Acid Reflux: The Search for Alternatives When PPIs Don't Work

Researchers are pursuing a variety of treatment options for the significant portion of patients whose reflux symptoms continue despite taking proton pump inhibitors.

Among patients who take proton pump inhibitors (PPIs) once daily, certain subgroups tend to have incomplete symptom resolution. Multiple studies have found that more than half of gastroesophageal reflux disease (GERD) patients on long-term acid-suppressive PPI therapy have persistent reflux. In addition, approximately 15% of patients with erosive esophagitis, 20% with Barrett’s esophagus, and 40% to 50% with non-erosive reflux disease or extraesophageal manifestations of GERD continue to experience reflux symptoms.

These patients need a new treatment approach. Researchers are examining ways to improve reflux control by developing better acid suppressors with more rapid onsets and longer durations, by testing prokinetic drugs, and by searching for ways to reduce esophageal sensitivity. The general consensus is that acid suppression alone will not work.

The authors of a forward-looking article on this topic published in the September 2012 edition of Expert Opinion on Emerging Drugs describe several novel investigational approaches to unresponsive disease. Among experimental PPIs, they note that tenatoprazole has a prolonged half-life of about 9 hours. A modified release formulation of dexlansoprazole releases the drug at 2 different pHs, creating double peak plasma concentrations. In addition, a handful of new drugs are under investigation: an extended-release formulation of rabeprazole, immediate-release formulations of omeprazole and esomeprazole, and new PPI molecular entities.

A different approach—transient lower esophageal sphincter relaxation (TLESR) reducers—builds on what we know about GABA_B agonists such as baclofen, which has been shown to reduce the number of TLESRs in humans. Several investigational agents may reduce TLESR more effectively.

The race is on to find drugs that can act directly on the esophagus and reduce its sensitivity. One candidate, AZD1386, is currently in human trials, and has been shown to decrease the esophageal pain perception threshold from heat. However, its effect on acid-induced, electrical, and mechanical pain was negligible. This agent also has an odd side effect: It causes a rise in body temperature, yet 50% of study subjects report feeling cold.

Clinicians have also used the prokinetics metoclopramide and cisapride to treat GERD, but their safety profiles may outweigh their benefits; metoclopramide has been associated with extrapyramidal side effects and movement disorders, and cisapride with serious cardiac events. In addition, mosapride and itopride are in clinical trials. Another prokinetic, rikkunshito, is a Chinese medicine containing hesperidin and L-arginine. A few studies have shown that it may be effective as an add-on therapy or on its own.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.