Medication Summary
The selection of pharmacologic treatment for irritable bowel syndrome (IBS) remains symptom directed. Agents used for the management of IBS symptoms include anticholinergics, antidiarrheals, tricyclic neuromodulators (tricyclic antidepressants [TCAs]), prokinetic agents, soluble fiber, antibiotics, chloride channel activators, guanylate cyclase C (GC-C) agonists, 5-hydroxytryptamine type 4 (5-HT4) agonists, 5-HT3 antagonists, sodium-hydrogen exchange 3 (NHE3) inhibitors, and mixed opioid agonist/antagonists.
The American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) have published guidelines on the pharmacologic management of IBS. Their recommendations are similar, with minor differences. From the pharmacology perspective, the guidelines consider prescription and over-the-counter medication, and complementary treatments such as fiber, peppermint oil, and probiotics. [4, 5, 6]
In their 2020 monograph on the management of IBS, the ACG recommends the following to relieve global symptoms of IBS [6] : soluble fiber, peppermint, and tricyclic neuromodulators. Antispasmodics and probiotics are not recommended. Recommended to relieve diarrhea-predominant IBS (IBS-D) symptoms are rifaximin, alosetron, and mixed opioid agonist/antagonists. Bile acid sequestrants are not recommended. To relieve constipation-predominant (IBS-C) symptoms chloride channel activators, guanylate cyclase activators, and the 5-HT4 agonist are recommended. Polyethylene glycol (PEG) products are not recommended for global symptom relief, but they do provide relief of constipation.
In their 2022 guideline on the management of IBS-D, the AGA recommends eluxadoline, rifaximin, rifaximin retreatment, alosetron, and loperamide. [4] In their 2022 guideline on the management of IBS-C, the AGA recommends tenapanor, plecanatide, linaclotide, tegaserod in appropriate patients, lubiprostone, and PEG laxatives. [5] For global IBS symptoms, the AGA recommends tricyclic neuromodulators and antispasmodics and notes that while SSRIs are not recommended for relief of global or pain symptoms in IBS, these agents may be useful for comorbid mood symptoms. The AGA also notes that there is a lack of data on serotonin-norepinephrine reuptake inhibitor (SNRI) use in IBS.
In a 2020 AGA clinical practice guideline on the use of probiotics in the management of gastrointestinal disorders, probiotic use in adults and children with IBS is recommended only in the context of a clinical trial. [75] While the authors acknowledge there is public interest in use of probiotics, significant knowledge gaps exist.
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. [80]
The safety and efficacy of linaclotide in the treatment of IBS-C were evaluated in two 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 1605 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. [80, 81, 82]
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 relative to those who received placebo. [13]
Rifaximin was approved by the FDA in 2015 for IBS-D. [83] 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 days) 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 1803 patients, determined that rifaximin is more effective than placebo for global symptom relief and bloating. Adverse event rates were similar to placebo. [84, 85] Rifaximin is a nonabsorbed antibiotic. Retreatment is sometimes needed and considered effective. [6]
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. [86, 87, 88] 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). [86, 87] Tegaserod has been "shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients." [88] Evidence also exists in animal models that tegaserod may have a protective effect in inflamed colons. [88]
Lubiprostone (Amitiza)
Lubiprostone 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 chronic idiopathic constipation and 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 and a REMS program approved by the FDA on June 7, 2002. Restrictions were because of reports of infrequent but serious GI adverse reactions (eg, ischemic colitis, serious complications of constipation). In September 2023, the FDA removed the REMS program mandate for prescribers. Prescribers should note the narrow therapeutic window and select patients appropriately, as well as provide counseling regarding possible side effects.
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. Because of the risk of pancreatitis, eluxadoline is not indicated in patients without a gallbladder, with a history of pancreatitis, or who drink more than 2-3 drinks daily.
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 Neuromodulators (aka 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 modulating the gut's microbiome; the exact mechanism by which they work is under study.
Rifaximin (Xifaxan)
Rifaximin is a semi-synthetic 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 microbiome of the gastrointestinal tract. Those with a positive lactulose breath test have particularly good response rates. It is indicated for IBS-D in adult men and women.
Bulk-Forming Laxatives
Class Summary
Bulk-forming laxative 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.
Methylcellulose (Citrucel)
Methylcellulose 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.
