United States: hyoscyamine, dicyclomine, belladonna, and propantheline. Given their mechanism of action, these agents are directed at those subgroups of IBS, with a predominant symptom of abdominal pain and stool patterns that are either mixed or more diarrheal in nature. The anticholinergic properties of these agents restrict their usefulness in clinical practice. Common side effects, including dry mouth, dizziness, blurry vision, confusion (particularly in elderly patients), urinary retention, and constipation, often limit the usefulness of these agents in the treatment of IBS. The propensity of these agents to promote constipation makes them a less attractive option for patients with IBS-C. Further, anticholinergics should be avoided in elderly patients, who are more prone to the development of significant side effects.
Although antispasmodics remain among the most commonly prescribed drugs for IBS, the clinical evidence supporting their use is limited. Of the 4 antispasmodics available in the United States, only dicyclomine has been assessed in placebo-controlled clinical trials involving patients with IBS. The first trial was a double-blind, crossover, placebo-controlled trial involving 29 patients divided into a spastic colon group or painless diarrhea group, each receiving 2 weeks of therapy. Although several methodological limitations exist in this study, including the lack of an IBS definition, a crossover study design, inadequate sample size, and short duration of therapy, a dose of dicyclomine 20 mg 3 times was superior to placebo in addressing bowel urgency and relief of pain with urgency. This second trial was a double-blind, placebo-controlled trial showing the superiority of 2 weeks of dicyclomine to placebo in the treatment of 71 patients with IBS with predominant constipation. Despite several methodological limitations associated with this study (only 71 of 97 enrolled patients were analyzed, short treatment period), dicyclomine was superior to placebo with regard to overall improvement of symptoms and decreased abdominal pain. However, the dose of dicyclomine used in this study (40 mg 4 times daily) led to frequent anticholinergic side effects and is not practically useful in routine clinical practice.
Given the lack of high-quality studies addressing the efficacy of specific antispasmodic agents, attempts to estimate the efficacy of this class of drugs for IBS have been undertaken through systematic review and meta-analysis. The most recent systematic review and meta-analysis of antispasmodics as a class was performed by the ACG IBS Task Force. The Task Force concluded that “Certain antispasmodics (hyoscine, cimetropium, and pinaverium) may provide short-term relief of abdominal pain/discomfort in IBS (Grade 2C). Evidence for long-term efficacy is not available (Grade 2B). Evidence for safety and tolerability are limited (Grade 2C).” The Task Force identified 22 studies suitable for inclusion in their systematic review. Only 1 of these studies involved a drug available in the United States. Three studies evaluated hyoscine, a different preparation than the agent, hyoscyamine, which is available in the United States. Drugs not available in the United States that were included in this analysis included otilonium, cimetropium, pinaverium, trimebutine, alverine, mebeverine, pirenzipine, prifinium, propinox, and a trimebutine/rociverine combination. Most of these clinical trials are dated, with only 3 of the studies performed in the last 10 years. The Task Force also acknowledged that these clinical trials were collectively fraught with methodological flaws, including diagnostic criteria used, inclusion criteria used, dosing schedule used, duration of therapy studied, study end points used to assess response, and study size (only 3 studies enrolled more than 100 patients). With these limitations in mind, the 22 trials collectively included data from 1778 patients with IBS. The pooled analysis of these studies revealed an RR of symptoms persisting with antispasmodics compared with placebo of 0.68 (95% CI 0.57–0.81) and an NNT of 5 to prevent IBS symptoms from persisting in 1 patient. A pooled analysis was also performed on the 13 studies, including 1379 patients in whom adverse effects were reported. The Task Force acknowledged significant heterogeneity among these patients; however, the RR of a patient experiencing side effects with antispasmodics was 1.62 (95% CI 1.05–2.50), with a number needed to harm with antispasmodics of 18 (95% CI 7–217).
Other systematic reviews have yielded mixed results regarding the efficacy of antispasmodics for IBS. A systematic review has recently been performed on mebeverine in the treatment of IBS. This analysis included the pooled results of 8 randomized clinical trials (6 compared with placebo) involving a total of 555 patients (63% female) of all IBS subtypes. The investigators reported that although well tolerated, the effect of mebeverine on global improvement and the specific symptom of abdominal pain was not statistically significant compared with placebo. A meta-analysis of smooth-muscle relaxants was performed on 23 randomized clinical trials, including the drugs cimetropium, hyoscine, mebeverine, otilium, pinaverium, and trimebutine. Collectively, global improvement and pain relief was reported in 56% and 53%, respectively, by those receiving the smooth-muscle relaxants compared with response rates of 38% and 41%, respectively, in the placebo group ( P <.001 in both cases). A smaller systematic review of 16 RCTs evaluating smooth-muscle relaxants reported an NNT of 1.6 to 6.7 to achieve symptom relief in patients with IBS with pain as predominant symptom. In this study, muscle relaxants were found to be efficacious in 13 of the 16 studies, although only 7 studies were considered to be of high quality.
Although the individual studies have primarily involved antispasmodics not available in the United States and have been criticized for their low quality, as a group they have shown efficacy in the treatment of abdominal pain in IBS. These agents are therefore likely to be most effective in those patients with IBS with a predominant symptom of abdominal pain. These agents can worsen constipation and should therefore be used cautiously in patients with IBS with a predominance of constipation.
Serotonergic agents
Serotonin (5-HT) is the neurotransmitter primarily produced and stored in enterochromaffin cells located throughout the intestinal epithelium, with 95% of total body concentration of 5-HT residing in the gastrointestinal tract. Acting through the intrinsic and extrinsic afferent nervous system of the gastrointestinal tract, 5-HT plays an important role in various aspects of gastrointestinal sensory, secretory, absorptive, and motility function. Recent research has identified abnormal serotonergic activity in association with IBS. Several studies describe increased serotonergic activity in association with IBS-D. Likewise, a decrease in serotonergic activity has been observed in IBS-C. The use of pharmacologic agents targeting serotonin receptors has therefore evolved from these observations of the role of 5-HT in gastrointestinal health and disease. Of the identified serotonin-receptor subtypes, the 5-HT 1p , 5-HT 3 , 5-HT 4 , and 5-HT 7 receptors are the most clinically relevant for gastrointestinal tract functioning. Receptor agonists of 5-HT 1 have been shown to improve gastric accommodation, slow gastric emptying, and stimulate activity of the migratory motor complex. Receptor antagonists of 5-HT 3 have been reported to slow small bowel transit, decrease intestinal secretion, and decrease colonic tone and transit. Agonists of the 5-HT 4 receptor have shown an ability to accelerate gastric emptying, improve gastric accommodation, accelerate small bowel transit, accelerate colonic transit, and possibly decrease visceral sensation. No 5-HT 1 or 5-HT 4 receptor agents are approved for the treatment of IBS in the United States or Canada. The 5-HT 4 agonist tegaserod was removed from the market in 2009 for safety issues. The 5-HT 3 antagonist alosetron is available through a restricted-access program for use in women with severe IBS-D who have failed conventional therapies.
Alosetron
Alosetron is the only 5-HT 3 antagonist approved by the US Food and Drug Administration (FDA) for the treatment of IBS-D ( Table 2 ). Rigorous, large clinical trials have consistently shown the efficacy of alosetron in the global and individual symptoms of IBS-D in women. A multicenter, placebo-controlled, randomized trial of 647 women with IBS-D or IBS-M reported superiority of alosetron in providing adequate relief of abdominal pain and discomfort compared with placebo for the 3 months of therapy (41% vs 29%). Alosetron also significantly decreased urgency, reduced stool frequency, and increased stool consistency. Constipation occurred in 30% of those taking alosetron compared with 3% in the placebo group. A second multicenter, randomized, placebo-controlled trial of 626 women (71% with IBS-D, 26% with IBS-M) also reported a superiority of alosetron over placebo in providing adequate relief of abdominal pain and discomfort for the 3 months of therapy (43% vs 26%). Alosetron significantly decreased urgency, reduced stool frequency, and increased stool firmness within 1 week of therapy, which persisted throughout the treatment period. Constipation occurred in 25% of those taking alosetron compared with 5% in the placebo group. The pooled effects of alosetron on QOL were also assessed in these 2 clinical trials. Compared with placebo, a significantly higher percentage of those receiving alosetron experienced improvement in 3 QOL domains, including food/diet, social functioning, and role-physical on the validated generic QOL instrument, the SF-36. Another 12-week, randomized, placebo-controlled trial was performed on 801 women with IBS (98% with IBS-D and 2% with IBS-M) and showed superiority of 1 mg twice a day of alosetron over placebo in adequately controlling urgency (73% vs 57%) and improving the global IBS symptoms (76% vs 44%). Participants in this trial also reported overall treatment satisfaction and satisfaction with 11 specific medication attributes of alosestron.
| Drug | FDA-approved IBS Indication | FDA-approved Dose | Special Prescribing Issues |
|---|---|---|---|
| Alosetron | Treatment of severe IBS-D in women failing conventional therapy | Initial dose of 0.5 mg twice a day for first 4 weeks Can increase to 1 mg twice a day for subsequent 4 weeks | Prescribing provider and patient receiving treatment must participate in a risk management plan Anatomic and biochemical abnormalities of the gastrointestinal tract must be excluded before initiating therapy Treatment must be stopped if no relief of symptoms experienced with 4 weeks of therapy at a dose of 1 mg twice a day |
| Lubiprostone | Treatment of IBS-C in women aged 18 years or older | 8 μg twice a day with food | Women of childbearing potential must have a negative pregnancy test documented before initiating therapy and use contraception while on therapy |
A 48-week, randomized, placebo-controlled clinical trial has been performed on 714 women with IBS (80% with IBS-D, 20% with more frequent urgency) to assess long-term safety and efficacy of alosetron at a dose of 1 mg twice daily. Those receiving alosetron experienced greater adequate relief of IBS pain in 9 of the 12 months of the study and greater control of urgency in all 12 months compared with placebo. There were no differences in adverse events or serious adverse events between the 2 groups except for constipation occurring more frequently in the alosetron group. A recent randomized, placebo-controlled trial of 705 women with IBS-D has reported efficacy of lower doses of alosetron in providing global improvement in IBS symptoms, adequate relief of IBS pain and discomfort, and improvement in bowel symptoms (0.5 mg and 1 mg total daily dose). Constipation was reported with less frequency in these lower treatment doses (9% on 0.5 mg/d and 16% on 1 mg/d). A dose-ranging, randomized, placebo-controlled trial has recently been performed on 662 men with IBS-D. In this 12-week treatment trial, those receiving 1 mg of alosetron twice daily were more like than those receiving placebo to report adequate relief of pain in discomfort (53% vs 40%). Firmer stool was reported at all doses of alosetron, although there was no significant effect of alosetron on urgency, bowel movement number, or bloating. Constipation was the most common side effect reported, and was dose related, occurring in 15% of those receiving 1 mg twice daily. There was a possible episode of ischemic colitis in a patient receiving alosetron at a dose of 0.5 mg twice daily.
An evidence-based systematic review has been performed by the ACG Task Force on IBS, with the Task Force concluding that “alosetron is more effective than placebo at relieving global IBS in male (Grade 2B) and female (Grade 2A) patients with IBS with diarrhea. Potentially serious side effects including constipation and colonic ischemia occur more commonly in patients treated with alosetron compared with placebo (Grade 2A). The benefits and harms balance for alosetron is most favorable in women with IBS-D who have not responded to conventional therapies (Grade 1B). The quality of evidence for efficacy of 5-HT 3 antagonists in IBS is high.” The most recent meta-analysis pooled the data from 8 clinical trials of alosetron and 3 clinical trials of the 5-HT 3 antagonist cilansetron (which was never marketed). This analysis, which included a total of 7216 patients with IBS, found 5-HT 3 antagonists more effective than placebo in treating IBS-D. The RR of IBS symptoms persisting with 5-HT 3 antagonists was 0.78 (95% CI 0.71–0.86) compared with placebo.
Alosetron was initially approved for the treatment of women with IBS-D in February 2000 and subsequently withdrawn from the US marketplace in November 2000 because of the infrequent occurrence of significant side effects, including severe complications of constipation and ischemic colitis. During this postmarketing period, 80 cases of ischemic colitis and 100 cases of serious complications of constipation had been reported. These postmarketing surveillance data were later reviewed by an expert panel, which reported a postadjudication rate of 1.1 cases of ischemic colitis per 1000 patient-years of alosetron use and 0.66 cases of serious complications of constipation with 1000 patient-years of alosetron use. A small number of hospitalizations, surgical interventions, and deaths were identified in affected patients taking alosetron. The panel also reported an increased rate of ischemic colitis in the alosetron treatment group compared with the placebo group in a pooled analysis of the available clinical trials (0.15% vs 0.0%, P = .03). In the clinical trial dataset, there was no difference in the occurrence of serious side effects between the alosetron and placebo groups, and all cases of ischemic colitis were reversible without long-term sequelae.
Largely as a consequence of phone calls and letters from patients, alosetron was reapproved by the FDA in June 2002 for the treatment of women with severe IBS-D failing to respond to conventional therapies. It is available for this specific indication through a risk management plan that includes specific dosing instructions, an educational program for prescribing physicians and patients to improve awareness and management of constipation and ischemic colitis, and a standardized patient monitoring program while on therapy. Alosetron is initially prescribed at a dose of 0.5 mg once or twice daily. After 4 weeks of therapy, this dose can be increased to a maximum of 1 mg twice daily if well tolerated and a higher dose is needed for symptom management. If adequate relief of IBS-D symptoms has not occurred after 4 weeks of therapy at a dose of 1 mg twice daily, alosetron should be discontinued. The complication risk of alosetron under this risk management plan has been carefully monitored since reapproval. Safety data from November 2002 to June 2008 including 203,939 prescriptions for 29,072 patients were recently reported. Compared with the postmarketing period before the withdrawal of alosetron, this analysis found a reduction in the absolute numbers of cases of ischemic colitis and complications of constipation, but no significant differences in the incidence rates for either complication (0.95 and 0.36 cases per 1000 patient-years, respectively). All cases were of short duration, with improvement after prompt withdrawal of alosetron under this risk management plan. There were no episodes of mesenteric ischemia, bowel perforation, surgical intervention, need for transfusion, toxic megacolon, or death.
Tegaserod
Tegaserod was the only 5-HT 4 receptor agonist available in North America for the treatment of women with IBS-C until it was voluntarily withdrawn from the market in 2009. Tegaserod is a selective 5-HT 4 receptor partial agonist approved in 2002 for the treatment of women with IBS-C. The efficacy and tolerability of tegaserod in the treatment of women with IBS-C was initially reported in 3 multicenter, double-blind, placebo-controlled trials involving more than 3000 patients from the Western hemisphere. These pivotal clinical trials consistently reported the superiority of tegaserod over placebo at improving global IBS symptoms and individual symptoms of abdominal pain, stool frequency, stool consistency, straining, and bloating. The results led to the FDA’s approval of tegaserod in April 2002 for short-term use in women suffering from IBS-C. The precise reason for the effect of tegaserod on the global symptoms of IBS has remained incompletely defined. In preclinical trials tegaserod has had promotility effects in the small and large intestine and modulation of visceral sensation. There was evidence to suggest tegaserod was also effective in the treatment of women with IBS-M.
The safety and tolerability of tegaserod was reported in multiple large 12-week clinical trials as well as a 12-month safety trial. The most commonly reported side effects included diarrhea, headache, and abdominal pain. Tegaserod was designated as a pregnancy category B drug by the FDA. Of the 31 pregnancies occurring during the clinical trials, there was a nonsignificant increased miscarriage rate of 17% (4/23) in women receiving tegaserod versus 12% (1/8) in the placebo group (not significant). No pregnancy-related complications were reported in the clinical trials. Although there were no reports of ischemic colitis in the clinical trials, 26 cases of possible colonic ischemia were reported during postmarketing surveillance, with an estimated incidence of 7 to 8 cases of colonic ischemia per 100,000 patient-years of tegaserod use. This finding led to the addition of a precaution on tegaserod labeling regarding the risk of colonic ischemia.
On March 30, 2007 the sales and marketing of tegaserod were suspended after a review of the clinical trials database uncovered unexpected increased incidence of cardiovascular and cerebrovascular events in the tegaserod treatment group compared with those taking placebo. A pooled analysis had been performed on clinical trials involving tegaserod. This analysis revealed a total of 13 cardiovascular ischemic events (3 myocardial infarctions, 1 sudden cardiac death, 6 cases of unstable angina, and 3 cerebrovascular accidents) in 11,614 patients treated with tegaserod compared with 1 event in the 7031 patients receiving placebo. Although the event rates were low (0.1% in the tegaserod group compared with 0.01% in the placebo group), the difference was found to be statistically significant ( P = .02). Furthermore, it was reported that all patients experiencing a cardiovascular ischemic event were either at risk or had a history of cardiovascular disease before study enrollment. The significance and explanation for this discrepancy remain unknown. There has been speculation that tegaserod may induce platelet aggregation through actions on 5-HT 4 receptors found on platelets. Several studies have used various patient databases to assess for increased cardiovascular ischemic events in those prescribed tegaserod. A case-control study involving more than 18,000 patients from the Intermountain Healthcare database in Utah identified 12 cardiovascular events in 2603 patients receiving tegaserod versus 54 cardiovascular events in 15,618 matched controls. This finding yielded an incidence rate of 0.46% in tegaserod users versus an incidence rate of 0.35% in controls (odds ratio = 1.27, 95% CI 0.68–2.38, P = .46). Investigators concluded that no association between tegaserod use and cardiovascular events was identified in their study. An observational cohort study was also performed on more than 100,000 patients using the Ingenix Research Database Mart, a US health insurance claims database. In this study researchers found no increase in cardiovascular ischemic events in those taking tegaserod versus matched controls over a period of 6 months (cardiovascular RR = 1.14 [95% CI 0.83–1.56], stroke RR = 1.09 [95% CI 0.49–2.02]). Despite the results of these retrospective database studies, no clear conclusions have been reached regarding the cardiovascular safety profile of tegaserod. Tegaserod remained available in the United States for a short time through a restrictive compassionate program. Tegaserod was completely removed from the market in 2009 and is no longer available in the United States or Canada. There are no plans by the manufacturer to reintroduce tegaserod to the market.
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