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Postgrad Med J 2001;77:82-88 ( February )
Review

Non-steroidal anti-inflammatory drugs and gastrointestinal damage - problems and solutions

R I Russell

University of Glasgow and Department of Gastroenterology, Royal Infirmary, Glasgow

Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for many years for analgesic, anti-inflammatory, and more recently in the case of aspirin, antithrombotic purposes. The use of NSAIDs continues to increase; over 22 million prescriptions are written every year in the UK, and over 70 million in the US. These figures underestimate their full use as aspirin and other NSAIDs are widely available as "over-the-counter" preparations.

The use of these drugs can also be expected to increase in the years to come, partly because of the increasing age of the population and partly because of possible new and developing indications, particularly in vascular disease and cancer prevention. It is therefore of importance to assess the safety and side effects of NSAIDs, and to consider how their safety may be improved. It has long been known that NSAIDs may have a range of side effects, of which the commonest are gastrointestinal.

It is the purpose of this paper to examine the nature, range, and causation of the gastrointestinal side effects associated with the use of NSAIDs, and to consider how these may be reduced or modified. NSAIDs may also be associated with other adverse effects, although these are much rarer than gastrointestinal problems; these include nephropathies, skin rashes, and hepatitis. NSAIDs may also interact with other drugs such as antihyperglycaemic or antihypertensive agents.

NSAIDs may be associated with many gastrointestinal problems, ranging from mild to severe dyspeptic symptoms, the development of gastric or duodenal ulceration, haemorrhage or perforation, and other events which may lead to hospitalisation or death.

Endoscopic studies have shown a prevalence rate of 14%-25% of gastric and duodenal ulcers in NSAID users,1 although the difficulty of having accurate control groups makes exact figures difficult to obtain. Although endoscopic studies tend to show more gastric than duodenal ulcers associated with NSAID use, patients presenting with gastrointestinal bleeding on NSAIDs may have a similar frequency of gastric and duodenal ulceration. Dyspeptic symptoms occur in up to 60% of patients taking NSAIDs and there is a poor correlation between symptoms and endoscopically proved lesions; up to 50% of endoscopically confirmed ulcers associated with NSAIDs are asymptomatic.

It has been estimated that the individual risk of hospitalisation with gastrointestinal complications of NSAIDs is between 1/50 and 1/150 patient years.2 The risk of an upper gastrointestinal bleed is between 1/100 and 1/500 patient years; the risk of a gastrointestinal related death is between 1/1000 and 1/5000 patient years.

The risk of serious ulcer complications in patients on NSAIDs has been calculated in various studies, the relative risk (RR) for a serious gastrointestinal event overall being reported as 2.74 in a large meta-analysis, upper gastrointestinal bleeding RR 3.09, perforation RR 5.93, and ulcer related death RR 7.62.3

NSAIDs may have adverse effects in all parts of the gastrointestinal tract, not only the stomach or duodenum; the oesophagus, small intestine and colon may also be affected.

A recent necropsy study of 713 patients has been reported, of whom 244 had NSAIDs prescribed during the six months before death and 464 had not; death in all patients was unrelated to NSAID use. Ulcers of the stomach or duodenum were found in 21.7% of patients on NSAIDs and 12.3% of those not on NSAIDs (p<0.001), and small intestinal ulceration was found in 8.4% of NSAID users and 0.6% of patients not on NSAIDs (p<0.001).4 Damage to the small intestine in NSAID users has also been demonstrated at enteroscopy. Patients with small intestinal damage associated with chronic NSAID use may present with chronic iron deficiency anaemia or hypoalbuminaemia due to blood or protein loss, and may develop overt bleeding, perforation, or strictures.

In the oesophagus, chronic NSAID use may be associated, although rarely, with oesophagitis, ulceration, or stricture formation.5

In the large bowel, NSAID use may lead to the development of a non-specific colitis (with abdominal discomfort, bloody diarrhoea, and weight loss). NSAIDs may also cause an exacerbation of ulcerative colitis or Crohn's disease, if the associated arthropathy in inflammatory bowel disease is treated with NSAIDs.6 7

High risk factors for NSAID related gastrointestinal damage include older age group (especially over 70), previous history of peptic ulceration, and probably the first three months of NSAID treatment. Other high risk factors are smoking, underlying respiratory or cardiovascular disease, and concomitant drug use, particularly corticosteroids, aspirin, and anticoagulants (box 2).8 Perioperative use is also a risk factor. Individual NSAIDs incurring highest risk include azapropazone, ketoprofen and piroxicam, and those with least risk include ibuprofen, diclofenac, and etodolac. Higher doses are associated with increased risk and also the use of more than one NSAID. There is also an increased risk of gastrointestinal complications with relatively low dose prophylactic aspirin, which is widely used nowadays.9 There is debate on the possible interaction and increased risk of Helicobacter pylori causing ulceration with NSAIDs, and this will be discussed in a later section. The balance of physiological association and clinical evidence tends to support the possibility of some interaction occurring, especially in those patients at high risk and possibly in those who have bled. Well planned, prospective controlled studies are required to provide more information on this with respect to different types and doses of NSAIDs, different forms and strains of H pylori, and different types of erosions and ulcers.

NSAIDs interfere with the cyclo-oxygenase (COX) pathways which lead to the production of prostanoids (prostaglandins, prostacycline, and thromboxane). This interferes with mucosal protection by reducing the effectiveness of the mucus-bicarbonate barrier; gastric acid, and possibly also pepsin, are thus more likely to cause damage. The fact that most NSAIDs are also weak acids may also be a contributory factor.

It is now known that COX exists as two separate isoforms, COX-1 and COX-2, which differ markedly in their tissue expression and regulation.10-12 COX-1 is constitutively expressed in most tissues, including the stomach, duodenum, platelets, and kidneys; COX-1 plays a key part in the production of prostaglandins which regulate important physiological processes such as gastrointestinal cytoprotection (maintaining an effective mucus-bicarbonate barrier, submucosal blood flow, quicker and more effective mucosal adaptation to initial tissue damage, and more rapid recovery when such damage occurs). It is also involved in vascular homoeostasis and the maintenance of good renal function and in maintaining normal physiological functions in many other cells. This is an important "housekeeping" role. COX-2, on the other hand, is normally undetectable in most tissues, but it can be induced rapidly, and in large quantitiesto 200-300-foldby cytokines, growth factors, and hormones in the presence of inflammation and other pathological processes (box 3). Platelets appear to contain only COX-1.

Most conventional NSAIDs are non-selective in their COX inhibition, exerting their anti-inflammatory effects through the inhibition of COX-2, but having adverse effects (such as gastrointestinal mucosal damage and nephrotoxicity) primarily due to inhibition of COX-1. Some existing and longstanding NSAIDs, such as etodolac, a known safer NSAID with respect to gastrointestinal damage and which is known to have reduced adverse effects on mucosal prostaglandins, has been subsequently found to have a degree of COX-2 inhibition selectivity.

Currently, a range of new and specific COX-2 selective inhibitor NSAIDs have been, and are being further developed with the hope of reducing possible gastrointestinal side effects; the preliminary clinical results, as we shall see later, are encouraging. One of these, rofecoxib, is now available in this country.

HEALING OF NSAID RELATED ULCERS
There is evidence from both animal and human studies that NSAIDs retard the healing of gastric ulcers. Although it is frequently stated that a first step if gastrointestinal problems occur with NSAIDs is to withdraw NSAIDs or reduce the dose, in practical terms this is generally unrealistic, especially when there is a major inflammatory condition such as rheumatoid arthritis.

It may be possible to reduce the dose of NSAIDs in some individuals. It is also appropriate to try alternative conventional NSAIDs as there is a wide variability in responses to individual drugs. Some NSAIDs are more likely than others to cause gastrointestinal problems; those associated with greatest risk include azapropazone, ketoprofen, and piroxicam.

H2-receptor antagonists, especially in high doses, do heal NSAID related ulcers while NSAIDs are continued,13 but proton pump inhibitors may be expected to be more effective, and have now been shown to be so. Omeprazole has been shown to heal gastric ulcers faster than ranitidine.14 In two large studies comparing omeprazole (20 mg or 40 mg daily) with misoprostol (200 �g four times a day), the proton pump inhibitors healed significantly more gastric and duodenal ulcers than ranitidine or misoprostol.

No extra benefit was gained from using omeprazole at the higher dose.15 16

PREVENTION OF NSAID RELATED GASTROINTESTINAL PROBLEMS
The lowest dose of the safest NSAID which is effective in individual patients should be used if possible.

Avoidance or reduction of risk factors may be possible in some patients, such as smoking, use in patients with a past history of dyspeptic problems or peptic ulcer, perioperative use, or cotherapy with other drugs such as corticosteroids, anticoagulants, or aspirin. Advice should be given about "over-the-counter" preparations.

There will inevitably be patients in whom additional requirements will be necessary, such as those who continue to require high dose NSAIDs or in those with risk factors which cannot be modified.

In such patients there has been much interest in recent years in attempting to reduce risk by the coprescription with NSAIDs of drugs which may improve mucosal protection (the prostaglandin analogue misoprostol) or reduce gastric acid (H2-receptor antagonists or proton pump inhibitors). More recently, newer NSAIDsselective COX-2 inhibitorsoffer the prospect of greater gastrointestinal safety.

PROSTAGLANDINS
The prostaglandin analogue misoprostol has shown a reduction in ulceration compared with placebo ranging from 50% to 90% over 3-12 months; the dose used initially was 200 �g four times a day and subsequently 400-600 �g per day. Protection has been generally similar for both gastric and duodenal ulcers.17 18 A large blinded study of misoprostol compared with placebo (the "MUCOSA" study) reported a significant reduction of gastrointestinal bleeding and perforation with misoprostol at 800 �g daily.19 In this study, 27% of patients withdrew because of side effects, principally diarrhoea. Diarrhoea remains a problem for many patients with this preparation. Misoprostol has also been combined with a standard NSAID, diclofenac (arthrotec), and this has proved popular with a number of patients.

Theoretically, prostaglandin analogues have an advantage over acid suppressants in that they should provide mucosal protection throughout the gastrointestinal tract.

ACID SUPPRESSION
As gastric acid is a factor in causing gastroduodenal damage associated with NSAID use, reduction of gastric acid by the coprescription of acid suppressant drugs has been studied.

The use of H2-receptor antagonists in standard doses for the prevention of NSAID associated ulcers has shown some protection against duodenal ulcers.20 and the use of high dose famotidine (40 mg twice a day) has been shown to significantly reduce the cumulative incidence of both gastric and duodenal ulcers in patients with rheumatoid arthritis on long term NSAID therapy.21

Proton pump inhibitors cause more effective acid suppression than H2-receptor antagonists, and several randomised controlled trials lasting 3-6 months using omeprazole 20 mg daily have shown efficacy in preventing both gastric and duodenal ulcers while continuing long term NSAIDs, with about a 75%-80% reduction in ulcers compared with placebo.15 16 22

The proton pump inhibitors were shown in two of these studies to provide more effective protection than ranitidine (150 mg twice a day) or misoprostol (200 �g twice a day).

Omeprazole 20 mg daily has also been shown to protect against bleeding from ulcers in long term NSAID users.23

NEWER NSAIDS: COX-2 SPECIFIC INHIBITORS
The search for safer NSAIDs has recently focused on the development of preferential or selective COX-2 inhibitors. These compounds aim to exploit the belief that COX-1 is associated predominantly with the production of protective prostaglandins and has a "housekeeping" role, whereas COX-2 is induced in inflammation and associated with inflammatory processes. The development of these concepts has been recently reviewed.24

The definition of, and screening for, COX-2 selectivity has given rise to much debate, involving a variety of suggested systems that includes purified recombinant enzyme, transfected cells, and whole blood assays. The latter method may be the most appropriate at present, but all drugs suggested as COX-2 specific inhibitors require to be shown to have no significant inhibition of gastric mucosal prostaglandins, in addition to a good clinical safety profile and effectiveness.

Conventional longstanding NSAIDs have been found to vary with respect to their relative COX-1 to COX-2 inhibition capacity, but all have a significant effect on COX-1, thus interfering with gastric mucosal protection.

One NSAID, etodolac, which has been used widely for some years, has been shown in several studies to be clinically effective and have reduced gastrointestinal toxicity, demonstrated endoscopically and clinically; these studies also found no significant reduction of gastric mucosal prostaglandins compared with naproxen.25 26 Etodolac has since been found to have some degree of COX-2 selectivity.27

Other drugs with probable relative COX-2 selectivity include nabumetone, nimesulide, and meloxicam.24

Newer more specific COX-2 inhibitors currently under study include celecoxib and rofecoxib (the latter now being available in this country). Preliminary results of studies with these drugs indicate effectiveness and a good gastrointestinal safety profile. Celecoxib (25-400 mg twice a day) was associated with a significantly reduced incidence of adverse upper gastrointestinal problems including ulcers, gastrointestinal bleeding, and perforation in patients with osteoarthritis and rheumatoid arthritis compared with standard NSAIDs.28 Rofecoxib (12.5-25 mg a day) demonstrated a lower incidence of endoscopic ulcers compared with ibuprofen in patients with osteoarthritis in a multicentre study over 24 weeks.29 Rofecoxib has also shown reduced occurrence of ulcers, perforations, and gastrointestinal bleeding.

COX-2 specific inhibitors have little, if any, effect on platelet function, and may therefore be associated with a marked reduction of gastrointestinal bleeding associated with NSAID use.

These studies are promising and more data are awaited. The long term safety of these drugs remains to be established, particularly with respect to the kidney and in the possible, although less likely, impairment of healing of pre-existing peptic ulcers. It is also theoretically possible that COX-2 inhibitors may have a benefit in preventing colon cancer and possibly also in Alzheimer's disease. COX-2 inhibitors will not be effective in cardiovascular protection unlike aspirin, as the protective effects provided by aspirin are mediated through COX-1.

LOW DOSE ASPIRIN
Aspirin is widely used in low doses in patients with suspected or definite vascular disease. Aspirin is a major cause of upper gastrointestinal problems, and is a frequent cause of upper gastrointestinal bleeding. Even in low doses (75 mg daily), aspirin has effects on platelet levels of COX, which it acetylates and to which it binds irreversibly, thus impairing platelet function. This causes changes in the bleeding time, platelet aggregation, and the synthesis of thromboxane, which remain for the life of the platelet. The damage is worse with longer acting NSAIDs with long half lives and an extensive enterohepatic circulation, such as piroxicam.

With increasing use, aspirin is now a major cause of upper gastrointestinal problems, and in particular, upper gastrointestinal bleeding. One recent study reported an overall odds ratio of 3.2 (95% confidence interval (CI) 2.3 to 4.4) in gastrointestinal bleeding for daily aspirin use of at least one month, compared with 3.8 (95% CI 3.1 to 4.5) for non-aspirin NSAID use.9 This can be expected to increase with increasing use of low dose aspirin, especially common in older age groups.

Platelets contain only COX-1; thus only drugs such as aspirin and those NSAIDs which inhibit COX-1 will inhibit platelet function. COX-1 sparing NSAIDs such as etodolac, nabumetone, nimesulide, meloxicam, are likely to have little effect on platelet dysfunction. The highly specific COX-2 inhibitors (celecoxib, rofecoxib), have almost no effect on platelet function, and are likely, as mentioned previously, to lead to marked reductions in upper gastrointestinal bleeding. However, if used with low dose aspirin, there is likely to be a loss of benefit.

COX-2 specific inhibitors will not be helpful in vascular disease, and cannot be considered as a replacement in this respect for low dose aspirin.

A new antiplatelet agent, clopidrogel may be safer than aspirin, although more costly. Clopidrogel requires to be further assessed, but may be helpful in patients with peripheral artery disease, and in stroke or myocardial infarction in whom aspirin is contraindicated, or in whom aspirin fails to achieve the required therapeutic effect.

WHAT TO DO ABOUT H PYLORI?
H pylori and NSAIDs are the two most common causes of peptic ulceration.

The possible interactions of H pylori and NSAIDs have led to much discussion recently and no clear picture emerges that can apply to all situations. In many ways, NSAIDs and H pylori have similar adverse effects on mucosal protective mechanisms, and despite H pylori itself producing small amounts of prostaglandins, there remains the possibility of an additive damaging effect when both are present.30 Studies on mucosal adaptation and on neutrophils raise the possibility of some inter-relationship that may allow damage to occur more readily when NSAIDs are taken in the presence of H pylori.31

The development of an ulcer when NSAIDs are given to patients who are H pylori positive may depend on the interaction of a number of factors, including previous exposure to NSAIDs, past history, gastric acid output, and the use of acid suppression drugs such as proton pump inhibitors.

Aspirin may have different interactions with H pylori, particularly with respect to the risk of gastrointestinal haemorrhage.

Gastrointestinal haemorrhage from ulcers may be in a different category from non-bleeding ulcers, and really requires to be studied separately; other factors may be involved, such as the possible antiplatelet effects of many NSAIDs, which may be a further factor in bleeding.

Clinical studies in this area have given conflicting results, although one study in patients not previously given NSAIDs clearly demonstrated an advantage in eradicating H pylori before starting NSAIDs; significantly fewer lesions developed over two months in patients in whom H pylori had been eradicated before starting NSAIDs.32 In such patients, especially if risk factors are present (older age group, previous ulcer history), eradication of H pylori before starting NSAIDs may be indicated.

A large multicentre study has found that eradication of H pylori did not reduce the rate of ulcer relapse in existing long term NSAID users.33 In this study, it was also reported in a subgroup of 41 patients with gastric ulcers found at baseline endoscopy that eradication of H pylori was associated with delayed ulcer healing. However, in another prospective, randomised study of 195 patients with H pylori infection and NSAID associated bleeding ulcers, eradication of H pylori did not impair healing of gastric or duodenal ulcers.34 A prospective, randomised clinical outcome study compared H pylori eradication alone with long term omeprazole for the prevention of recurrent ulcer haemorrhage in high risk users of aspirin or non-aspirin NSAIDs.35 The results to date indicate that eradication of H pylori alone did not prevent recurrent ulcer bleeding associated with non-aspirin NSAIDs, but H pylori eradication alone was as effective as maintenance omeprazole in preventing recurrent haemorrhage associated with low dose aspirin. Perhaps the antiplatelet effects of NSAIDs are relevant there.

H pylori testing would probably not be indicated in patients who have already been on NSAIDs or aspirin for some time without any adverse effects. In patients with a past history of peptic ulcer or dyspepsia on NSAIDs, long term acid suppressive agents such as proton pump inhibitors are indicated even after eradication of H pylori.

More scientific and clinical data are required on these complex inter-relationships.

Conclusions:
The use of NSAIDs continues to increase, especially in the elderly.
NSAIDs may have adverse effects in any part of the gastrointestinal tract: oesophagus, stomach, duodenum, small intestine, or colon.
Risk factors for gastrointestinal damage due to NSAIDs include age, previous ulcer history, first three months of treatment, smoking, underlying cardiovascular or respiratory disease, concomitant drug use with corticosteroids and anticoagulants, high dose and multiple NSAIDs, and possibly in some cases H pylori.
Low dose prophylactic aspirin may also be associated with adverse gastrointestinal effects.
Healing of NSAID related ulcers can be achieved while NSAIDs are continued by the use of H2-receptor antagonists in high doses, or more effectively by proton pump inhibitors.
Prevention of NSAID related gastrointestinal problems may be achieved by identifying and if possible reducing risk factors, the coprescription of prostaglandin analogues or acid suppressive drugs (especially proton pump inhibitors), or by using the currently being developed and promising COX-2 specific inhibitors.
The development of COX-2 specific inhibitors offers the hope of real progress in producing much safer and effective NSAIDs.

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Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation

Mark Pimentel, M.D., Anthony Lembo, M.D., William D. Chey, M.D., Salam Zakko, M.D., Yehuda Ringel, M.D., Jing Yu, Ph.D., Shadreck M. Mareya, Ph.D., Audrey L. Shaw, Ph.D., Enoch Bortey, Ph.D., and William P. Forbes, Pharm.D. for the TARGET Study Group

N Engl J Med 2011; 364:22-32January 6, 2011

Comments open until January 12, 2011

Abstract
Article
References
Citing Articles (1)
Comments
Background

Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS.

Full Text of Background...
Methods

In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study.

Full Text of Methods...
Results

Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups.

Full Text of Results...
Conclusions

Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.)

Full Text of Discussion...

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Source Information

From Cedars�Sinai Medical Center, Los Angeles (M.P.); Beth Israel Deaconess Medical Center and Harvard Medical School � both in Boston (A.L.); University of Michigan Health System, Ann Arbor (W.D.C.); Connecticut Gastroenterology Institute at Bristol Hospital, Bristol (S.Z.); University of North Carolina at Chapel Hill, Chapel Hill (Y.R.); and Salix Pharmaceuticals, Morrisville, NC (J.Y., S.M.M., A.L.S., E.B., W.P.F.).

Address reprint requests to Dr. Forbes at 1700 Perimeter Park Dr., Morrisville, NC 27560.

Members of the TARGET Study Group are listed in the Supplementary Appendix, available at NEJM.org.
Media in This Article
Figure 1Study Design.
Figure 2Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies.
Article Activity

1 article has cited this article

The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurring symptoms of abdominal pain, bloating, and altered bowel function in the absence of structural, inflammatory, or biochemical abnormalities.1 IBS often does not respond to current treatment options, including dietary and lifestyle modifications, fiber supplementation, psychological therapy, and pharmacotherapy.2,3 Because no reliable biologic or structural markers have been identified, the effects of pharmacotherapy are typically assessed by asking patients to report whether they had adequate relief of IBS symptoms (with a binary response of yes or no).4 Given the limitations of available therapies, there is an unmet medical need for novel therapeutic approaches.

Patients with IBS may have alterations in the intestinal microbiota,5-7 thus leading investigators to consider targeting the intestinal microbiota for the treatment of this condition. Although some patients have had improvement with neomycin therapy, clinical trials have shown that it has marginal efficacy, and side effects limit the use of the drug.8 The use of systemic antibiotics has been reported with mixed results.9

Rifaximin (Xifaxan, Salix Pharmaceuticals) is an oral, nonsystemic, broad-spectrum antibiotic that targets the gut and is associated with a low risk of bacterial resistance.10-12� It has shown efficacy in small-scale studies of IBS. 13,14 We present the results of two large-scale, identically designed, multicenter trials � TARGET 1 and TARGET 2 � of 3 months' duration that examined the relief of IBS symptoms after a 2-week course of rifaximin.
Methods
Study Patients

Eligible patients were at least 18 years of age; had undergone a colonoscopic examination within the previous 2 years; had received a diagnosis of and had current symptoms of IBS (as assessed according to the Rome II diagnostic criteria for IBS15), in particular, symptoms of abdominal pain and discomfort; and did not have adequate relief of global IBS symptoms and of IBS-related bloating at both the time of screening and the time of randomization. Eligible patients rated the average daily amount of abdominal pain and of bloating as a score of 2 to 4.5 on a 7-point Likert scoring system (with 0 indicating not at all; 1, hardly; 2, somewhat; 3, moderately; 4, a good deal; 5, a great deal; and 6, a very great deal) and rated the average daily consistency of their stools as 3.5 or more on a 5-point scale for stool consistency (with 1 indicating very hard; 2, hard; 3, formed; 4, loose; and 5, watery) over the course of at least 7 days.

Exclusion criteria were constipation-predominant IBS (according to the definition in the Rome II criteria15), a history of inflammatory bowel disease, diabetes, unstable thyroid disease, previous abdominal surgery (other than cholecystectomy or appendectomy), human immunodeficiency virus infection, and renal or hepatic disease. Patients were excluded if they were currently taking alosetron, tegaserod, lubiprostone, warfarin, or antipsychotic, antispasmodic, antidiarrheal, probiotic, or narcotic drugs or if they had taken antibiotics within the previous 14 days or rifaximin within 60 days before signing the informed-consent form for the study. Patients were allowed to take antidepressant agents of the selective serotonin-reuptake inhibitor and tricyclic antidepressant classes, provided that they had been taking a stable dose for at least 6 weeks. All patients provided written informed consent before study-related procedures were initiated.
Study Design and Procedures

The protocols were approved by the institutional review board or independent ethics committee at each center, and the studies were conducted in accordance with applicable laws and regulations (see the Supplementary Appendix, available with the full text of this article at NEJM.org). After a screening phase of 7 to 13 days, eligible patients were randomly assigned with the use of an interactive voice-response system to either rifaximin or placebo, in a 1:1 ratio. The randomization code was computer-generated, and randomization was performed in blocks of four, stratified according to center. After completing the 14-day study-treatment period, patients were evaluated for 10 additional weeks. Study visits were conducted on days 1, 7, 14, 28, and 84, and patients were monitored by means of telephone calls on days 42, 56, and 70. Efficacy assessments were obtained daily by means of an interactive voice-response system over the course of the entire study (Figure 1Figure 1Study Design.).

The protocol was designed by Salix Pharmaceuticals in collaboration with the academic authors. Data were collected by investigators at each center (see the Supplementary Appendix) and were monitored by Quintiles (a contract research organization) under the supervision of Salix Pharmaceuticals. The data were analyzed by personnel at Salix Pharmaceuticals, in collaboration with the academic authors. All the authors participated in the interpretation of the data and in the writing of the manuscript. The first two authors wrote the first draft of the manuscript, and all the authors, in addition to an employee of Salix, assisted in the revision of subsequent drafts. All the authors made the decision to submit the manuscript for publication. The trial protocol, including the statistical analysis plan, is available at NEJM.org. All the authors vouch for the completeness and veracity of the data and analyses, as well as the fidelity of this report to the trial protocol.
Efficacy and Safety End Points

The primary end point was the proportion of patients who had adequate relief of global IBS symptoms for at least 2 of the 4 weeks during the primary evaluation period (weeks 3 through 6). This end point was determined from the response (yes or no) to the following question, which was asked weekly: "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?" The threshold for clinical relevance � adequate relief during at least 2 weeks per month � was defined prospectively. In addition, the proportion of patients who reported that they had adequate relief during at least 2 weeks per month ("monthly response") during months 1, 2, and 3 was assessed to identify the onset and duration of the therapeutic effect. Patients who started to take antibiotics (other than the study medication) or who took more than two doses of a medication that was prohibited per the study protocol were considered not to have had a response to treatment starting from the time the medication was initiated, regardless of their response data.

The key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating during the primary evaluation period, was determined from the response (yes or no) to the weekly question, "In regard to your symptoms of bloating, as compared with the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating?" The onset and duration of relief of bloating were also assessed in an analysis of monthly response, as described above for the primary end point.

For other secondary end points, the proportion of patients who had relief was determined from the patients' daily assessments of IBS symptoms, bloating, and abdominal pain and discomfort (as rated on a 7-point scale); relief was defined as a score of either 0 (not at all) or 1 (hardly) for at least 50% of the days in a given week or a score of 0 (not at all), 1 (hardly), or 2 (somewhat) for 100% of the days in a given week for at least 2 of the 4 weeks during a given month.

An exploratory end point, which was included at the request of the Food and Drug Administration (FDA), was the proportion of patients who had relief of the composite of abdominal pain and discomfort and loose or watery stools (as measured by improvement in stool consistency), on the basis of daily assessments. Relief was defined as a decrease of at least 30% from baseline in weekly mean ratings of IBS-related abdominal pain or discomfort and a weekly mean stool-consistency score of less than 4 (with 4 indicating loose stools and lower scores indicating more formed stools) for at least 2 of the 4 weeks during a given month. This exploratory end point is consistent with the recommended composite end point for IBS with diarrhea in a recently released draft of FDA guidelines.16 Safety assessments included the monitoring of adverse events, results of clinical laboratory testing, findings from physical examinations, and vital signs.
Statistical Analysis

We estimated the sample size for each study assuming that 40% of the patients in the placebo group and 55% in the rifaximin group would meet the criteria for the primary end point (i.e., would have adequate relief of global IBS symptoms, as assessed weekly) for at least 2 of the first 4 weeks after treatment. With these assumptions, a sample of 300 patients would be needed in each group for the studies to have 95% power to show the 15-percentage-point difference between the groups, at a significance level of 0.05.

All efficacy and safety analyses were performed on a modified intention-to-treat population, which included all patients who received at least one dose of the study drug. Missing data were imputed with the use of the last-observation-carried-forward method, whereby missing values were replaced with the last nonmissing value; baseline values were not carried forward. Two sensitivity analyses were conducted, one in which missing data were regarded as indicating that the patients who terminated the study prematurely had had no relief of symptoms, and the other in which missing data were imputed with the use of the multiple-imputation method.

Binary data (i.e., data on the proportion of patients who had or did not have adequate relief of symptoms) were analyzed with the use of logistic regression; fixed-effect terms included the study group and the analysis center. There were five analysis centers, which we formed prospectively by grouping the study centers according to geographic region in order to assess the effects of geographic location on the end points. For the analysis of ordinal data (i.e., data on the number of months in which patients had relief for at least 2 weeks per month), we used the proportional-odds model for the ordinal outcome. The number of consecutive months with relief during the first 3 months after treatment was summed for each patient, so that each patient received a score of 0, 1, 2, or 3.

We analyzed the changes from baseline in continuous outcomes (i.e., symptom scores) by fitting fixed-effects linear models to the data. An initial model with terms for treatment, analysis center, baseline ratings of the response variable, and interaction of baseline ratings with treatment was fitted. The interaction term was tested at the 0.05 level. A nonsignificant interaction was dropped from the model in subsequent analyses.

Spearman correlation analyses were applied to the mean change from baseline in daily assessments of adequate relief of IBS symptoms (yes or no) to determine whether the weekly assessments of adequate relief paralleled the pattern seen with the daily assessments. Safety data were summarized with the use of descriptive statistics.
Results
Study Patients

A total of 1260 patients who had IBS without constipation were enrolled in the studies (623 patients in TARGET 1 and 637 in TARGET 2) and underwent randomization at one of 179 investigative sites in the United States (1217 patients) and Canada (43 patients) (Figure 2Figure 2Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies.). The studies were conducted in parallel from June 2008 through August 2009. In TARGET 1, all the patients who underwent randomization took at least one dose of the study drug. In TARGET 2, two patients (one in each group) underwent randomization but did not receive a study drug. Thus, 1258 patients received at least one dose of the study drug and were included in the modified intention-to-treat population. More than 90% of the patients completed the entire 12-week study. The baseline characteristics of the patients were similar in the two studies and across treatment groups (Table 1Table 1Demographic and Baseline Characteristics of the Modified Intention-to-Treat Population in the Two Studies.). The rate of adherence to the study drug, defined as the use of at least 70% of the dispensed tablets, was at least 97% in both study groups in both studies.
Efficacy during the Primary Evaluation Period (Weeks 3 through 6)
Adequate Relief of Global IBS Symptoms

Significantly more patients in the rifaximin group than in the placebo group met the criteria for the primary end point of adequate relief of global IBS symptoms for at least 2 of the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined) (Figure 3AFigure 3Analyses of Primary, Key Secondary, and Other Secondary End Points.). The last-observation-carried-forward method was applied in the case of 5.8% of the patients in the rifaximin group and 5.7% of the patients in the placebo group in TARGET 1 and in the case of 5.4% in the rifaximin group and 8.4% in the placebo group in TARGET 2. Overall, sensitivity analyses that were performed to address the effect of missing values yielded results that were consistent with those of the primary efficacy analysis (see the Supplementary Appendix). On the basis of daily assessments of IBS symptoms, the proportion of patients with a response to treatment, as rated on a 7-point scale during the primary evaluation period, was significantly greater in the rifaximin group than in the placebo group (42.7% vs. 30.6%, P<0.001, in TARGET 1; 37.8% vs. 28.4%, P=0.007, in TARGET 2; 40.2% vs. 29.5%, P<0.001, in the two studies combined) (Figure 3A).
Adequate Relief of IBS-Related Bloating

Significantly more patients in the rifaximin group than in the placebo group met the criteria for the key secondary end point, adequate relief of IBS-related bloating for at least 2 of the first 4 weeks after treatment (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined) (Figure 3A). Sensitivity analyses that were performed to assess the effect of missing values yielded similar results (see the Supplementary Appendix). On the basis of daily assessments of IBS-related bloating as rated on a 7-point scale during the same primary evaluation period, a significantly greater proportion of patients in the rifaximin group than in the placebo group had relief (39.2% vs. 32.5%, P=0.05, in TARGET 1; 43.5% vs. 30.9%, P<0.001, in TARGET 2; 41.3% vs. 31.7%, P<0.001, in the two studies combined) (Figure 3A).
Relief of IBS-Related Abdominal Pain and Loose or Watery Stools

A significantly greater proportion of patients in the rifaximin group than in the placebo group had relief of IBS-related abdominal pain and discomfort during the primary evaluation period (44.3% vs. 36.3%, P=0.03, in TARGET 1; 42.9% vs. 34.4%, P=0.02, in TARGET 2) (Figure 3A). In an assessment of the composite end point of abdominal pain or discomfort and loose or watery stools, significantly more patients in the rifaximin group than in the placebo group had relief during the primary evaluation period (46.6% vs. 38.5%, P=0.04, in TARGET 1; 46.7% vs. 36.3%, P=0.008, in TARGET 2), and a significantly greater proportion of patients in the rifaximin group had relief with respect to the individual components of this end point (Figure 3A).
Efficacy during the Entire Study Period (Months 1 through 3)
Durability of Response on the Basis of Weekly Assessment

In analyses of the monthly response evaluated on the basis of weekly assessments, more patients in the rifaximin group than in the placebo group in both studies had adequate relief of global IBS symptoms within the first month, with continued relief during the first 2 months and during all 3 months in both studies (P=0.05 in TARGET 1, P=0.005 in TARGET 2, and P<0.001 in the two studies combined, for relief during all 3 months) (Figure 3B). With respect to IBS-related bloating, in TARGET 1, significantly more patients in the rifaximin group than in the placebo group had adequate relief in the first month, with continued relief during the first 2 months, but there were no significant between-group differences with respect to relief during all 3 months; in TARGET 2, significant benefits of rifaximin were seen with respect to IBS-related bloating for all 3 months (P=0.10 in TARGET 1, P=0.003 in TARGET 2, and P=0.001 in the two studies combined, for relief during all 3 months) (Figure 3B). The percentages of patients in each group with adequate relief of global IBS symptoms in TARGET 1 and TARGET 2 are provided in Figure 4Figure 4Percentage of Patients with Adequate Relief of Global IBS Symptoms in the TARGET 1 and TARGET 2 Studies Combined., and in Figure 1A and 1B in the Supplementary Appendix.
Durability of Response on the Basis of Daily Assessment

The analyses of monthly response evaluated on the basis of daily assessments also support a durable response to rifaximin in patients with IBS over the course of 3 months. Patients treated with rifaximin, as compared with patients who received placebo, had adequate relief of global IBS symptoms during the entire 3 months of the study (P=0.003 in TARGET 1, P=0.01 in TARGET 2, and P<0.001 in the two studies combined) and of IBS-related bloating (P=0.01 in TARGET 1, P<0.001 in TARGET 2, and P<0.001 in the two studies combined) (Figure 3B).

An analysis of the monthly response evaluated on the basis of daily assessments of IBS-related abdominal pain and discomfort showed that significantly more patients in the rifaximin group than in the placebo group had relief for the entire 3 months (P=0.05 in TARGET 1, P=0.04 in TARGET 2, and P=0.01 in the two studies combined) (Figure 3B). An analysis of the monthly response evaluated on the basis of the assessment of the composite end point of abdominal pain and stool consistency also showed a significant benefit with rifaximin as compared with placebo (P=0.04 in TARGET 1, P=0.01 in TARGET 2, and P=0.001 in the two studies combined) (Figure 3B).

The mean improvement from baseline in daily symptom scores (global IBS symptoms, IBS-related bloating, IBS-related abdominal pain or discomfort, stool consistency, and the percentage of days with stool urgency) was greater for the patients who received rifaximin than for the patients who received placebo (Figure 2 through 6 in the Supplementary Appendix).
Responsiveness and Construct Validity of Patient-Reported Outcomes

The response of patients with respect to adequate relief of global IBS symptoms and of IBS-related bloating was consistent with the response with respect to other IBS-related assessments. In addition, patients who had adequate relief of global IBS symptoms and of IBS-related bloating had greater improvements in daily symptom-severity scores than did patients who did not have adequate relief, regardless of study group, during each week in each study (P<0.001).

We tested the validity of using assessments of global IBS symptoms to measure changes in IBS symptoms by examining the correlation between these measures and changes in daily severity scores and bowel function; the results support the validity and usefulness of the primary end point of global IBS symptoms. Evidence for convergent validity (Spearman's correlation of 0.40 or higher) was observed between weekly adequate relief of global IBS symptoms and measures of daily symptom severity and bowel function.
Safety

The safety profile of rifaximin was similar to that of placebo (Table 2Table 2Adverse Events during the 12-Week Study.). Serious adverse events were recorded in 10 patients in the rifaximin group (1.6%) and 15 patients in the placebo group (2.4%). There were no cases of Clostridium difficile�associated diarrhea or ischemic colitis. No deaths were reported.
Discussion

Treating IBS is important because the symptoms cause substantial impairment in health-related quality of life, leading to increased use of health resources and reduced work productivity.17-20 These two phase 3 studies showed that a short course of rifaximin leads to sustained amelioration of the symptoms of IBS without constipation in a subgroup of affected patients.

The antibiotic effect of rifaximin is the presumed mechanism for its sustained beneficial effects in patients with IBS. A response to antibiotic therapy in patients with IBS has been shown to correlate with normalization of the results of lactulose hydrogen breath tests.8,13 However, there is debate about which antibiotic-related effect is most important. On the basis of existing data, there are three reasonable explanations: rifaximin affects gut bacteria and reduces bacterial products that negatively affect the host, the effect on gut flora reduces local mucosal engagement of bacteria such as the immune responses of the host, or the antibiotic alters both the bacteria and the host response. Whatever the final pathway, the durable effects suggest that rifaximin is affecting an underlying cause of IBS that is linked to an alteration in the intestinal microbiota.6,7,21,22 Some patients in both of our studies did not have a response to treatment, a finding that is consistent with the results of other placebo-controlled clinical trials involving patients with IBS23-25 and that may reflect differences in the underlying cause of the symptoms.

Similar percentages of patients in the rifaximin group and in the placebo group had adverse events. In this short-term study, the incidence of infections was similar in the two groups, and there were no cases of C. difficile�associated diarrhea or ischemic colitis.

In summary, the results of these two phase 3 studies showed that treatment with rifaximin at a dose of 550 mg three times daily for 14 days provides better relief of symptoms of IBS than does placebo for up to 10 weeks after completion of therapy.

Supported by Salix Pharmaceuticals.

Dr. Pimentel reports receiving grant support (to his institution) and consulting fees and honoraria from Salix Pharmaceuticals and reports that Cedars�Sinai Medical Center holds patents licensed by Salix Pharmaceuticals; Dr. Lembo reports receiving consulting fees from Salix Pharmaceuticals, Ironwood Pharmaceuticals, Prometheus, Ardelyx, Theravance, GlaxoSmithKline, and AstraZeneca, receiving payment for participation in several advisory-board meetings relating to the development of rifaximin for the treatment of IBS, and receiving payment as a member of the speakers' bureau of Salix Pharmaceuticals; Dr. Chey reports receiving consulting fees and honoraria from Procter & Gamble, Ortho-McNeil, Prometheus, and Salix Pharmaceuticals, payment for the development of educational presentations, and payment or reimbursement for travel and accommodations from Procter & Gamble, Prometheus, and Salix Pharmaceuticals; Dr. Zakko reports receiving grant support (to his institution), consulting fees, payment for the development of educational presentations, and payment or reimbursement for travel and accommodations from Salix Pharmaceuticals and holding stock in Salix Pharmaceuticals; Dr. Ringel reports receiving consulting fees from Salix Pharmaceuticals, Ironwood Pharmaceuticals, Procter & Gamble, Pfizer, and Danisco, participating in several advisory-board meetings related to the development of rifaximin for the treatment of IBS, receiving payment for the development of educational presentations and as a member of the speakers' bureau of Salix Pharmaceuticals, and receiving research grants from Danisco USA, General Mills, and SmartPill. Drs. Yu, Mareya, and Bortey report being employees of and holding stock in Salix Pharmaceuticals; Dr. Shaw reports being an employee of Salix Pharmaceuticals and reports that she holds stock in the company; and Dr. Forbes reports being an officer and employee of Salix Pharmaceuticals and holding stock in the company.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.
Source Information

From Cedars�Sinai Medical Center, Los Angeles (M.P.); Beth Israel Deaconess Medical Center and Harvard Medical School � both in Boston (A.L.); University of Michigan Health System, Ann Arbor (W.D.C.); Connecticut Gastroenterology Institute at Bristol Hospital, Bristol (S.Z.); University of North Carolina at Chapel Hill, Chapel Hill (Y.R.); and Salix Pharmaceuticals, Morrisville, NC (J.Y., S.M.M., A.L.S., E.B., W.P.F.).

http://www.nejm.org/doi/full/10.1056/NEJMoa1004409#t=article

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