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Evidence-Based Management of Irritable Bowel Syndrome With Diarrhea
Mark Pimentel, MD

Evidence-Based Management of Irritable Bowel Syndrome With Diarrhea

Mark Pimentel, MD
Individuals with IBS have a lower health-related QOL compared with the US general population.12,13 Recall that for patients to meet the diagnostic criteria of IBS, they have to have experienced symptoms for at least 6 months, thereby adding to the burden of disease.3 Despite the effect of IBS on QOL, the burden of IBS still may be underestimated because it is not life-threatening and is not associated with a decreased life expectancy.14

Individuals who have been diagnosed with IBS are more likely to report that GI symptoms affect their QOL than those who have not yet received a diagnosis; nevertheless, many individuals experiencing IBS-related symptoms remain untreated.4 Patients with IBS-D and IBS-M have a lower QOL than those with IBS-C.14 Areas in which patients with IBS experience statistically poorer health-related QOL than the US general population include increased fatigue, role limitations, and pain.12

Patients with IBS have significantly lower scores for physical functioning, physical role limitations, bodily pain, emotional well-being, emotional role limitations, energy/fatigue, social functioning, and general health than the US general population.12 For many of these QOL measures, patients with IBS also show more impairment than patients with other chronic diseases, such as gastroesophageal reflux disease, diabetes, depression, or end-stage renal disease.12

The domains of pain/discomfort and depression/anxiety were reported by patients with IBS as contributing to the greatest loss of QOL.15 Although referral of patients with probable IBS to a gastroenterologist resulted in a nonsignificant increase in QOL at 3 months, this improvement was not maintained upon repeated survey at 1 year.15

Individuals with IBS who have lower QOL and higher levels of anxiety are more likely to have other functional comorbidities.5 Patients with IBS and comorbidities experience more severe symptom burdens than those with IBS alone. Approximately half of all patients with IBS experience coexisting functional conditions, including fibromyalgia, chronic fatigue syndrome, chronic headache, and chronic back pain, with an incidence nearly twice that of those without IBS.5

IBS is also responsible for lost productivity at work,14  including increased work absenteeism (ie, percentage of work time missed due to health problems). A UK-based study reported that those with IBS are twice as likely to miss work compared with healthy coworkers, and in the United States, those with IBS miss an average of 3 to 4 more days of work annually compared with healthy coworkers. The severity of IBS symptoms is significantly associated with the need to take time off work (P <.05); an average of 1 day per month is missed in those with severe IBS symptoms.16

IBS symptoms are also associated with work presenteeism (ie, working but at reduced capacity or competence). Presenteeism is more subjective than absenteeism, so estimated time lost to the former varies widely, from 2% to 32%. Like absenteeism, presenteeism significantly increases with IBS symptom severity (P <.001).16

In a survey study of 66,491 adults in the United States,17 patients with IBS-D had statistically significantly more work absenteeism than controls (5.1% vs 2.9%, respectively; P = .004), more presenteeism (17.9% vs 11.3%; P <.001), and greater overall work productivity loss (ie, absenteeism + presenteeism) (20.7% vs 13.2%; P <.001). In this study, patients with IBS-D also missed significantly more work days each year compared with controls (10.1 d/y vs 6.2 d/y; P = .031).17  

In addition to interfering with work, IBS interferes with daily activities and personal and social relationships.14 Patients with IBS-D have a significantly higher degree of daily activity impairment than controls (29.6% vs 18.9%; P <.001).17 The partner burden with IBS was higher than that for partners of healthy individuals and comparable with that for other diseases, such as dementia. Partner burden with IBS was higher than that for caregivers of patients with terminal cancer. This burden rose with increasing severity of IBS and poorer sexual and relationship satisfaction.18

Approaches to Treatment of IBS-D

IBS is a symptom-based disorder. Therefore, treatments address the symptom of abdominal pain and the bowel symptoms of diarrhea and constipation. Treatment of IBS should include nonpharmacologic management, such as lifestyle and dietary interventions, and pharmacologic agents19 and should be based on the nature and severity of the predominant symptoms (eg, abdominal pain and diarrhea).20

Treatments should be individualized for patients in a stepwise manner according to symptoms. Therapy comprising a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, more exercise, stress reduction, and antispasmodics or tricyclic antidepressants for pain should be sustained for 1 month before discontinuation due to lack of efficacy. For patients with diarrhea, loperamide or a bile acid sequestrant can also be given. If diarrhea persists, treatment with alosetron, eluxadoline, or rifaximin is suggested.2 Refractory IBS is characterized by continuing symptoms, reduced QOL, and ongoing medical appointments despite treatment. In patients with refractory IBS, pain is frequently a major concern. Often, patients have comorbid psychiatric conditions. Therefore, management of symptoms requires a multidisciplinary approach with medication and nonpharmacologic management, including psychological therapy.2

The management of IBS is challenging because its pathogenesis is not completely understood. There is evidence that GI motility and secretion, visceral hypersensitivity, abnormalities of the enteroendocrine and immune systems, genetics, infections, changes in the intestinal microflora, and inflammation may all play a role in its pathogenesis, suggesting there are areas for further research.21

Nonpharmacologic Management

Nonpharmacologic interventions that reduce symptoms of IBS include patient education; reassurance by clinicians; regular exercise, including walking and yoga; and stress management through meditation, counseling, and sufficient sleep.7 Although dietary modifications have not been proved to improve symptoms of IBS, dietary changes are reasonable for individuals for whom specific foods appear to initiate symptoms.7

For example, consumption of FODMAPs should be limited to those individuals in whom they cause bloating and gas. Other foods to avoid include excess fats, hard-to-digest carbohydrates, excess caffeine, and carbonated beverages. Adequate water and fiber intake are recommended for patients with IBS-C (Table 12).7

Overview of Pharmacologic Interventions for IBS-D

Agents used for the pharmacologic management of IBS vary in their efficacy, the quality of evidence that supports their use, the length of time recommended for treatment, and their adverse event profiles. Some of these agents are not indicated (FDA approved) for IBS and are used off-label. In addition, the use of some approved agents is restricted; for example, alosetron is indicated only for women with severe IBS-D.22

The most current FDA Guidance for Industry on clinical evaluation of drugs for the treatment of IBS includes capturing patient-reported outcomes (PROs).23  The FDA recommends development of a multi-item PRO assessment instrument to capture the clinically important signs and symptoms of the IBS target population (eg, IBS-D or IBS-C), which should be studied in separate clinical trials owing to their significantly different signs and symptoms.23 Trials should be randomized and placebo controlled and include a period of training patients on the method of PRO data collection, followed by a treatment period of at least 8 weeks for agents that will be administered on a chronic basis.23 Recommended primary end points for IBS-D trials include abdominal pain intensity and stool consistency as both clinical trial entry criteria and in the definition of “responder” for clinical trial results.23

As the American Gastroenterological Association (AGA) pointed out in 2014, studies of the use of pharmacologic agents in IBS have generally used placebos as comparators (controls), and as a result, there is a lack of comparative effectiveness trials in patients with IBS.20 It is a challenge to evaluate the comparative effectiveness of different pharmacological agents due to the variation among study end points across clinical trials. For example, prior to the FDA-defined criteria for responder to pharmacological IBS-D therapy in 2012, adequate global relief was considered a critical efficacy outcome in clinical trials. Trials may inconsistently report outcomes which make it difficult to assess across agents for effectiveness (ie, quality of life improvements, abdominal pain, frequency of bowel movements, stool consistency).20 Although some treatments have limited benefit in the short term, there are no interventions that alter the long-term natural history of IBS, nor is there agreement on a gold standard for treatment of this condition. The high rate of response to placebo in IBS trials complicates clinical trial end points.21,24

It is not possible to directly compare the results of the clinical trials for current IBS therapeutics because these trials were conducted at different times, enrolled diverse patient populations, used varying diagnostic criteria for IBS, and defined responses and end points differently.24 Nevertheless, in evaluating pharmacologic treatments for IBS and selecting agents for use for individual patients, adverse events and the number needed to harm (NNH) should be taken into account.25 The NNH is a measure of the relative risk of adverse events (AEs) and evaluates the number of patients needed to be treated (NNT) to observe an AE or harm. Although AEs vary in severity and clinical significance, discontinuation of treatment can be considered highly suggestive of significant AEs.25

The efficacy and safety of pharmacologic agents for IBS, including data for harm events, where available, are discussed in detail in the next sections. Both the AGA and the American College of Gastroenterology (ACG) discuss the use of these agents in their guidelines for the management of IBS. It should be noted that the most recent guidelines from both the AGA and ACG were published in 201420,26 and therefore predate the approval of eluxadoline and rifaximin for IBS-D.27

Clinical Efficacy and Safety of Off-Label Pharmacologic Agents for IBS-D

A number of pharmacologic agents have been used to treat IBS-D despite lack of approval by the FDA for this indication; therefore, use of the agents discussed in this section is considered off-label. These agents include antidepressants, smooth muscle antispasmodics, and a synthetic, opioid receptor agonist antidiarrheal agent.

Antidepressants

 
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