Gut Feelings: Irritable Bowel Syndrome and Inflammatory Bowel Disease

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a chronic, functional, gastrointestinal (GI) disorder characterized by symptoms of abdominal pain associated with altered bowel habits.^1,2 A 2012 report noted that the cost of IBS is estimated to be $1.56 billion in indirect costs and $1.35 billion in direct costs.^1,3 Based on the Rome III criteria, IBS can be further subtyped as either diarrhea-predominant IBS (IBS-D) or constipation-predominant IBS (IBS-C).^1,4 Various pathophysiologic mechanisms responsible for the etiology of IBS include altered GI motility, visceral hypersensitivity, altered fecal flora, inflammation, increased intestinal permeability, bacterial overgrowth, genetic predisposition, and food sensitivity.^1,2

Constipation-Predominant IBS

In the American College of Gastroenterology (ACG) guidelines, OTC treatment is limited to bulking laxatives (eg, psyllium) or polyethylene glycol. Prescription agents for treating IBS-C include antispasmodic agents, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and prosecretory agents.⁵ The only recommended antispasmodic in the United States is dicyclomine, but it has limited long-term clinical use due to anticholinergic adverse effects (AEs; eg, blurred vision, dry mouth, dizziness, constipation).⁵ Although TCAs may modulate central and peripheral pain by inhibiting serotonin and norepinephrine uptake in IBS-C, their clinical use in providing symptomatic relief is weak, as noted by the ACG. In addition, TCAs have an extensive AE profile and lack FDA approval for treating IBS-C. Among the SSRIs, only fluoxetine, citalopram, and paroxetine have been studied. Although these 3 medications may mediate central and enteric pain, as well as improve patients’ overall well-being, data on using these medications in patients with IBS-C are limited, and further study is required. The 2 prosecretory agents granted FDA approval for treating IBS-C are lubiprostone and linaclotide; lubiprostone is indicated for women with IBS-C.⁵

Diarrhea-Predominant IBS

Treatment options for IBS-D are more symptomatic due to the lack of these medications undergoing prospective, randomized, double-blind, placebo-controlled trials.⁶ Dietary modifications that patients with IBS-D can incorporate include diets that are low in fiber, low in carbohydrates, gluten-free, and low in fermentable foods; however, these diets have not yet been studied to determine IBS-D symptom improvement. OTC options for IBS-D include the use of probiotics and loperamide, with both options improving diarrhea. Although OTC probiotics may also alleviate symptoms of bloating and pain in patients with IBS-D, they have not been tested and offer little therapeutic benefit. Prescription agents that improve symptoms in patients with IBS-D include diphenoxylate-atropine, antispasmodics, bile acid sequestrants, TCAs, and alosetron; however, anticholinergic effects limit the clinical use of diphenoxylate-atropine, antispasmodics, and TCAs.⁶

New Treatments for IBS

In May 2015, the FDA approved rifaximin (Xifaxan) and eluxadoline (Viberzi) for use in patients with IBSD. Rifaximin was previously approved for traveler’s diarrhea caused by Escherichia coli in adults and children 12 years and older, as well as for reducing the risk of hepatic encephalopathy recurrence in adults. The recommended dose is 550 mg 3 times daily for 14 days, and this therapy may be repeated in patients who experience recurrence.⁷ Eluxadoline is a mu-opioid receptor agonist, delta-opioid receptor antagonist, and kappa-opioid receptor agonist. By exerting its effects with opioid receptors in the gut, eluxadoline reduces intestinal contractility and neurogenically mediated secretions, resulting in reduced GI transit and fecal output.^1,8 The recommended dosage of eluxadoline is 100 mg twice daily with food. Eluxadoline should be discontinued immediately if patients experience unusual or severe abdominal pain, or severe constipation lasting longer than 4 days; the most common AEs are nausea and constipation. Eluxadoline produced a high rate of euphoria in human abuse potential studies, but this effect is less compared with oxycodone. Because of these results, the Drug Enforcement Administration classified eluxadoline as a schedule IV controlled substance.⁹

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a general term describing ulceration and/or inflammation in the GI tract, and is usually classified as either Crohn’s disease (CD) or ulcerative colitis. The Centers for Disease Control and Prevention (CDC) has estimated the total health care cost of IBD to be approximately $1.7 billion annually. With no cure for IBD, managing patients with IBD involves inducing and achieving remission, minimizing AEs, and improving quality of life.¹⁰

Along with the use of systemic corticosteroids and methotrexate, treatment of IBD may include the use of biologic response modifiers (BRMs), with antitumor necrosis factor (TNF)—α biologics being the most noted. In 2013, the American Gastroenterological Association (AGA) published guidelines for inducing and maintaining CD remission; therein, the AGA suggested that the clinical use of BRMs will increase exponentially.¹⁰

In 2015, a survey conducted by the AGA noted that 91% of physicians prescribe BRMs for their patients with IBD.¹¹ As efficacious as BRMs are, pharmacists must be aware of significant barriers with this therapy, especially its cost. In the same survey, 60% of physicians noted they adjusted their patients’ treatment due to their insurance plans. Treatment with BRMs, especially anti—TNF-α biologics, is further complicated by their AE profile, which includes potential immunosuppression, tuberculosis, and malignancies. Pharmacists must be prepared to address the limitations of BRM regimens to improve access to affordable care.

Mongersen

Among the increased prescribing of BRMs, the investigational drug, mongersen, shows promise in treating CD through a distinguished mechanism. The protein, SMAD7, is known to inhibit transforming growth factor (TGF)-β1, an immunosuppressive cytokine, and its decreased activity is associated with CD inflammation. Mongersen is an oral SMAD7 antisense oligonucleotide that downregulates SMAD7 activity, restoring TGF-β1 levels and activity, and suppressing CD-associated inflammation.¹²

A double-blind, placebo-controlled, phase 2 trial that evaluated the safety and efficacy of mongersen treatment in patients with CD was published in March 2015. Among study participants who received mongersen 40 mg daily and 160 mg daily, 55% and 65%, respectively, achieved clinical remission at day 15, and maintained remission for at least 2 weeks longer than patients who received a placebo (P <.001 for both groups). Longer studies evaluating clinical safety and efficacy, along with mucosal healing, are warranted.

Brian J. Catton, PharmD, graduated from the Bernard J. Dunn School of Pharmacy at Shenandoah University in Winchester, Virginia, in 2010. He received the Distinguished Young Pharmacist Award with the New Jersey Pharmacists Association in 2014 and founded its New Practitioner Network in 2015. He is a Scientific Communications Manager at AlphaBioCom in King of Prussia, Pennsylvania. His areas of interest include pediatrics, immunizations, drug-therapy management, social media, patient counseling, and immuno-oncology.

References

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• Brandt LJ, Chey WD, Foxx-Orenstein AE, et al; American College of Gastroenterology Task Force on Irritable Bowel Syndrome An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. doi: 10.1038/ajg.2008.122.
• Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10(7):712-721, e714. doi: 10.1016/j.cgh.2012.02.029.
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• Thomas RH, Luthin DR. Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents. Pharmacotherapy. 2015;35(6):613-630. doi: 10.1002/phar.1594.
• Lacy BE. Emerging treatments in neurogastroenterology: eluxadoline—a new therapeutic option for diarrhea-predominant IBS. Neurogastroenterol Motil. 2016;28(1):26-35. doi: 10.1111/nmo.12716.
• Tanzi MG. Two new choices for patients with IBS-D. American Pharmacists Association website. pharmacist.com/two-new-choices-patients-ibs-d. Published July 1, 2015. Accessed January 5, 2016.
• Viberzi [package insert]. Cincinnati, OH: Patheon Pharmaceuticals, Inc; 2015.
• Rosenberg C. Rules - 2015 - Proposed Rule - Placement of Eluxadoline Into Schedule IV. Drug Enforcement Administration website. deadiversion.usdoj.gov/fed_regs/rules/2015/fr0811.htm. Published August 11, 2015. Accessed January 5, 2016.
• Bhat S, Khamo N, Abdou S, Hanson R, Khiani V, Stubbings J. The pharmacist's role in biologic management for IBD in a health system—integrated practice model. Am J Pharm Benefits. 2015;7(5):215-220.
• American Gastroenterological Association. AGA survey reveals respondents' views on biosimilars. pharmacist.com/aga-survey-reveals-respondents-views-biosimilars. Published July 1, 2015. Accessed January 5, 2016.
• Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. New Engl J Med. 2015;372(12):1104-1113. doi: 10.1056/NEJMoa1407250.