Some Laryngopharyngeal Reflux Resists PPI Treatment

A patient presents with cough, saying she feels as if there’s something stuck in her throat and sometimes her throat burns. These symptoms are consistent with laryngopharyngeal reflux (LPR) and, after taking a careful history and a detailed symptom profile, her otolaryngologist decides to put her on a proton pump inhibitor (PPI), the No. 1 medication indicated for LPR.

At a six-week follow-up, the patient’s symptoms haven’t diminished. She thought she was getting relief in the first month, but at the time of her appointment she is experiencing the same suite of irritating symptoms. What is the best course of action now?

This problem—how best to proceed with LPR patients who don’t respond to treatment—is a tricky one. The issue has been discussed, dissected and argued about by otolaryngologists. The jury is out on this issue, and there’s no good published evidence basis for creating practice guidelines.

“There have been several panels at academic meetings on this topic in the last few years,” said John Krouse, MD, PhD, chair and professor of otolaryngology-head and neck surgery at Temple University in Philadephia. “It’s a common problem: patient failures and incomplete responses.”

If there’s any consensus, it’s this: Reevaluate the diagnosis. “It’s a very challenging group of patients,” said John DelGaudio, MD, director of the Emory Sinus, Nasal, and Allergy Center and vice chair and professor of otolaryngology-head and neck surgery at Emory University in Atlanta. “If they don’t respond to proton pump inhibitors, reevaluate and be more diligent in ruling out other causes.”

The Basics of LPR

Symptoms of LPR may or may not include the sensation of a globus in the throat that won’t dislodge, postnasal drip, intermittent hoarseness, chronic sore throat and frequent throat clearing. “LPR is an extension of gastroesophageal reflux disease [GERD],” Dr. Krouse said. However, patients may have no clear GERD symptoms, such as heartburn or indigestion.

“Some degree of gastric regurgitation is normal,” said Kenneth Altman, MD, PhD, an associate professor of otolaryngology at Mount Sinai Hospital in New York City. “The problem is when it’s often, severe or it results in pathologic changes.”

It’s not clear how often LPR is diagnosed compared with the more common GERD. (See “Controversies Surrounding the Management of Patients with Reflux Disease,” below). But if it continues to follow in its big brother’s footsteps, it’s undoubtedly on the rise. Dr. Altman documented a quadrupling of GERD cases over about a decade, from 1990 to 2001 (Laryngoscope. 2005;115:1145-1153).

The standard approach to diagnosing LPR is to take a good history: How long have symptoms been occurring and when do they occur? Also, most otolaryngologists will do a laryngoscopy and look at the vocal cords, said Dr. Altman. This will provide the two basic indices of a diagnosis: the reflux symptom index (RSI), which includes the severity of symptoms such as hoarseness, throat clearing and coughing; and the reflux finding score (RFS), which checks for signs such as edema of the vocal cords and subglottis, and thick mucus.

Dr. Altman reviewed clinical practice guidelines for reflux disease in an abstract published in The Laryngoscope, in which he and his co-authors noted that most contributions to the guidelines came from gastroenterologists and not otolaryngologists (2011;121:717-723). Diagnosing by symptomology and prescribing medication comprised the most common approach for uncomplicated GERD. Defining GERD versus LPR and long-term management of patients were more variable and define the basis for the controversy that continues today.

Dr. Altman said that once a diagnosis is reached, the first thing to do is educate the patient about reflux. Some people may be prone to reflux because of their anatomy and physiology, but they may also have diet and lifestyle behaviors that contribute. “In my opinion, the first line of treatment is diet and behavior modification,” he told ENTtoday. “Acidic foods are a culprit, and our highly processed foods tend to be acidic.” In addition, he counsels patients on the seven most common things prevent reflux: foods and drinks that are carbonated, spicy, fatty, minty, caffeinated or alcoholic and—last but not least—tobacco.

The standard treatment regiment involves PPIs such as omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix) and esomeprazole (Nexium). Otolaryngologists who prescribe PPIs will also advise patients about dietary and behavioral changes that can help.

Positive patient response to PPI treatment reinforces the idea that LPR was the problem, said Dr. Altman. Conversely, when they don’t respond, physicians should go back and re-assess the diagnosis.

Treating the Nonresponsive Patient

Patients who don’t respond to initial PPI treatment may warrant further testing, as with a pH or impedance probe to measure the number of reflux episodes over a day or two, said Dr. Altman. “Otherwise, you’re wasting everyone’s time and delaying a diagnosis. Everyone talks about tests and the costs of health care. But what about the costs of delayed diagnosis—or treating when there’s no disease?”

There are consequences of reflux in the esophagus, he added. “Pepsin, acid, stomach contents—they all have effects on the lining of the esophagus and the throat, such as swelling or other changes. Look in the esophagus for those things,” he said. “LPR is a continuum of reflux disease in my opinion, although there is some debate on this.”

If reflux is suspected, either based on physical evidence or partial response to medicine, some otolaryngologists advise doubling the dose of PPIs. “I do think that some people do better, but there’s no convincing evidence base behind that,” said Dr. Krouse. “Anecdotally, yes.”

Otolaryngologists sometimes add an H2 blocker at bedtime, such as famotidine (Pepcid) or ranitidine (Zantac), to boost the pharmacologic effect.

Another factor to consider, said Dr. Krouse, is that patients have often had the problem for a long time. “You can’t expect to fix it right away. It might need several months to see signs of improvement,” he said. Doctors need to be patient and use good clinical judgment. Dr. DelGaudio asks his patients to be patient. “I tell them they may notice improvement in the first few weeks, but really it takes two to three months to see effect.”

While PPIs are the standard of care, results from clinical trials with these drugs do not reliably support their use. A systematic review of PPIs in LPR found that combined data from the best designed studies—randomized, placebo-controlled trials—found no overall benefit from using the drugs (Laryngoscope. 2006;116:144-148). Severity and frequency of symptoms after treatment were not statistically different between the placebo and drug treatment groups.

Additionally, given the fact that LPR is a symptom-based, descriptive diagnosis, misdiagnosis may dilute any positive effects of PPIs. Still, the fact remains that no one’s ever shown a cost-effective benefit to PPI medications, said Mark Courey, MD, an otolaryngologist at the University of California San Francisco School of Medicine. “Physicians need to be responsible about cost-effective treatments,” he said. “LPR is difficult to confirm, and is often overdiagnosed.”

If Not LPR, Then What?

“LPR is a diagnosis that otolaryngologists love,” said Dr. Krouse, but other things can cause the symptom profile of LPR, including allergies, sinusitis, asthma or any chronic inflammatory airway disease. “LPR is common, but allergy affects 25 percent of the population. Patients with allergies frequently have very similar symptoms,” he added. “Patients could have both problems: LPR and allergic airway disease. I advise my residents: Don’t close your mind that LPR is the correct and only diagnosis.”

Dr. DelGaudio suggested a few other conditions otolaryngologists should rule out: increased tone (hypertonicity) in the upper esophageal sphincter, the presence of masses in the pharynx or larynx and whether cervical osteophytes are impinging on the laryngopharyngeal area. “Age and weight can increase the risk of LPR, as can hiatal hernia, other issues with stomach emptying and esophageal musculature,” he said.

When reevaluating a patient, consider that there could be reflux other than the common acidic reflux. “It could be weakly acidic reflux, which is more difficult to treat, or even nonacidic reflux,” said Dr. DelGaudio. In those cases, PPIs are not going to be as effective, and otolaryngologists may want to consider fundoplication surgery, which strengthens the lower esophageal sphincter and diminishes reflux. This allows the esophagus and the larynx to heal.

Other pathologies can result from chronic LPR. “When you regurgitate stomach contents, enzymes like pepsin stick to the lining of the throat. Then every acid episode (either food going down or reflux coming up) interacts with the pepsin and starts to digest the larynx,” Dr. Altman said. Once the pepsin is seeded, it leads to a condition with a complex physiology—too complex for PPIs to restore, because they only treat the acid component.

A strict low-acid diet may be helpful in nonresponsive patients, according to a recent study of 20 patients with LPR who had failed to respond to twice-daily PPI treatment and H2 block at bedtime (Ann Otol Rhinol Laryngol. 2011;120:281-287). The researchers put the patients on a strict low-acid diet for two weeks, in which all foods and beverages with pH levels lower than five were eliminated from the diet. Improvement was seen in 19 people and complete resolution of symptoms in three.

Dr. Courey approaches the diagnosis more broadly from the get-go. “Reflux symptoms are really nonspecific indicators of laryngeal irritation,” he said. “Yes, reflux could be the problem, but it’s not the only possibility.” He advocates behavioral therapy, specifically voice therapy, to lessen the stress on the larynx. “We work with patients to increase the efficiency of voice production,” he added, which includes sessions with a vocal pathologist to enhance voice coordination, respiratory support and laryngeal action, trying to get patients to feel the balance among those three components of voice production.

Furthermore, Dr. Courey said 75 percent of his patients are helped by this approach, and have measurable reductions in their reflux symptom index score. “Is it a placebo effect? Maybe, but it doesn’t matter. It’s better than taking a pill with side effects,” he said.

Resolving the problem of how to treat LPR is not easy, and the philosophy on appropriate approaches will probably develop over the next few years. However, without good evidence-based data, finding clear answers will likely take longer than that.