How do I integrate new IBS therapeutics into clinical practice?

Irritable bowel syndrome (IBS) is a complex, multifactorial disorder characterized by chronic or recurrent abdominal pain associated with altered bowel habits. My general approach is to identify the predominant or most bothersome symptoms and the most likely pathophysiologic mechanisms underlying these symptoms. Then I target treatment toward these predominant symptoms and mechanisms. Validating symptoms, building trust, developing a therapeutic alliance and establishing continuity of care are the cornerstones of treating IBS.

Patients often require medications to help treat their symptoms associated with IBS. Factors I consider when choosing a therapy include the patient’s response to previous treatments, including their effectiveness and associated side effects, the severity of symptoms, drug cost, the patient’s motivation and preference for certain types of treatment, comorbid conditions, and potential adverse events of the treatment. These factors, as well as the available scientific evidence, and my clinical experience help guide my choice of therapies.

One of the newer therapies approved by the U.S. Food and Drug Administration (FDA) for IBS with constipation (IBS-C) is plecanatide, which is a guanylate cyclase-C agonist in the same class of agents as linaclotide. Plecanatide is available as a once-daily 3-mg oral tablet. Compared with placebo, plecanatide significantly improves abdominal pain, increases the number of complete spontaneous bowel movements, and improves stool consistency. Alternatively, linaclotide is a once-daily gel capsule available in 72-, 145- and 290-μg doses. Similar to plecanatide, linaclotide, at a daily dose of 290-μg, also significantly relieves abdominal pain and symptoms related to IBS-C when compared with placebo.

Improvement in bowel habits with these medications typically occurs within the first week of treatment, but the maximal effect in abdominal pain and bloating relief may take up to 12 weeks. Thus, if pain is a predominant symptom, then these medications should be continued for two to three months to assess their maximal effect. If the patient’s stool frequency is more than three times per week, I may start linaclotide at 145 μg daily and see how they respond. Although this is the FDA-approved dose for chronic idiopathic constipation, if I have any concern about diarrhea — the main adverse event of linaclotide — I will try this dose first. If patients do not have significant relief of constipation within one to two weeks, then I increase the dose to 290 μg daily, which is the FDA-approved dose for IBS-C. If I have difficulty finding an optimal dose to treat symptoms, then I advise the patient to dissolve the gel capsule contents of linaclotide in a small amount of water. I ask the patient to use this liquid form and take a portion of the dose. In this regard, I like the flexibility of the linaclotide dosing.

Because plecanatide was only recently approved by the FDA for IBS-C, some insurance companies may not yet approve the use of plecanatide without the patient first trying lubiprostone, a chloride channel 2 activator, or linaclotide. Because no head-to-head comparisons of linaclotide and plecanatide currently exist, I cannot accurately compare their efficacy. However, my impression in the limited number of patients in whom I have used plecanatide is that the 3-mg dose of plecanatide is comparable to the 145-μg dose of linaclotide. Although plecanatide showed a relatively lower incidence of diarrhea than linaclotide, this adverse event can still occur. Some of my patients prefer the effect of plecanatide on their IBS-C symptoms over linaclotide. They report that their stool is more formed, which is associated with improved sensation of evacuation.

If a patient with IBS-C has mild to moderate symptoms that are unresponsive to fiber supplementation and over-the-counter laxatives, then I will prescribe lubiprostone or plecanatide. In some of my elderly patients, I prefer to use a medication with little risk of diarrhea, because these patients have more difficulty reaching the bathroom in time and they tend to prefer medications that have been on the market for a longer period of time. For moderate to severe symptoms, I prescribe plecanatide or linaclotide. For more severe symptoms related to IBS-C, especially in patients with decreased stool frequency and increased abdominal pain and bloating, I initially prescribe linaclotide once-daily 290 μg.

Factors I consider when choosing a therapy include the patient’s response to previous treatments, including their effectiveness and associated side effects, the severity of symptoms, drug cost, the patient’s motivation and preference for certain types of treatment, comorbid conditions, and potential adverse events of the treatment.

Approved for the treatment of IBS with diarrhea (IBS-D), eluxadoline is a first-in-class, mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that is minimally absorbed. When compared to placebo, both doses of twice-daily eluxadoline (75 and 100 mg) improved abdominal pain and stool consistency in patients with IBS-D, including those whose condition did not respond to loperamide. However, a significant effect on lowering abdominal pain alone was not observed (i.e., 30 percent reduction in pain rating). Due to its increased risk of pancreatitis and sphincter of Oddi dysfunction, eluxadoline is contraindicated in patients without a gallbladder and in those with a history significant for alcohol abuse.

Based on my experience with eluxadoline, I prefer to use the lower, twice-daily dose of 75 mg in patients whose moderate symptoms occur two to three days per week. Eluxadoline can be associated with constipation and, if this occurs, patients taking it can feel more uncomfortable than when they were experiencing diarrhea. If patients have moderate to severe symptoms most days of the week, then I usually prescribe twice-daily eluxadoline 100 mg. If they have predominant abdominal pain with diarrhea, then eluxadoline can be tried; however, a low-dose tricyclic agent should be considered first due to the visceral analgesic and anticholinergic effects of this drug class.

Although the focus of this article is on the newer pharmacologic treatments for IBS, it is important to consider that patients can also significantly benefit from nondietary and nonpharmacologic therapies (e.g., behavioral therapy) as well as other pharmacotherapy. In summary, the choice of a pharmacologic agent depends on multiple factors, including scientific evidence, and patient- and clinician-related factors. Typically, I discuss the various therapeutic options with a patient and we make a decision together — a process called shared decision-making. I feel that this approach gives patients a greater sense of control and empowerment. It also supports the concept that treating IBS is based on a partnership between the patient and the health care professional.

Dr. Chang is a speaker for Allergan and sits on the advisory board for Synergy. Dr. Chang is Clinical Research Councilor of the AGA Institute Governing Board.

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