February 2015, Vol 3, No 2 - Inside Gastrointestinal Health
Drew Ringeling, PharmDc

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal system.1

It is a chronic condition that can be characterized by abdominal discomfort with altered bowel pattern for >3 months.1,2 IBS is diagnosed clinically because there is no known biomarker associated with the disorder. This makes estimating the prevalence of the disorder a difficult task, as clinicians use a variety of tools to make their diagnoses.1 However, it is estimated that approximately 10% to 15% of the adult population is affected by the disease.3 It is more commonly found in women and prevalence of the disorder also decreases with age, as most patients range in age from 15 to 65 years.4

The Rome III diagnostic criteria for functional gastrointestinal disorders allow clinicians to diagnose patients with IBS, and further classification is based on patients’ stool consistency. Constipation (C) is the predominant symptom seen in patients with IBS-C, whereas patients with IBS-D frequently experience diarrhea (D). A mixed (M) pattern of both diarrhea and constipation is classified as IBS-M.1 According to the Rome III diagnostic criteria, patients must experience abdominal discomfort >3 days per month for the past 3 months to be diagnosed with IBS.1 This abdominal pain must also be relieved with defecation or associated with a change in stool frequency/consistency.5

American Gastroenterological Association Guidelines

Because IBS affects a wide range of patients and can manifest as a variety of symptoms, choosing the appropriate therapy can be challenging. The American Gastroenterological Association (AGA) recently updated their guidelines on the pharmacologic management of IBS to provide clinicians with an evidence-based tool designed to find the most appropriate therapy for their patients.3 The goal is that these guidelines will allow physicians and patients to better weigh each option and choose the drug best suited for the patient’s needs.

The AGA guidelines are categorized into a series of 9 questions, each specific to a drug used in the management of IBS. The effects of each drug were also analyzed for their clinical meaningfulness (threshold >10%).5 The strength of each recommendation and rate the quality of evidence used to make each recommendation were also indicated. The recommendations are classified as either “strong” or “conditional (weak).”3,5 Strong recommendations indicated that most patients would want to choose this therapy option, and adherence to this option could also be used as a performance indicator for clinicians. A strong recommendation also implied that it can be adapted as policy in most cases. Conditional recommendations suggested that although the majority of patients would want the treatment, a significant amount of patients would not. See the Table for a list of the 9 drugs and the strengths of their recommendations. Clinicians would be encouraged to examine the evidence behind this type of recommendation to help the patient make a decision regarding their therapy.

Table

IBS-Constipation

The first question in the guideline addressed whether linaclotide should be used in patients with IBS-C. The AGA strongly recommends using linaclotide (vs no drug treatment) based on high-quality evidence. Specifically, two phase 3, randomized controlled trials (RCTs) showed that linaclotide provided clinically meaningful relief of abdominal pain and increased the number of spontaneous bowel movements. These studies used the US Food and Drug Administration (FDA) responder outcome for IBS-C (ie, patients with >30% reduction in abdominal pain and an increase of at least 1 spontaneous bowel movement per week) as the primary end point,5 which has been shown to be clinically meaningful, and has excellent specificity and reasonably high sensitivity. In addition, investigators in a third study found that linaclotide resulted in a global improvement of symptoms. The guidelines do note that cost and a small risk of diarrhea may discourage patients from using this treatment option.

The next recommendation pertained to lubiprostone. The AGA conditionally recommends the use of lubiprostone (vs no drug treatment) in patients with IBS-C. The quality of this evidence was found to be moderate based on the results of 2 RCTs, which demonstrated that lubiprostone significantly improved global outcomes and reduced abdominal pain; however, these outcomes were not clinically significant. In addition, lubiprostone was not associated with an increased rate of spontaneous bowel movements compared with placebo.5

Polyethylene glycol (PEG) laxatives were also evaluated, and the AGA conditionally recommended using them (vs no drug treatment) in patients with IBS-C. This recommendation was supported by low quality evidence; only 1 study was found that evaluated the use of PEG laxatives in patients with IBS-C.1 PEG showed no benefit in relieving symptoms or in reducing abdominal pain, but this may be the result of limitations in trial design.5 Because there is an abundance of evidence showing PEG’s efficacy in the treatment of chronic constipation, it is still an option for patients with the need for specific symptom relief.

IBS-Diarrhea

Treatment options for patients with IBS-D were also addressed, and the AGA considered the use of rifaximin in patients with IBS-D. Based on moderate quality evidence, they conditionally recommended using rifaximin (vs no drug treatment) in patients with IBS-D. The FDA responder end point for IBS-D (ie, patients with >30% reduction in abdominal pain and >50% reduction in number of days per week with at least 1 loose stool) was evaluated in 2 of 3 RCTs analyzed.5 Rifaximin showed a lower failure rate of the FDA responder in the relief of global symptoms, and in the relief of abdominal pain. However, these results were not found to be clinically significant.5

The AGA guidelines also discussed the use of alosetron in patients with IBS-D and conditionally recommended it (vs no drug treatment) in patients with IBS-D to improve global symptoms. Alosetron improved abdominal pain and IBS-related global symptoms in multiple RCTs evaluated. However, because global relief of symptoms was only measured in 2 of the 8 studies conducted, evidence for its use was rated moderate.5 Global relief, along with reduction in abdominal pain, was found to be clinically significant in these studies. The AGA stated that for women with IBS-D who have severe abdominal pain and did not respond to traditional therapy, alosetron would be an appropriate option.5

Loperamide was conditionally recommended for the treatment of patients with IBS-D, but this recommendation was supported by very low quality evidence. Only 2 small trials evaluated the use of loperamide specifically for IBS, and neither defined the diagnostic criteria used.5 In these studies, loperamide did not yield a significant benefit in global relief of symptoms; however, abdominal pain and stool consistency were significantly improved.5 Because of an abundance of data showing its efficacy in reducing stool frequency, the AGA suggests it may be useful in patients with IBS-D.

Other General Recommendations

The use of tricyclic antidepressants (TCAs) in patients with IBS was given a conditional recommendation based on low quality evidence. Eight RTCs were included in the review, and uncertainty regarding blinding was a limitation in many of these studies. TCAs were shown to improve global relief of symptoms and provide abdominal pain relief, although pain relief was not clinically meaningful.5 Withdrawal from therapy because of adverse effects was also significantly higher with TCAs, although this is low quality evidence as the population was not specifically patients with IBS.5

According to the AGA guidelines, selective serotonin reuptake inhibitors (SSRIs) should not be used in patients with IBS. This is a conditional recommendation based on low quality evidence. The efficacy of SSRIs in IBS was evaluated in 5 RCTs. Each study included a global assessment of efficacy, although the method used differed between each study.5 SSRI use resulted in a lower failure rate of symptom relief, but this result was not significant. Abdominal pain relief was also evaluated; SSRIs did not significantly reduce pain when compared with placebo.5

The final question addressed by the AGA was the use of antispasmodics. They conditionally recommended using antispasmodics (vs no drug treatment) in patients with IBS, based on low quality evidence. Antispasmodics were associated with a clinically meaningful improvement in global symptoms and the improvement in abdominal pain compared with placebo.5 However, risk for bias was significant and variation among the trials was a major concern. Also, most studies evaluating these older drugs predate Rome diagnostic criteria; therefore, the definition of IBS varied between each study.5 It is important to note that these drugs are classically used for postprandial symptoms in IBS, but no RCTs have directly looked at this indication.5

Conclusion

These guidelines, built with the hopes of providing clinicians with a tool on which to base treatment choices, evaluate the safety and efficacy of 9 pharmacologic options for IBS. It should be noted that overall quality of the studies is determined to be low.5 Reasons for this are numerous: diagnostic criteria change over time, and IBS does not have biomarker or quantitative primary end points that can be measured in all studies.5 Although IBS presents with a wide variety of symptoms and is difficult to treat, these guidelines should help clinicians make an appropriate treatment decision that is aligned with the patient’s needs and values.




References

  1. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71-80.
  2. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
  3. Weinberg DS, Smalley W, Heidelbaugh JJ, Sultan S. American Gastroenterological Association institute guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014;147:1146-1148.
  4. World Gastroenterology Organisation. WGO practice guideline - irritable bowel syndrome: a global perspective. www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/20_irritable_bowel_syndrome.pdf. Published April 20, 2009. Accessed December 22, 2014.
  5. Chang L, Lembo A, Sultan S. American Gastro­enterological Association institute technical review on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014;147:1149-1172.
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