Current Gastroenterology Reports (2019) 21: 25 https://doi.org/10.1007/s11894-019-0692-7 LARGE INTESTINE (B CASH AND S KHAN, SECTION EDITORS) Update on Pharmacotherapy for Irritable Bowel Syndrome Akhil Munjal1 & Bhavtosh Dedania2 & Brooks Cash2 Published online: 25 April 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Irritable bowel syndrome (IBS) is a functional GI disorder that affects a large percentage of the population and presents a significant socio-economic burden on the society. In this article, we reviewed the evidence supporting various pharmacological treatment options for IBS. Recent Findings Rifaximin, eluxadoline, and alosetron have demonstrated that they reduce symptom severity improving quality of life in patients with IBS–diarrhea. Ramosetron is a promising agent in development. Peppermint oil has also demonstrated a positive impact on some symptoms of IBS. For IBS with constipation, traditional laxatives have failed to demonstrate significant benefit. However, lubiprostone, linaclotide, and plecanatide have demonstrated improvement of IBS with constipation in large, placebo-controlled trials. Tenapanor, a sodium/hydrogen exchanger 3 inhibitor, appears to be a promising treatment option in the pipeline. Summary There are multiple pharmacologic agents with a variety of mechanisms that have demonstrated efficacy in IBS with diarrhea and constipation. There are no established pharmacologic agents for IBS with a mixed bowel pattern. There is a promising pipeline for additional novel therapies for IBS. Keywords Irritable bowel syndrome . Pharmacologic therapies . Diarrhea . Constipation Introduction and higher utilization of healthcare resources. Patients with severe IBS symptoms miss more days of work leading to Irritable bowel syndrome (IBS) is a chronic functional gastro- decreased productivity. Many patients undergo extensive intestinal (GI) disorder affecting a sizable percentage of the medical evaluation including endoscopic, laboratory, and ra- adult population, with a prevalence as high as 15% in Europe diologic tests that are often unrevealing as IBS has no reliable and North America [1]. IBS has an especially high prevalence biomarkers [2]. Multiple proposed theories and mechanisms in working-age adults and represents a significant socio- regarding the pathophysiology of IBS include altered GI mo- economic burden on patients and society. There is a significant tility, visceral hypersensitivity, alteration in the brain-gut axis, reduction in the quality of life of patients afflicted with IBS alteration of the gut microbiome, including food intolerances, post-infectious immune reactivity, and chronic intestinal in- This article is part of the Topical Collection on Large Intestine flammation. However, the exact etiology is still unclear and it is likely that there are multiple and inter-related factors lead- * Brooks Cash ing to IBS symptom generation [3]. Based on the Rome IV [email protected] criteria [4, 5], IBS is characterized by pain or discomfort as- Akhil Munjal sociated with altered bowel habits, including both constipation [email protected] and diarrhea, and can include postprandial urgency, abdomi- Bhavtosh Dedania nal bloating, or distention. Conventional therapies for many [email protected] years have consisted of anti-diarrheal and laxative medica- tions for bothersome bowel habits and anti-spasmodic or pain 1 Department of Internal Medicine, University of Texas Health Science medications for the sensory symptoms of IBS. This article will Center at Houston/McGovern Medical School, 6431 Fannin Street, focus on recent pharmacological advances in IBS Houston, TX 77030, USA pharmacotherapy. 2 Division of Gastroenterology, University of Texas Health Science IBS is broadly classified based on abnormal bowel habits Center at Houston/McGovern Medical School, 6431 Fannin Street, MSB 4.234, Houston, TX 77030, USA into four broad categories: IBS-D (predominantly diarrhea), 25 Page 2 of 7 Curr Gastroenterol Rep (2019) 21: 25 IBS-C (predominantly constipation), IBS-M (mixed pattern (incidence of 0.3% in pooled meta-analysis studies) [6]and including both diarrhea and constipation), and IBS-U (unclas- complications arising from constipation. The medication was sifiable within the three previously mentioned subtypes) [5]. withdrawn from the market in 2000 due to safety concerns; In addition, IBS is not static and patient symptoms can change however, due to its clinical utility in appropriately selected over time between different subtypes. An overview of phar- patients, it was made available again in 2002 under the aus- macologic therapies that are frequently used to treat the spec- pices of strict prescribing restrictions and a risk management trum of IBS as well as emerging pharmacologic therapies is program. In January 2016, the FDA removed the restrictive listed in Table 1. requirements of the risk evaluation and mitigation strategy (REMS) due to accumulated favorable safety data. The body of evidence demonstrating beneficial effects of alosetron is large. A randomized controlled trial by Cremonini Irritable Bowel Syndrome–Diarrhea et al. studied 705 women with IBS-D over a period of 12 weeks [7]. Subjects were randomized into various treat- Alosetron ment groups with different doses of alosetron vs placebo. This study showed a statistically significant improvement in Alosetron is a 5-HT3 receptor antagonist approved by the US quality of life in IBS-D patients who received one or more Food and Drug Administration (FDA) for treating IBS-D in doses of alosetron when compared with placebo, with the women refractory to “conventional” therapies. 5-HT3 recep- most common adverse effect being constipation. Treatment tor stimulation is associated with increased gastrointestinal with alosetron 0.5 mg daily and 1 mg BID decreased lost motility and secretion, and alosetron, being an antagonist, workplace productivity hours − 11.0 ± 3.3 and − 21.1 ± slows down fecal transit through the colon and provides more 4.1 h, p < 0.05, and lost social/leisure hours − 6.7 ± 0.8 and time for water absorption, resulting in a decrease in total mois- − 7.0 ± 0.9 days, p < 0.01, respectively. Another study by ture and volume of fecal waste products. Alosetron has been Camilleri et al. on 647 females with IBS-D or alternating associated with adverse events such as colon ischemia bowel patterns (IBS-A) yielded similar results. Patients were randomized into placebo vs 1 mg alosetron daily. It was found Table 1 Existing and emerging (*) IBS therapies that a greater proportion of participants in the alosetron group • IBS–Diarrhea reported adequate relief compared with the placebo (133 • Anti-diarrheals (41%) vs 94 (29%), respectively), for the 3 months of treat- – • Loperamide ment, with a statistically significant difference of 12% (4.7 • Diphenoxylate/atropine 19.2) between the groups. They also reported that patients in • Anti-spasmodics the treatment group had decreased urgency and stool frequen- • Dicyclomine cy and firmer stool texture [8]. • Hyoscyamine Currently, the use of alosetron is restricted to women with • Peppermint oil severe IBS-D without adequate response to conventional ther- • Antibiotics apy and with chronic IBS symptoms (greater than 6 months) • Rifaximin without any anatomical or biochemical abnormalities of the GI • 5-HT3 antagonists tract. Contraindications to the drug include history of chronic • Alosetron or severe constipation, strictures of the GI tract, history of • Ramosetron* perforation or adhesions, ischemic colitis, inflammatory bowel • Mixed opioid receptor agonist/antagonist disease, diverticulitis, and severe hepatic impairment. • Eluxadoline • IBS–Constipation Rifaximin • Laxatives • Osmotics Rifaximin is a gut-specific oral broad-spectrum antibiotic with • Stimulants very low systemic absorption and bioavailability. It primarily • Chloride channel activators acts by interfering with bacterial DNA transcription. Its exact • Lubiprostone effects on the generation and perception of IBS symptoms are • Guanylate cyclase receptor activators unknown, but leading theories suggest alterations in the gut • Linaclotide microbiome metabolism and/or host–microbiome interaction. • Plecanatide Two large randomized clinical trials (TARGET 1 and • Sodium/hydrogen exchanger 3 inhibitor TARGET 2) of 1260 IBS patients without constipation eval- • Tenapanor* uated the efficacy of rifaximin for improving IBS symptoms. Patients were randomized to receive 550 mg of rifaximin three Curr Gastroenterol Rep (2019) 21: 25 Page 3 of 7 25 times daily vs placebo for 2 weeks and then followed up for a improvement in groups randomized to 100 mg and 200 mg period of 10 more weeks. It was observed that a significantly BID dosing when compared with placebo. The 200 mg BID higher proportion of patients in the rifaximin group had ade- regimen was associated with more adverse effects, and there- quate relief of global IBS symptoms during the first 4 weeks fore, only 75 mg and 100 mg BID regimens were chosen for after treatment (41% vs 31% in TARGET 1 and 41% vs 32% phase 3 trials [14]. in TARGET 2) with a similar incidence of adverse effects [9]. The study population for the two phase 3 trials included Rifaximin has also been studied in a randomized trial in pa- patients who met Rome III criteria for IBS-D. Patients were tients with IBS-C (Rome II criteria), and this study found that randomized to receive either eluxadoline at a dose of 75 mg rifaximin