Refractory GERD: Reaching for the high-hanging fruit*

COMPARED TO OTHER GASTROINTESTINAL (GI) SYMPTOM COMPLEXES, the medical management of gastroesophageal reflux disease (GERD) appears fairly straightforward. Whereas there are few pharmacotherapeutic options for many other GI symptoms for which patients may seek medical advice, the majority of patients with troublesome GERD symptoms can be rendered asymptomatic with a once-daily dose of a proton pump inhibitor (PPI) within 4 to 8 weeks of starting therapy. Thus, many may consider GERD an easily treated problem that can be vanquished with the mere stroke of a pen. Yet as a gastroenterologist, I find my patients with GERD to be some of the most difficult to treat. The patients I see are the relatively small group who do not obtain relief with that PPI prescription. Unfortunately, there are currently few therapeutic options that are effective in alleviating GERD symptoms that persist despite PPI use. While I often recommend that patients take their PPI twice daily instead of once, or switch to another PPI, this decision is based on limited data from uncontrolled open-label trials with significant methodologic flaws.1,2 Stepping down PPI therapy from double-dose to standard doses is successful for most patients.3 There are no other proven therapies, and I am left with limited therapeutic options for patients with refractory GERD. These patients are the proverbial high-hanging fruit that are the most difficult to reach. However, these fruit can grow the largest, rewarding those who develop tools to snare them. It is important to gain a better understanding of GERD pathophysiology to devise better strategies for helping these patients to obtain relief. GERD has been traditionally thought of as the reflux of acidic gastric contents into the esophagus, resulting in symptoms and/or esophageal injury. The gold standard diagnostic criteria for GERD involves 24-hour esophageal pH monitoring, requiring an intra esophageal pH of less than 4 for more than 4% of the time over a 24-hour period. It is generally believed that if there is no gastric acid production, there can be no reflux symptoms. However, reflux symptoms often persist. Studies confirm that the majority of patients with GERD-like symptoms, despite high-intensity (double-dose or greater) PPI therapy, have a very low prevalence of reflux by the gold standard definition.4 So what are the mechanisms responsible for ongoing symptoms? Because PPIs have been so effective in relieving GERD symptoms, the basic mechanism that enables gastroesophageal reflux has been mostly ignored. I am referring here to the presence of both anatomic factors, such as the presence of a hiatus hernia, and physiologic factors, specifically the function of the lower esophageal sphincter (LES). It is possible that non-acid gastric contents that access the esophagus through a faulty LES may cause symptoms. Another possibility may be that GERD-like symptoms are independent of gastroesophageal reflux, and are merely interpreted as GERD. A new clinical tool may help both investigation and management. With multichannel impedance manometry (MIM), an impedance catheter is passed transnasally into the esophagus. It detects the presence of gas and fluid in the esophagus, and the direction of travel (i.e., towards the stomach with a swallow, towards the mouth with gastroesophageal reflux). With MIM and pH monitoring, reflux episodes can be counted and separated into acidic and non-acidic events. If further combined with a patient symptoms diary, a clinician can determine the relationship of GERD-like symptoms to reflux events. Using MIM, researchers have shown that patients with GERD who are treated with PPIs do not have fewer reflux events, but the refluxate composition changes from primarily acidic to primarily non-acidic.5 Baclofen, which decreases LES relaxation frequency, decreases reflux events and symptom burden.6 Unfortunately, due to its side-effect profile, baclofen will likely not be widely used for refractory GERD symptoms. However, there may be other medications that improve LES function and have similar effects. It is also possible that surgical interventions may be useful for patients with refractory GERD symptoms who have ongoing non-acidic reflux.7 Hopefully, the development of MIM will foster further research into the pathophysiology of refractory GERD, allowing pharmaceutical developers to better identify potential therapeutic targets, and giving clinicians the tools necessary to pluck the juiciest fruit right from the highest reaches of the trees. Meanwhile, pharmacists should strive to identify patients with symptoms refractory to PPI therapy, who may be candidates for a PPI reduction or discontinuation. ■

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