An evidence-based review of treatment options for irritable bowel syndrome

Abstract

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits with a duration of at least 3 months. IBS is prevalent, expensive to treat, and is associated with significantly impaired health-related quality of life and reduced productivity. The burden of IBS is staggering, with an estimated 3.6 million physician visits in the United Sates annually and over $20 billion in direct and indirect expenditures. Treatment of IBS traditionally has been limited to an individual symptom-specific approach, but the importance of addressing the emotional context simultaneously is gaining acceptance. This article reviews the current therapies, including probiotics, 5HT₃ antagonists, 5HT₄ agonists, antidepressants, and lubiprostone, with a focused appraisal of the role of rifaximin from a managed care perspective. Emerging agents are also discussed. (Formulary. 2012; 47:319–329.)

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by abdominal pain and altered bowel habits.¹ IBS is further differentiated as constipation predominant (IBS-C), diarrhea predominant (IBS-D) or mixed (IBS-M) subtype. Patients with IBS-M have bowel habits that alternate between diarrhea and constipation, a condition that occasionally is referred to as alternating IBS (IBS-A).² IBS is a prevalent and expensive condition associated with significantly impaired health-related quality of life (HRQOL) and reduced productivity. Based on strict criteria, the worldwide prevalence is estimated to be 7% to 10%.¹ Community-based data indicate that IBS-D and IBS-M subtypes are more prevalent than IBS-C, and switching among subtypes may occur.¹ IBS is 1.5 times more common in women than in men, is more common within low socioeconomic groups, and is more commonly diagnosed in patients younger than 50 years.¹ The burden of IBS is staggering. It is estimated to be the reason for 3.6 million physician visits in the United Sates annually and more than $20 billion in direct and indirect expenditures. The economic burden of IBS stems from its high prevalence and from the disproportionate use of resources during diagnosis and treatment, including sequential diagnostic tests, invasive procedures, and abdominal operations. The burden is especially heavy in patients with severe symptoms and poor HRQOL.¹ This article reviews the current therapies with a focused appraisal of the role of rifaximin from a managed care perspective.

No definite biomarkers or physiologic disturbances associated with IBS have been identified. However, under the biopsychosocial model, IBS is thought to result from a combination of factors, including serotonergic dysregulation, genetic predisposition to inflammation, bacterial overgrowth, altered GI flora, and abnormal pain processing and pain memory.³

In patients with typical IBS symptoms and the absence of alarm features (anemia, weight loss, rectal bleeding, nocturnal symptoms, and a family history of colorectal cancer, inflammatory bowel disease, or celiac sprue), no further diagnostic testing is recommended because the likelihood of uncovering organic disease is low. However, routine serologic screening for celiac sprue should be pursued in patients with IBS-D and IBS-M. Colonoscopic imaging should be performed in patients with IBS and alarm features, to exclude organic diseases, and in those older than 50 years to screen for colorectal cancer.¹

Both psychiatric (eg, depression and anxiety) and physical comorbidities are common in patients with IBS.^4,5 Patients with comorbid GI or other somatic disorders (eg, fibromyalgia, chronic pelvic pain, temporomandibular joint disorder, interstitial cystitis) report more severe IBS symptoms and lower HRQOL and have disproportionally higher use of healthcare resources.^4,5

Treatment of IBS traditionally has been limited to an individual, symptom-specific approach, and the importance of addressing the emotional context simultaneously is gaining acceptance.

GOALS OF TREATMENT

Because there is no cure for IBS, the primary goals of therapy are to alleviate severe symptoms, reduce the number of exacerbations, and identify and treat any comorbidities, including psychosocial factors.⁶ Psychological stress can induce GI symptoms, and patients with IBS who experience stressful events are more likely to have symptom exacerbations; therefore, identifying and addressing psychosocial factors is crucial.^6–8 Patients with mild symptoms may even respond to a positive patient-provider relationship that involves education, reassurance, diet, and lifestyle modifications.^1,6 A positive patient-provider relationship can reduce the number of healthcare visits and improve patient satisfaction.⁹ Cognitive behavioral therapy has been shown to be more effective than education alone in treatment of IBS symptoms among patients without a previously diagnosed psychological condition.¹⁰ In some patients, however, drug therapy may be the best choice. Due to the variability in presentation and symptoms, drug therapy should be individualized to target patient-specific symptoms.

TREATMENT

Diet, Fiber, Laxatives, and Loperamide. Many patients can self-identify certain foods that seem to trigger their symptoms, but specific types of food have not been associated with IBS symptoms.⁶ Although certain foods may exacerbate symptoms in some patients, it is more likely that food intake, in general, is more responsible for the symptoms rather than specific foods.⁶ Patients may self-restrict their diets to avoid symptoms, but patients should be reassured to avoid an overly restrictive diet.⁶ Fiber, a bulking laxative, may play a role in treatment of patients with IBS-C. Ford et al. conducted a systematic review and meta-analysis of use of fiber for patients with IBS.¹¹ Twelve trials were identified involving a total of 591 patients. Although fiber can increase stool frequency and consistency, it showed no benefit over placebo in alleviating symptoms or abdominal pain in patients with IBS.^11,12 There are little data to support its use in patients with IBS-D or IBS-M.^1,6 Fiber supplements are also poorly tolerated, with adverse effects that include bloating, abdominal distention, and flatulence.^1,11 Fiber should be used in patients with IBS-C to help increase stool frequency and consistency, but it will not improve abdominal pain, bloating, or other symptoms.¹² Polyethylene glycol can be used to increase bowel movement frequency and stool consistency in patients with IBS-C, but it is not effective at reducing abdominal pain or other IBS symptoms.¹³

Data are limited with regard to the use of loperamide, a poorly absorbed opioid analog that acts as an antimotility agent with antisecretory properties in IBS.¹⁴ Loperamide has been demonstrated to be effective in treating watery diarrhea, so it would be expected to improve stool consistency and frequency in patients with IBS-D.¹⁵ One small trial in patients with IBS-D reported improved stool consistency (P<.002), pain (P<.05), and urgency (P<.02).¹⁶ ACG guidelines suggest the use of loperamide for loose stools, but the recommendation is not based on strong evidence.¹

Antispasmodics. Hyoscyamine and dicyclomine are the only 2 antispasmodic agents available in the United States. Hyoscyamine is the levo-isomer of atropine, a belladonna alkaloid that acts by competitively and reversibly inhibiting the acetylcholine receptor on smooth muscle, inhibiting contractions and GI motility.^14,17 Hyoscyamine has not been approved by FDA as a safe and effective drug, as it was marketed before the 1962 legislation requiring efficacy data before approval. Dicyclomine is a weak muscarinic receptor antagonist with nonspecific direct spasmolytic effects on the GI tract.¹⁴ There is little literature to support the use of antispasmodics for use in IBS. A meta-analysis of the use of antispasmodics identified 3 clinical trials of hyoscine (also known as scopolamine), which had end points of global symptom improvement (not specific symptoms such as pain or bloating) and did not differentiate the subtypes of IBS.¹¹ The antispasmodics commonly cause anticholinergic adverse effects that include dry mouth, dry eyes, constipation, dizziness, and urinary retention, although the meta-analysis documented antispasmodics to be generally well tolerated.^11,17 The ACG IBS guidelines recommend the use of hyoscine for short-term relief of abdominal pain or discomfort, although strong data are lacking and the formulations studied are not available in the United States. The guidelines do not take a position on the use of dicyclomine due to lack of evidence.¹

Probiotics. Probiotics are considered medical foods in the United States, and they contain live bacterial cultures, most commonly from the Lactobacillus or Bifidobacterium genus.¹⁸ Interest in the use of probiotics for treatment of IBS spawns from the bacterial overgrowth theory, as well as the lack of strong, widely effective drug therapy options for use in patients with IBS. The theorized mechanism for probiotics' effectiveness is that indigenous microflora create a competitive barrier to invading organisms.¹⁸ When the host becomes stressed through illness, diet, or other factors such as antibiotic use, the barrier may be compromised, which allows pathogens to colonize the intestinal lumen.¹⁸

A meta-analysis by Hoveyda et al. of 14 probiotic trials documented a small improvement in overall IBS symptoms; however, effects on individual symptoms such as abdominal pain, flatulence, and bloating were conflicting. Most trials reported no adverse effects, and no trial reported any severe reactions.¹⁸ Another systematic review of probiotics in IBS included 18 trials and analyzed data on both efficacy and by strain of bacteria used.¹⁹ Nine of the trials used a combination of bacteria; other trials used Lactobacillus (6), Bifidobacterium (3), and Streptococcus (1). Probiotics in aggregate had a statistically significant effect over placebo with respect to improving global IBS symptoms, abdominal pain, and flatulence, but not bloating.¹⁹ The ACG guidelines give probiotics a weak recommendation due to the lack of long-term data, although their adverse-effect profile is favorable.¹

Serotonin Modulators: 5HT₃ antagonists and 5HT₄ agonists. Alosetron is a 5HT₃ receptor antagonist that is FDA approved for use in women who have diarrhea-predominant IBS symptoms, and it is the only serotonin modulator available in the United States. 5HT₃ receptors are ligand-gated ion channels that affect neuronal depolarization and play a role in visceral pain, GI transit, and intestinal secretions.²⁰ By inhibiting these receptors, both pain and GI motor function are decreased. A meta-analysis documented that alosetron was superior to placebo in both global IBS symptoms and individual symptoms of urgency and abdominal pain, with a number needed to treat (NNT) of 8.²¹ However, alosetron was also found to be associated with severe cases of constipation and ischemic colitis, which led to its withdrawal from the market in 2000. It was relaunched in 2002 for use in women with IBS-D who have failed conventional treatment, with mandatory enrollment in a risk and evaluation mitigation strategy (REMS) program administered by FDA and the manufacturer. Specifically, the REMS program requires that the medication guide and the risks of alosetron be discussed with the patient. The patient must read and sign the patient acknowledgement form before the written prescription, with special sticker affixed, is issued. Although alosetron has been shown to be more effective than placebo, the risk of serious adverse effects limits its use. The ACG guidelines recommend alosetron be used only in women with IBS-D who have failed conventional therapy, which is consistent with FDA and manufacturer labeling.^1,20

Tegaserod, a 5HT₄ agonist, was available as an effective treatment for women with IBS-C but was withdrawn from the market in 2007 due to an increased risk of cardiovascular events. When all patients in tegaserod trials were aggregated, it was determined that 0.11% of patients receiving tegaserod had new incidence of stroke, myocardial infarction, or unstable angina compared with 0.01% on the placebo arms.²² Tegaserod is available only through the manufacturer and only in extenuating and emergency situations that are life-threatening or require hospitalization.²³ There are no widely available 5HT₄ agonists available in the United States; however, renzapride and cisapride are available in Europe, and several agents are undergoing clinical development.

Lubiprostone. Lubiprostone is a selective C-2 chloride channel activator that increases excretion of chloride ions into the intestinal lumen. The higher concentration of chloride increases the osmotic gradient, resulting in passive water flow into the lumen.²⁴ Lubiprostone is FDA approved for treatment of symptoms in female adults with IBS-C at a dose of 8 µg twice daily. Limiting the IBS indication for lubiprostone to women was based on the small number of men in IBS trials (8.4% of patients). Approval of lubiprostone for IBS-C was based on a large trial by Drossman et al., in which 1,171 patients were randomly assigned to placebo or lubiprostone 8 µg twice daily.²⁵ The primary outcome of this trial was the difference between lubiprostone and placebo for global IBS symptoms. Secondary end points were the individual symptoms of abdominal pain, bloating, and constipation severity. Patients receiving lubiprostone were more likely to respond to treatment compared with placebo (17.9% vs 10.1%), although overall response rates were not high.²⁵ Mean improvement from baseline was also significantly higher with lubiprostone compared with placebo for abdominal pain and bloating (P=.028 and P=.044, respectively).²⁵ Although response rates were not particularly impressive, lubiprostone was effective at increasing the consistency and frequency of bowel movements and reducing the IBS symptoms of abdominal pain and bloating. Patients were treated for 12 weeks, after which continuation of therapy was not shown to be effective, and discontinuation of therapy was not associated with rebound of symptoms.²⁵ A 12-week course of lubiprostone is an option in women with IBS-C; however, because of the high cost and low overall response rates, bulking agents or polyethylene glycol (which have shown significant efficacy in increasing bowel movements and are available without prescription) may be more cost-effective options.^11–13

Antidepressants. Antidepressants have long been used as a treatment for IBS because stress and psychosocial factors can play a large role in IBS symptoms.^7,8 There is a high incidence of psychiatric comorbidity, most commonly depression and anxiety, in patients with IBS.⁵ Serotonin plays a key role in regulation of communication between the brain and the enteric nervous system that innervates the intestines.²⁶ The vast majority of serotonin in the body is contained in the enteric nervous system, and it has been shown that serotonin can transmit pain and bloating sensations as well as affect intestinal transit and secretions.^26,27 Antidepressants also can play a role in nociception in the central nervous system, and there is evidence that tricyclic antidepressants (TCAs) are stronger than selective serotonin reuptake inhibitors (SSRIs).¹ This leads to the theory that through multiple mechanisms, antidepressants could be useful in treatment of abdominal pain.

Both TCAs and SSRIs have been studied as potential treatments for IBS symptoms. Drossman et al. analyzed the effect of the desipramine 150 mg a day versus placebo in 431 patients who did not have a previously diagnosed psychiatric condition.¹⁰ The primary outcome was global patient satisfaction. In the per-protocol analysis, this study did not demonstrate a significant difference between desipramine and placebo; however, the post-hoc intent-to-treat analysis, which excluded patients with nondetectable blood levels of the study drug, showed a significant difference. In this study, there was a 19% drop-out rate in the treatment group due to adverse effects compared with a 5% drop-out rate in the placebo group. The most commonly reported adverse effects were classic anticholinergic symptoms, with 48% of patients reporting dry mouth, 32% reporting sleep disturbance, and 26% reporting constipation. Patients who dropped out reported an average of 3.5 different reactions.¹⁰ A small trial (N=54) demonstrated that a low dose of amitriptyline (10 mg/day) was more effective than placebo at reducing episodes of loose stools (P<.05), feelings of incomplete defecation (P<.05) and complete resolution of all symptoms (P=.01), with no significant difference in adverse effects.²⁹ Psychiatric comorbidities were not evaluated in this study. A meta-analysis of studies involving 12 antidepressants (of which 10 were TCAs and 2 were SSRIs) documented significant improvement in symptoms and pain ratings (NNT, 3.2).³⁰

Following the serotonin theory, SSRIs have also been studied as treatment for IBS, although evidence has been contradictory. In the largest trial of SSRIs for IBS, 257 patients were randomly assigned to receive paroxetine, psychotherapy, or usual care.³¹ Both psychotherapy and paroxetine improved abdominal pain and HRQOL. At 1-year follow up, psychotherapy was associated with reduction in overall healthcare costs, whereas paroxetine therapy was not. In addition, there was a 50% drop-out rate in the paroxetine group.³¹ Duloxetine has also been studied, but only small open-label trials have been conducted.²⁶ Overall, the number of trials of SSRIs for treatment of IBS is limited, and few results have shown statistical significance.

The ACG guidelines suggest use of antidepressants when peripheral agents have failed, as antidepressants improve global IBS symptoms.¹ There is more evidence with TCAs; however, adverse effects, specifically anticholinergic effects, are common and less safe in the elderly population. TCAs may be more beneficial in patients with IBS-D because of their anticholinergic effects, and because of their prokinetic effects, SSRIs may play a role in patients with IBS-C; however, this has not been confirmed by clinical trials.¹

Linaclotide, a guanylate cyclase C receptor agonist, has been studied for IBS-C and has shown efficacy over placebo in several large phase 3 trials. It is similar to lubiprostone in that it increases chloride and bicarbonate excretion into the intestinal lumen. In 2 identical 12-week trials (N=642 and N=630), the primary end point was an increase in bowel movements to at least 3 per week and an increase from baseline of at least 1 bowel movement per week during the 12-week trials. The end point was met in 19.4% and 21.3% of patients receiving the higher dose of linaclotide in each trial, as compared with 3.3% and 6.0%, respectively, of patients on the placebo arms (P<.01 for both trials). In the linaclotide groups, diarrhea led 4.2% of patients to drop out. As in trials of other drugs targeting constipation, nearly 90% of participants were women.³³ Linaclotide was approved by FDA on August 30, 2012, to treat IBS-C and chronic idiopathic constipation (CIC) in both men and women. Standard dosing for linaclotide in IBS-C is 290 µg 30 minutes before the first meal of the day and 145 µg for CIC. Linaclotide does carry a black box warning that the drug should be avoided in patients aged 17 years or younger and is contraindicated in pediatric patients up to 6 years of age. Linaclotide is expected to be available to patients in the fourth quarter of 2012.

RIFAXIMIN

Rifaximin is a structural analog of rifampin that is poorly absorbed (<0.4%), resulting in the bulk of the dose being contained in the intestinal lumen.^34,35 It has a broad range of activity, covering anaerobes and gram-positive and gram-negative organisms. Rifaximin is especially effective at reducing bacterial overgrowth in the small intestine.³⁴ Proposed mechanisms of action for rifaximin in IBS include elimination of intestinal bacteria that produce products that induce IBS symptoms; reduction of local mucosal interaction with the bacteria, resulting in less irritation; or both, which aligns with the small intestinal bacterial overgrowth (SIBO) theory.³⁶ Compared with other treatments for IBS, the use of rifaximin is well studied in IBS-D.

There have been 4 trials to analyze the use of rifaximin in patients with IBS. The first trial involved 87 patients with IBS-D according to ROME I criteria.³⁷ Patients were randomly assigned to rifaximin 400 mg 3 times a day for 10 days. The primary outcome was global improvement in IBS symptoms, and secondary outcomes were improvement in individual symptoms of IBS. Responses were obtained via weekly patient questionnaires at baseline, during treatment, and for 10 weeks after treatment. On the questionnaires, patients were asked to measure individual symptoms of abdominal pain, diarrhea, constipation, bloating, urgency, incomplete evacuation, and gas on a visual analog scale ranging from zero to 100 mm. For the primary outcomes, patients in the rifaximin group reported an average improvement of 36.4% compared with 21% in the placebo group (P=.02).³⁷ For the secondary outcomes, there was a statistically significant difference between groups for bloating, but there was no difference in abdominal pain, diarrhea, or constipation. Of note, there was a considerably high placebo response in this study.

Sharara et al. assessed the effect of rifaximin on 124 patients reporting gas-related symptoms.³⁸ Patients were randomly assigned to rifaximin 400 mg or placebo twice daily for 10 days. Fifty-seven percent of patients met ROME II criteria for IBS. The primary end point was the percentage of patients taking the study drug and reporting any symptom improvement at the conclusion of treatment and at 10 days of follow-up. The secondary end point was individual symptoms scored on a 4-point scale. Patients with IBS were analyzed separately from those without IBS. At the conclusion of treatment, 40.5% of patients with IBS in the rifaximin group reported symptom improvement compared with 18.2% of patients in the placebo group (P=.04). At 10 days, patients with IBS reported a 27% response rate compared with 9.1% in the placebo group (P=.05). There was also a statistically significant decrease in bloating from baseline in the rifaximin group (P=.01), but no other secondary measures reached statistical significance. This trial took the approach of recording response at the conclusion of treatment as well as at 10 days after treatment, and the considerable 13% decrease in patient response rate only 10 days after treatment ended should cause one to question the long-term effectiveness of rifaximin in the treatment of IBS.

These 2 early trials served as the background for the TARGET trials, 2 large scale, identical, randomized, double-blind, placebo-controlled trials.³⁶ In these trials, patients were randomly assigned to rifaximin 550 mg or placebo 3 times a day for 14 days. The primary end point was the percentage of patients who reported adequate relief of IBS symptoms, with adequate relief defined as relief of symptoms for at least 2 of the first 4 weeks after treatment. Secondary end points included daily assessments of individual and global symptoms on a 7-point scale, with adequate relief defined as zero (not at all) or 1 (hardly) for at least 4 of the 7 days or zero (not at all), 1 (hardly), or 2 (somewhat) on every day in a given week for at least 2 of 4 weeks during the month.³⁶ These trials also evaluated weekly and daily bloating, abdominal pain, and stool consistency with the same relief definitions already mentioned. During the primary efficacy phase (the first 4 weeks after treatment), patients reached the primary end point 40.7% of the time in the rifaximin group compared with 31.7% of the time in the placebo group (P<.001).³⁶ There was also a statistically significant difference in the secondary outcomes of global daily symptoms (P<.001), daily bloating (P<.001), daily abdominal pain (P=.003), and daily stool consistency (P<.001).³⁶ Consistent with the earlier rifaximin trials, efficacy decreased as time after the study increased. Although no significant between-group differences, with respect to relief, were observed during all 3 months, response rate dropped in parallel in both treatment and placebo groups.³⁶

To evaluate the efficacy of this trial, the primary end point must be kept in mind. Adequate relief of symptoms was defined as relief for at least 2 of the first 4 weeks after treatment (half of the time), and scores were assessed weekly as patients were asked to recall their symptoms during the past week and sum them up in a yes-or-no response to the question, "In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you in the past 7 days had adequate relief of your IBS symptoms?"³⁶ In summary, patients in the TARGET trials reported adequate relief of symptoms (defined as at least 2 of 4 weeks after treatment) 40.7% of the time in the rifaximin group and 31.7% of the time in the placebo group. The daily symptom analysis had similar results. Although this end point of symptom improvement 50% of the time is recommended by the ROME III committee, the overall efficacy of rifaximin was not impressive in comparison with placebo, although it was statistically significant. ^36,39 The placebo effect (31.7% of patients) was more than 3 times the absolute difference (9%) in efficacy between the treatment and control groups. The large placebo effect in patients with IBS is not surprising, as patients who received an open-label placebo had significantly better symptom relief than the no-treatment controls.⁴⁰ This may speak to the psychological factors of IBS. Additionally, patients were not assessed for use of antidepressants, which could be a potential confounder because antidepressants have shown some efficacy in treating IBS symptoms.²⁶ It should also be noted that the TARGET trials were funded by the manufacturer of rifaximin, and all of the named investigators reported either being direct employees of or having received honoraria from the manufacturer, representing a potential conflict of interest.

Considering the declining effect of rifaximin over time, as observed in clinical trials, and the potential for antibiotic resistance with repeated use, there is concern regarding the effectiveness of rifaximin retreatment in patients with IBS. Pimentel et al. conducted a chart review to analyze the efficacy of rifaximin in retreated patients.⁴¹ Review of 187 charts of nonconstipated patients with IBS found that 169 received initial treatment with rifaximin. Of those, 71 patients had been retreated with rifaximin. Forty-eight were subsequently treated a third time, 22 patients had a fourth treatment, 7 had a fifth treatment, and 4 patients had a sixth treatment. Response (either good or no response) was evaluated subjectively by the investigators from chart notes; patient declaration of overall improvement in IBS symptoms was sought. It was determined that 76% of patients responded to the first treatment, 79% responded to a second treatment, 78% responded to a third treatment, 67% responded to a fourth treatment, and 75% responded to a fifth treatment. The authors noted no significant decrease in efficacy with the number of retreatments. They also analyzed the duration between treatments, which was a minimum median of 4 months in all retreatments (although there was great variability). There was no observed shortening of the duration of the effect.

On the basis of this chart review, by the lack of decreased response rates, development of resistance to rifaximin seemed to be minimal. However, recurrence of symptoms after treatment and retreatment with rifaximin is concerning. Of the 169 patients initially treated with rifaximin (including those with a good response), 42% received retreatment. Of those patients, 68% required a third course; 46% of patients receiving a third course required a fourth; 41% of patients receiving a fourth course required a fifth; and 45% of patients receiving a fifth course required a sixth.⁴¹ In addition, this review does not take into account other, concurrent treatments for IBS, with the exception of other antibiotics. Although there is no evidence for the development of resistance in gut flora, in a small trial, intake of oral rifaximin lead to resistance of skin staphylococci to rifampin.⁴² It was postulated that the close structural relationship between rifaximin and rifampin, and the subtherapeutic systemic absorption, caused an increase in rifampin-resistant staphylococci isolates. The authors caution against use of rifaximin in patients at risk for such infections.

Although the dosing of rifaximin in IBS has varied greatly in trials, the most studied and most effective dose was 550 mg 3 times daily. In the TARGET trials, patients in the rifaximin group were slightly more likely to experience nausea, vomiting, and diarrhea. The rifaximin group was less likely to experience abdominal pain and flatulence, which also can be symptoms of the disease.³⁶

Role in Therapy. The place in therapy for rifaximin is unclear. Most trials were performed in patients with IBS-D, and rifaximin consistently was shown to be better than placebo for treatment of global IBS symptoms and bloating. The 2009 ACG IBS guidelines recommend a short-term course of rifaximin as an option for nonconstipated patients with bloating symptoms.¹ Although the guidelines were published before the TARGET trials, the ACG cited concerns regarding durability of the rifaximin effect in patients with a chronic, recurrent disease such as IBS, as well as the potential for microbial resistance with continuous or intermittent use of antibiotics; these issues were not addressed by the TARGET study group. On March 7, 2011, FDA denied the supplemental new drug application for rifaximin for the proposed indication of treatment of IBS-D.⁴³ Reasons cited by the FDA Gastrointestinal Drugs Advisory Committee include lack of data to support the long-term safety and effectiveness of nonabsorbable antibiotics for the management of IBS symptoms; that the SIBO theory of IBS is not fully developed and does not meet the basic epidemiological criteria of causality; and concerns regarding the potential for development of antibiotic resistance.⁴⁴ On February 21, 2012, the manufacturer of rifaximin announced the initiation of TARGET 3, a phase 3 study to assess the repeat treatment efficacy and safety of rifaximin for IBS-D.⁴⁵ Due to lack of impressive improvement in symptoms compared with placebo, high cost (up to an average wholesale price of $1,000 for a 14-day treatment course), and lack of long-term durability of response and unknown long-term administration schedule, use of rifaximin should not be encouraged for patients with IBS-D at this time.⁴⁶

FORMULARY CONSIDERATIONS

The cost of most of the older agents used to treat IBS, such as loperamide, hyoscyamine, and dicyclomine, typically is covered by managed care organizations. Coverage of probiotics may prove to be challenging because they are considered a medical food, which typically is excluded from benefit. Probiotics are available in various combinations and products, and they lack standardized dosing. Lubiprostone can be considered after treatment with polyethylene glycol has failed, but patients should be monitored for response beyond 12 weeks. Until long-term safety and effectiveness data are available, we do not endorse use of rifaximin in patients with IBS-D. Finally, the serious adverse effects associated with alosetron render it the last resort for women with IBS-D, and prescribing should be restricted to gastroenterologists registered in the REMS program.

Dr Szkotak is a clinical pharmacist, Health Plan of San Joaquin, French Camp, Calif. Dr Shek is professor and vice chair of pharmacy practice, University of the Pacific, Stockton, Calif., and director of pharmacy and residency program, Health Plan of San Joaquin, French Camp, Calif.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

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