Current and emerging pharmacological treatment options for irritable bowel syndrome

Nov. 17, 2017

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects between 10 and 20 percent of the population in most countries and has significant impact on health care costs and quality of life. A disorder of the brain-gut axis, IBS is divided into subtypes according to the predominant stool pattern and has several associated pathophysiological mechanisms.

In articles recently published in Gastroenterology and Hepatology, Gut and the Handbook of Experimental Pharmacology, Mayo Clinic gastroenterologist Michael Camilleri, M.D., and co-authors provide an overview of available and emerging pharmacological options for the treatment of IBS.

"The current approach to IBS remains focused on treating the patient's predominant or most troublesome symptoms," says Dr. Camilleri. "Most pharmacotherapies have a modest impact and lack high-quality evidence supporting their efficacy. And none have been shown to alter the disease-modifying mechanisms leading to gut dysfunction, or the long-term natural history of the disorder."

Available treatments that target constipation-predominant (IBS-C) and diarrhea-predominant IBS (IBS-D) are effective; treatments to address IBS-related pain are somewhat limited.

"Research leading to better understanding of pathophysiological mechanisms associated with IBS will help develop more effective interventions targeting those mechanisms and high-quality, randomized, controlled trials testing their efficacy," explains Dr. Camilleri.

Antispasmodics

This group of drugs inhibits the action of acetylcholine at muscarinic receptors, or by blocking calcium channels on gastrointestinal (GI) smooth muscle. Prescribed for abdominal pain and global symptom relief, first line treatment options include hyoscyamine and dicyclomine. Other treatment options available in other countries but not yet approved in the United States are otilonium bromide, cimetropium and pinaverium.

Peppermint oil

The menthol in this oil has antispasmodic properties, inhibiting smooth muscle contractility in the GI tract by blocking calcium influx. Multiple small studies suggest that peppermint oil is superior to placebo for global improvement of IBS symptoms and improvement in abdominal pain. However, larger studies are needed to collect sufficient data about the efficacy and safety of this agent.

Antidepressants

Evidence related to the treatment of IBS with antidepressants and psychological therapies continues to accumulate. Although the exact mechanism of action remains unclear, antidepressants affect GI motility and sensation, in addition to their central effects. Tricyclic antidepressants (TCAs) prolong orocecal and whole-gut transit times, and selective serotonin reuptake inhibitors (SSRIs) decrease orocecal transit time. Based on these findings, TCAs are recommended for the treatment of IBS-D, and SSRIs for the treatment of IBS-C.

Opioid receptor agonists

These drugs slow GI and colonic transit, increase fluid absorption, and reduce pain sensation. Used as anti-diarrheal agents for many years, loperamide and diphenoxylate are µ-opioid receptor agonists. Eluxadoline is an approved novel κ- and μ-opioid receptor agonist and δ-opioid receptor antagonist with efficacy in treating IBS-D. The Food and Drug Administration (FDA) recommends that patients with a history of biliary obstruction, cholecystectomy, pancreatitis, severe liver impairment or severe constipation, and patients who consume more than three alcoholic drinks per day, should not be prescribed eluxadoline.

5-HT3 receptor antagonists

Drugs that act on the 5-HT3 receptor can retard colonic transit and reduce visceral pain through effects on the brain, visceral afferents and the enteric nervous system. This class of drugs is used to treat IBS-D and includes alosetron (for severe IBS-D in female patients), ramosetron (not approved in the United States) and off-label use of ondansetron. The drug dosage needs to be titrated to avoid constipation.

Experimental visceral analgesic therapies

  • Histamine H1 receptor antagonist (ebastine) — this nonsedating drug can reduce visceral hypersensitivity and overall IBS symptoms and abdominal pain.
  • Neurokinin-2 receptor antagonist (ibodutant) — can produce a dose-dependent improvement in overall symptoms, abdominal pain and stool pattern in IBS-D in females, but not in males.
  • Selective inhibitor of translocator protein (TSPO) — can improve abdominal pain in patients with IBS.

GABAergic agents

This group of drugs, including gabapentin and pregabalin, reduces the release of several excitatory neurotransmitters involved in pain mechanisms. Small studies testing gabapentin and pregabalin suggest that these drugs may relieve pain and other symptoms in patients with IBS.

Bile acid sequestrants

About 25 percent of patients with IBS-D show evidence of bile acid (BA) malabsorption. BA sequestrants may thus be especially useful in patients with evidence of excessive BA synthesis or fecal excretion. Small open-label studies have yielded promising results and require replication in randomized, controlled trials.

Nonabsorbable antibiotics

Several studies suggest that rifaximin can improve global IBS symptoms and relieve bloating, possibly by treating small intestinal bacterial overgrowth detected on hydrogen breath testing or by accelerating colonic transit. The FDA has approved the use of rifaximin for patients with IBS-D with up to two repeat treatments in case of recurrence of symptoms.

Intestinal secretagogues

This group includes chloride channel-related agents, such as lubiprostone, linaclotide and plecanatide, and sodium-hydrogen exchangers, such as tenapanor. Lubiprostone and linaclotide are approved by the FDA for the treatment of chronic idiopathic constipation (CIC) and IBS-C. Plecanatide is approved for CIC and will be reviewed by the FDA for approval for IBS-C in the first quarter of 2018.

5-HT4 receptor agonists

This class of drugs includes tegaserod, prucalopride, naronapride, velusetrag and mosapride. Large trials have demonstrated the efficacy of tegaserod in relieving IBS-C symptoms, including abdominal pain or discomfort or both, bloating and constipation. Newer unapproved medications in this class, including prucalopride, naronapride, velusetrag and YKP10811, have fewer cardiovascular liabilities when compared with tegaserod.

For more information

Camilleri M. Medical therapies in the pipeline for irritable bowel syndrome. Gastroenterology and Hepatology. 2017;13:550.

Camilleri M, et al. Irritable bowel syndrome: Pathophysiology and current therapeutic approaches. Handbook of Experimental Pharmacology. 2017; 239:75.

Camilleri M, et al. Dietary and pharmacological treatment of abdominal pain in IBS. Gut. 2017;66:966.