9 Things to Know About Medical Therapies for IBS

Issue: July 2018

While diet-based and microbiome-based therapies gain speed in the gastroenterology world, irritable bowel syndrome has seen recent approvals in the medical therapy realm. Healio Gastroenterology and Liver Disease took the opportunity to speak with Lin Chang, MD, about what the practicing gastroenterologist needs to know about IBS treatment today.

Healio: How do you approach medical therapy in a patient with IBS-D?

There are multiple factors that I consider when determining treatment options in patients with IBS-D. These include the patient’s symptom presentation, their previous treatment history and preferences, pathophysiologic mechanisms that are likely to be contributing to their symptoms, scientific evidence of the mechanism of action, efficacy and safety of the treatments, and my clinical experience. Information about the patient’s clinical presentation, including the predominant symptoms (eg, pain, diarrhea, incontinence), coexistent conditions (eg, functional dyspepsia, anxiety, fibromyalgia) guides the treatment approach.

I consider the patient’s perspective on treatments they are interested or motivated in trying (eg, diet, pharmacotherapy, behavioral approaches), their expectations of treatment (eg, are they realistic?), and success or failure of past treatments. Providing education, realistic expectations and support through a therapeutic patient-provider relationship helps the patient understand the goals of the treatment approach and improve compliance.

The severity of symptoms also guides therapy. In patients with milder forms of IBS-D, dietary therapies (eg, low FODMAP diet), antidiarrheals, and antispasmodics can be recommended. For moderate to severe symptoms, efficacious treatment options include Xifaxan (rifaximin, Salix), Viberzi (eluxadoline, Allergan) in patients with a gallbladder and without alcohol abuse, and neuromodulators (eg, low dose tricyclic agents). A subset of patients with IBS-D may have bile acid diarrhea, and thus a bile acid sequestrant may relieve symptoms. If bloating is a predominant symptom of IBS-D, dietary modification and rifaximin can be considered earlier in the approach. In IBS-D patients with chronic, predominant abdominal pain, a low dose tricyclic agent is an appropriate choice. The 5HT3 antagonist, Lotronex (alosetron hydrochloride; Sebela), can be very efficacious in treating severe IBS-D when other treatments fail but is on restricted use due to its association with ischemic colitis.

In patients who prefer non-pharmacologic treatments, experience side effects with medications, or have symptom-related anxiety or coexistent mood disorders, behavioral therapies should be considered and include cognitive behavioral therapy, hypnotherapy, and mindfulness-based stress reduction.

Healio: How about IBS-C?

Much of my treatment approach with regard to considering multiple factors is similar to what I do for IBS-D.

In patients with mild symptoms, dietary modification with fiber supplementation is efficacious, although I usually suggest starting at lower than the recommended daily dose of fiber to avoid or minimize discomfort, bloating and gas. The patient can gradually increase the fiber dose to achieve relief of constipation symptoms. As with IBS-D and IBS-M patients, a dietitian consult can be very valuable. I find that patients like following a structured plan that can include increased fiber, avoiding or eating certain foods, magnesium supplementation that acts as an osmotic laxative, and probiotics. Dietary therapy improves their symptoms and gives them a sense of control over their symptoms.

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In patients with mild to moderate symptoms but without significant abdominal pain, a trial of an osmotic laxative, such as polyethylene glycol (PEG), is a reasonable and inexpensive treatment option. PEG has been shown to improve bowel habits but not significantly reduce abdominal pain in IBS-C. Amitiza (lubiprostone, Takeda) is efficacious in relieving mild to moderate IBS-C symptoms. I also use this medication in older patients who prefer to try a medication that has been available for a long time and is less likely to cause diarrhea since they have a harder time getting to the bathroom quickly.

In patients with moderate to severe symptoms including those with pain-predominant symptoms, a guanylate cyclase-C agonist, ie, Linzess (linaclotide, Allergan/Ironwood) and Trulance (plecanatide, Synergy), is efficacious in treating abdominal (eg, pain, bloating) and constipation symptoms in IBS-C. Linaclotide comes in three doses (72, 145, and 290 µg/day), which allow flexibility and adjustment of an optimal dose to treat symptoms. Plecanatide is available as a single dose of 3 mg/day and is tolerated well.

In IBS-C patients with persistent abdominal pain despite normalizing bowel habits, a serotonin-norepinephrine reuptake inhibitor (SNRI), low doses of a tricyclic agent (TCA) or one with more confined pharmacologic targets (eg, duloxetine) can be useful. TCAs have SNRI properties and additional anticholinergic and antihistamine receptor antagonist activity, and thus it is less desirable to use in constipation. However, if used, the constipation treatment may need to be increased if constipation symptoms worsen. Like IBS-D, behavioral or integrative medicine approaches can be very helpful in patients.

Healio: And for IBS-M?

There is a lack of randomized, controlled clinical trials studying efficacy of treatment in patients with IBS-M. This is likely due to the difficulty of determining the treatment responder definition since these patients have both diarrhea and constipation. Studies have shown that IBS-M patients report multiple GI symptoms that IBS-C and IBS-D patients experience.

It’s important to obtain a more detailed description of the bowel habit and pain pattern since IBS-M symptoms range from a more constipation-predominant to a more diarrhea-predominant pattern. A typical pattern in IBS-M is several days of no or small, hard stools followed by 1 to 2 days of abdominal pain with frequent bowel movements that are initially hard or formed and become progressively loose or watery. I find that treating the constipation symptoms reduces symptoms and can even mitigate the diarrheal phase. I try to avoid the patients going back and forth using antidiarrheals for diarrhea symptoms and constipation medications for constipation symptoms. Like the other IBS bowel habit subtypes, dietary and behavioral therapies should be considered as they can be helpful to reduce multiple symptoms.

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Healio: What do you think are the top 3 most important advances in the medical treatment of IBS over the past 10 years?

Dietary therapy, namely low FODMAP (fermentable oligo- di- mono-saccharides and polyols) diet, for IBS. This treatment reduces symptoms in 50% to 75% of IBS patients, although patients should not remain on full FODMAP exclusion after the initial 4 to 6 weeks. Reintroduction of FODMAPs should be conducted preferably under the guidance of a GI dietitian.
Microbiome-directed therapies including dietary modification, antibiotics and probiotics although the latter appears to have less significant benefit than the other two therapies.
Prosecretory agents including guanylate cyclase C agonists, linaclotide and plecanatide, and the chloride channel 2 (ClC2) activator, lubiprostone, have all been approved for the treatment of IBS with constipation.

Healio: Do you think gut microbiome research in IBS is more hit or hype?

Studies support that the gut microbiome contributes to the pathophysiology of IBS. A gastrointestinal infection can trigger the onset of IBS, ie, post-infection IBS, in a subset of patients. Further, the fact that microbiome-targeted therapies, such as the low FODMAP diet, antibiotics and probiotics have been shown to relieve symptoms of IBS, suggests that the gut microbiome contributes to the pathophysiology of IBS.

The presence of small intestinal bacterial overgrowth in IBS is a controversial issue. Given that IBS is a multifactorial condition, it is conceivable that the microbiome is not a single contributing factor. Multiple factors such as diet, intestinal barrier function, gut immune function, visceral hypersensitivity and altered gut motility may interact with gut microbiota and metabolites to increase the risk for IBS and/or severity of symptoms in IBS.

Clinical research studies evaluating the efficacy of these microbiome-targeted therapies in IBS should be used to guide treatment in IBS patients. The low FODMAP diet has been shown to be efficacious in all bowel habit subtypes of IBS, although more recent trials have studied this diet in predominantly non-constipated IBS patients. Rifaximin, a broad spectrum, non-absorbable antibiotic has been shown to be efficacious in improving abdominal pain, stool consistency and bloating in patients with IBS-D. Probiotics have been demonstrated to reduce overall IBS symptoms, bloating and in some studies, constipation. There are emerging studies that are evaluating the predictive ability of certain biomarkers of treatment response, eg, lactulose hydrogen breath test for rifaximin and stool microbial pattern for low FODMAP diet. Further data are needed.

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Healio: What are the benefits of guanylate cyclase C (GCC) agonists for abdominal symptoms in IBS patients?

Studies have demonstrated efficacy of both available guanylate cyclase C agonists in reducing abdominal pain and bloating in addition to constipation symptoms. However, abdominal pain and bloating gradually decline over weeks with the maximal beneficial effect occurring in 8 to 12 weeks. The effect on bowel habits occurs more rapidly. Thus, these medications should be continued for 2 to 3 months before determining their maximal effect on abdominal pain and bloating.

Healio: How is eluxadoline different than loperamide? In whom might eluxadoline be useful? Whom should we avoid treating with eluxadoline?

Eluxadoline is a m- and k-opioid agonist and d-opioid antagonist, while loperamide is an m-opioid agonist. The mixed opioid effects of eluxadoline is thought to potentiate its beneficial effect on abdominal pain and reduce its potential to cause constipation. Randomized, placebo-controlled trials have demonstrated that eluxadoline is efficacious in patients with IBS-D. However, eluxadoline is contraindicated in patients who lack a gallbladder and history of alcohol abuse due to an increased incidence of sphincter of Oddi dysfunction and pancreatitis.

Healio: Any highlights from DDW on medical treatments for IBS that you would like to discuss?

There were several interesting IBS treatment studies presented at the DDW meeting.

Plecanatide was shown to have long-term safety and tolerability over 1 year in patients with IBS-C. Diarrhea was reported in 6.7% of patients but led to study discontinuation in 2.7% of patients. An interesting study found that circulating blood levels of pro-uroguanylin (inactive propeptide and precursor of uroguanylin in the small intestine) and uroguanylin (natural ligand of GC-C receptors) are lower in patients with IBS-C and chronic idiopathic constipation (CIC) compared with that in healthy control participants. This may reflect a paracrine hormone insufficiency of pro-guanylin in the small intestine in patients with chronic constipation. It would be interesting to see if levels predict therapeutic response to a guanylate cyclase C agonist, eg, plecanatide and linaclotide.

Randomized clinical trials comparing the efficacy of kiwifruit (2 per day), which contain 3.4 g fiber/100 g, and psyllium (7.5 g per day) were conducted in patients with IBS-C and CIC. Compared with psyllium, kiwifruit was found to significantly increase complete spontaneous bowel movement frequency and other GI symptoms, improve quality of life, and accelerate colon transit in constipated patients. These studies were not conducted in large sample sizes, but the findings suggest that kiwifruit may be an effective first-line alternative to psyllium in IBS-C and CIC.

There were also three controlled trials assessing the efficacy of fecal microbial transplantation (FMT) in IBS. FMT using fresh stool administered via nasojejunal/duodenal route was associated with significant improvement in overall IBS symptoms and bloating in non-constipated patients compared with the patient’s own stool (placebo). Significant reductions in other individual IBS symptoms was demonstrated with FMT and not with placebo although there was no group difference. FMT was also associated with significant changes in gut microbiota, which appear to be related to treatment success. Two other studies compared FMT administered by oral capsules vs placebo in IBS. Neither showed a significant benefit of FMT on IBS symptom severity vs placebo. However, one of these studies conducted in IBS-D patients found that there may be efficacy in the subgroup of patients with post-infection IBS. Larger, controlled trials assessing FMT in IBS are needed.

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Healio: What do you think the future holds for the medical treatment of IBS?

There are ongoing efforts in drug development, microbiome related treatments, and behavioral and complementary alternative medicine approaches for the treatment of IBS. Additionally, identification of phenotypic subgroups within IBS that may respond differentially to different treatments will likely be a focus in future research studies. This line of research will also aim to identify therapeutic biomarkers that predict response to treatment.

References:
Halkjær S, et al. Abstract 914. Presented at: Digestive Disease Week; June 2-5, 2018; Washington, D.C.
Holvoet T, et al. Abstract 617. Presented at: Digestive Disease Week; June 2-5, 2018; Washington, D.C.

For more information:
Lin Chang, MD, is a professor of medicine at the David Geffen School of Medicine at UCLA and the Vice-Chief of the Vatche and Tamar Manounkian Division of Digestive Diseases. She can be reached at LinChang@mednet.ucla.edu.