Medication Summary
The selection of pharmacologic treatment remains symptom directed. Agents used for the management of symptoms in irritable bowel syndrome (IBS) include anticholinergics, antidiarrheals, tricyclic antidepressants, prokinetic agents, bulk-forming laxatives, serotonin receptor antagonists, chloride channel activators, and guanylate cyclase C (GC-C) agonists.
A systematic review found that several antispasmodics, including peppermint oil, pinaverium, trimebutine, and cimetropium/dicyclomine, significantly outperformed placebo at improving irritable bowel syndrome symptoms and global assessment scores. [33] Pinaverium and cimetropium are not available in the United States. The National Institutes of Health's (NIH's) National Center for Complementary and Integrative Health (NCCIH) provides information regarding a small amount of research that suggests that peppermint oil may improve IBS symptoms. [4]
The 2009 American College of Gastroenterologists (ACG) position statement on the management of irritable bowel syndrome noted that the antidiarrheal agent loperamide effectively reduced stool frequency and improved stool consistency, but it did not relieve pain, bloating, or other global irritable bowel syndrome symptoms. [3] As noted earlier, the 2014 ACG monograph on the management of irritable bowel syndrome and chronic idiopathic constipation found insufficient evidence to recommend prebiotics or synbiotics, or loperamide, in irritable bowel syndrome, and no evidence that polyethylene glycol improved overall symptoms and pain in affected patients. [32] The most recent 2018 ACG monograph on the management of IBS has upheld these aforementioned recommendations. [52]
A Spanish expert consensus panel on functional digestive disorders have made evidence-based recommendations on the use of linaclotide, a GC-C receptor agonist, for the management of the constipation-predominant disease (IBS-C) subtype. [53] Their recommendations include continuous (not sporadic) use of linaclotide therapy for moderate to severe IBS-C, patient education regarding the risk of diarrhea and its management options, and the maintenance of linaclotide therapy for potentially long periods on the basis of the lack of tachyphylaxis or potential risks. [53] In 2018, another GC-C receptor agonist, plecanatide, was approved by the FDA for treatment of IBS-C in adults. [54]
Rifaximin was approved by the FDA in 2015 for IBS-D. [55] A total of 1260 patients with IBS without constipation were enrolled in the TARGET 1 and TARGET 2 phase III trials at 179 investigative sites in the United States and Canada. Results showed that treatment with rifaximin (550 mg PO tid for 14 d) provided better symptom relief (eg, bloating, abdominal pain, loose/watery stools) compared with placebo, although the placebo effect was tremendous. Similarly, a 2012 meta-analysis of five studies, incorporating 1,803 patients, determined that rifaximin is more effective than placebo for global symptom relief and bloating. Adverse event rates were similar to placebo. [56, 57]
Tegaserod was reintroduced in the United States in 2019 after it had been suspended from the market in 2007 because of cardiovascular (CV) safety concerns. [58, 59, 60] The reapproved tegaserod indication is for women younger than 65 years with IBS-C who are without a history of CV ischemic disease and who have a low risk of developing CV disease. FDA approval was based on three multicenter, double-blind, placebo-controlled trials that stratified data from women with IBS-C (N = 2470). [58, 59] Tegaserod has been "shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients." [60] Evidence also exists in animal models that tegaserod may have a protective effect in inflamed colons. [60]
IBS Agents
Class Summary
Linaclotide and lubiprostone enhance chloride-rich intestinal fluid secretions without altering the sodium and potassium concentrations in the serum. Linaclotide was approved by the FDA in August 2012 to treat chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults. [61]
The safety and efficacy of linaclotide in the treatment of IBS-C were evaluated in 2 double-blind, placebo-controlled phase III clinical trials in which linaclotide met all four primary endpoints for changes in abdominal pain and constipation in each trial. The trials involved 1,605 patients aged 18-87 years, of which 807 were treated with linaclotide 290 mcg. Both trials showed a significantly higher proportion of responders in the linaclotide group compared with the placebo group. [61, 62, 63]
Tenapanor, an inhibitor of sodium-hydrogen exchange (NHE3) transporter, was approved in September 2019 for IBS-C. Approval was based on two phase III trials (N = 1226) that showed a statistically significant improvement in stool frequency and abdominal pain compared with those who received placebo. [6]
Lubiprostone (Amitiza)
This agent activates chloride channels on the apical part of the small bowel epithelium. As a result, chloride ions are secreted and sodium and water passively diffuse into the lumen to maintain isotonicity. This medication is FDA approved for use in idiopathic constipation and in irritable bowel syndrome with constipation.
Linaclotide (Linzess)
Guanylate cyclase agonist; activation of guanylate cyclase receptors in the intestinal neurons leads to increased cyclic guanosine monophosphate (cGMP), anion secretion, fluid secretion, and intestinal transit; it appears to work topically rather than systemically; when administered PO, linaclotide activates chloride channels in intestinal epithelial cells to increase intestinal fluid secretion; indicated to treat chronic idiopathic constipation and for IBS-C in adults.
Plecanatide (Trulance)
Plecanatide is a guanylate cyclase C (GC-C) agonist. Plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of intestinal epithelial cells. GC-C activation leads to increased cyclic guanosine monophosphate (cGMP), which, in turn, stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. It is indicated for IBS-C in adults.
Alosetron (Lotronex)
Alosetron is a 5-HT3 receptor antagonist. This agent controls irritable bowel syndrome symptoms through its potent and selective antagonism of serotonin 5-HT3 receptor type. These receptors are extensively located on the enteric neurons of the GI tract, and stimulation causes hypersensitivity and hyperactivity of the intestine. It is indicated only for women with severe diarrhea-predominant IBS who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the GI tract excluded, and have not responded adequately to conventional therapy.
Limiting its use to this severely affected population is intended to maximize the benefit-to-risk ratio. The drug was previously removed from the US market but was reintroduced with new restrictions approved by the FDA on June 7, 2002. Restrictions are because of reports of infrequent but serious GI adverse reactions (eg, ischemic colitis, serious complications of constipation), including some that resulted in hospitalization and, rarely, blood transfusion, surgery, or death. In order to prescribe, physicians must be enrolled in the Prescribing Program for Lotronex.
Under the new management plan, serious adverse events have been few. [28]
Tegaserod (Zelnorm)
Tegaserod is a serotonin type-4 (5-hydroxytryptamine-4 [5-HT4]) receptor partial agonist. It stimulates the peristaltic reflex and intestinal secretions, inhibits visceral sensitivity, enhances basal motor activity, and normalizes impaired motility throughout the gastrointestinal tract. It is indicated for adult women younger than 65 years who have irritable bowel syndrome with constipation (IBS-C). Its use is further restricted to women without a history of cardiovascular risk.
Eluxadoline (Viberzi)
Eluxadoline is a mu opioid receptor agonist. It also is a delta opioid receptor antagonist and a kappa opioid receptor agonist. The multiple opioid activity is designed to treat the symptoms of IBS-D while reducing the incidence of constipation that can occur with unopposed mu opioid receptor agonists. It is indicated for IBS-D in adult men and women.
Tenapanor (Ibsrela)
Tenapanor is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for absorption of dietary sodium. NHE3 inhibition reduces sodium absorption from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency. It is indicated for adults with IBS-C.
Anticholinergics
Class Summary
Anticholinergic agents are antispasmodics that inhibit intestinal smooth-muscle depolarization at the muscarinic receptor. These agents help relieve symptoms of intestinal spasms in irritable bowel syndrome.
Dicyclomine hydrochloride (Bentyl)
Dicyclomine blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and CNS. This drug decreases fecal urgency and pain. It is useful in patients with diarrhea-predominant symptoms. Adverse effects are dose dependent.
Hyoscyamine (Anaspaz, Levbid)
Like dicyclomine, hyoscyamine is useful in patients with diarrhea-predominant symptoms and blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects. The drug decreases fecal urgency and pain.
Antidiarrheals
Class Summary
These agents are nonabsorbable synthetic opioids. They prolong the GI transit time and decrease secretion via peripheral µ-opioid receptors. They reduce visceral nociception via afferent pathway inhibition.
Diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025 mg (Lomotil)
This drug combination consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive GI propulsion and motility, but it may exacerbate constipation.
Loperamide (Imodium)
Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.
Tricyclic Antidepressants
Class Summary
Tricyclic antidepressants have both antidepressive and analgesic properties. Agents such as imipramine and amitriptyline are efficacious in treating symptoms of irritable bowel syndrome. The use of tricyclic antidepressants in irritable bowel syndrome is off label.
Imipramine (Tofranil)
Imipramine increases pain threshold in the gut, thereby providing a visceral analgesic effect. It prolongs oral-cecal transit time; reduces abdominal pain, mucorrhea, and stool frequency; and increases global well-being variably. It is effective in irritable bowel syndrome in doses that are subtherapeutic for antidepressive actions, suggesting an independent mechanism of action in this disorder.
Amitriptyline (Elavil)
Like imipramine, amitriptyline provides a visceral analgesic effect at doses subtherapeutic for antidepressive actions. It also prolongs oral-cecal transit time, reduces abdominal pain, mucorrhea, and stool frequency, and increases global well-being variably.
Antibiotics
Class Summary
Antibiotics may play a role in the treatment of irritable bowel syndrome by preventing the overgrowth of intestinal bacteria.
Rifaximin (Xifaxan)
Rifaximin is a semisynthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, blocking one of the steps in transcription. This results in inhibition of bacterial protein synthesis and consequently inhibits the growth of bacteria. The exact mechanism of action for IBS-D is not known, but it is thought to be related to changes in the bacterial content in the gastrointestinal tract and reduction of gas. It is indicated for IBS-D in adult men and women.
Bulk-Forming Laxatives
Class Summary
These products are made of natural and semi-synthetic hydrophilic polysaccharides and cellulose derivatives that dissolve or swell in the intestinal fluid, forming emollient gels that facilitate the passage of intestinal contents and stimulate peristalsis. As fiber supplements, these products may improve symptoms of constipation and diarrhea, but their use in irritable bowel syndrome is controversial.
Methylcellulose (Citrucel)
This agent promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.
Psyllium (Metamucil, Fiberall, Reguloid, Konsyl)
Like methylcellulose, psyllium promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.
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Irritable Bowel Syndrome (IBS). What is IBS? IBS is a condition that involves recurrent abdominal pain as well as abnormal bowel motility, which can include diarrhea and/or constipation.
