COVER STORY

GERD BEYOND THE ESOPHAGUS

Researchers are finding that acid reflux can touch off asthma, laryngitis, and even otitis media

As research into gastroesophageal reflux disease (GERD) continues, clinicians are discovering more about the disorder. New therapies, new sequelae, and new definitions are emerging. For starters, experts now believe GERD is not one disease but a group of several disorders.

Charles Ponte, Pharm.D., CDE, BC-ADM, explained that GERD has been separated into at least two separate disorders: erosive esophagitis (EE) and nonerosive reflux disease (NERD). Many people are now using GERD as an umbrella term for esophageal reflux disorders, said Liza Takiya, Pharm.D., CDE, BCPS, assistant professor of clinical pharmacy at the University of the Sciences in Philadelphia. However, another way to look at it is GERD applies to reflux with some esophageal structural changes, and NERD is reflux without these changes. In both cases, patients can be symptomatic or asymptomatic.

It is important to diagnose EE and NERD and get the symptoms under control promptly, Takiya said. Treatment of NERD can prevent reflux esophagitis, EE, and Barrett's esophagus. This is particularly critical with EE. Without proper treatment, EE can progress to more serious disorders. One of these, according to Ponte, a professor of clinical pharmacy and family medicine at West Virginia University, is stricture, a formation of scar tissue below the esophageal mucosa. The scar tissue narrows the esophagus, and this eventually causes swallowing difficulties. Left untreated, stricture can become so severe that even swallowing liquids is difficult.

Long-term EE can also progress to Barrett's esophagus. In Barrett's, some of the normal epithelium in the esophagus is altered and becomes columnar epithelium. In an unlucky few patients, these tissue changes develop into esophageal cancer, the most serious complication of acid reflux, said Ponte.

In addition to learning more about the esophageal consequences of reflux and EE, researchers are finding that all sorts of nonesophageal conditions may have an association with reflux. Asthma, insomnia, laryngitis, and even otitis media have been linked to acid reflux.

Conditions GERD can trigger

"The movement of acid to the bronchioles and into the oral cavity can have serious implications," Takiya said, "such as the exacerbation of asthma and development of tooth decay." Acid reflux can actually trigger an asthma attack, said Ponte. There are two possible mechanisms for this. In some cases, the reflux can be so high up that stomach acid gets into the lungs, causing irritation and triggering an attack.

Another possibility is that acid may irritate the vagus nerve via the esophagus. The vagus would then respond by shrinking airways and consequently causing an asthma attack. This scenario could be aggravated in the presence of xanthines (e.g., theophylline). Although not used as extensively now as in the past, xanthines are still sometimes prescribed for asthma, and, in this case, that would be a mistake. These drugs can actually lower esophageal sphincter pressure and tone, which would increase reflux and worsen asthma.

Ponte noted that chronic cough is another thing to watch for. Sometimes coughing is the only symptom of asthma. However, vagal nerve stimulation can also cause cough, and it is important to rule out acid reflux as the cause. Chronic cough is one of several atypical GERD symptoms, said Takiya. It may also be secondary to asthma, postnasal drip, and other conditions, so proper diagnosis is critical.

Probably the predominant symptom of acid reflux is heartburn. Because heartburn often occurs at night, many people with reflux also develop insomnia. In October 2001, the American Gastroenterological Association (AGA) began a multi-city survey to get an idea of just how many people are suffering with heartburn and insomnia. Teaming up with local physicians, the organization has asked heartburn sufferers whether the discomfort keeps them awake at night. So far, more than half of the respondents are reporting that it does (see Table 1).

Table 1
Nighttime heartburn city scores

This is right in line with numbers from a national survey the AGA had already conducted. Results at the national level indicated that about 75% of people with heartburn also reported difficulty sleeping. "The local statistics are mirroring the national ones," said Colleen Morrison, an AGA spokeswoman. "They seem fairly consistent." AGA expects to complete the local surveys in October of this year. By then, the organization will have results from 25 cities.

Although Donald O. Castell, M.D., has spent most of his career treating this type of disorder, he was surprised to see such high numbers. "I must admit I would not have predicted this," he said. "It was like a wake-up call." Castell is a professor of medicine and director of the Esophageal Disorders Program at the Medical University of South Carolina. Nighttime heartburn is of particular concern, he said, because acid stays in the esophagus longer, and research has shown this is more likely to lead to complications. The next step for AGA would be a nationwide educational campaign for both prescribers and patients.

Researchers have investigated whether acid reflux may play a role in another sleep disorder: apnea. Two recent studies have found that many patients with sleep apnea also have reflux. However, it still hasn't been proven that reflux actually causes apnea. It is possible that patients who are prone to one are also prone to the other. Investigators have concluded that controlled trials in sleep apnea patients should be conducted to see whether GERD therapy is effective in relieving apnea. They have also recommended that people with sleep apnea be evaluated for GERD.

Evidence of causality between GERD and laryngitis is more substantial. In fact, clinicians have coined the term reflux laryngitis to refer to laryngitis caused by acid reflux. The problem is that diagnosing and treating the condition is not as straightforward as it might seem. Both laryngoscopy and pH testing have been evaluated, and neither has proven to be a reliable diagnostic tool.

Furthermore, proton pump inhibitors (PPIs) are not always effective in treating reflux laryngitis, and so far, no diagnostic method has been able to predict which patients will respond to PPIs. For now, the only option is a trial of a high dose of a PPI. Uncontrolled studies (and one controlled trial) indicate the majority of patients will improve with this therapy, although more studies are needed to pinpoint doses and length of therapy.

Probably the most interesting study of acid reflux was conducted by a team of researchers in Britain. They hypothesized that stomach acid might make its way from the throat to the ear in children with acid reflux. The acid could irritate the mucosa of the middle ear, and this inflamed tissue could become a welcome home for bacteria. The team examined ear fluid samples from 54 children with otitis media with effusion (referred to as "glue ear" in Britain). They found pepsin or pepsinogen in 45 (83%) of the samples. Although the researchers admitted more studies are warranted to confirm the results, they suggested antacids may be helpful in preventing pediatric ear infections.

Drug developments

PPIs have been the most commonly prescribed drugs for EE and NERD. "PPIs are much better than H₂ antagonists, and they're quicker," said Ponte. In a nutshell, they work by inhibiting the proton pumps (H+/K+ ATPase) that produce gastric acid. The pumps are located in the parietal cells in the stomach lining, and they produce acid in response to histamine, acetylcholine, and gastrin stimulation of the cells.

Of the five PPIs available (see Table 2), all appear to be equally effective for healing and relief of GERD symptoms, said Rosemary Berardi, Pharm.D., FCCP, FASHP, professor of pharmacy at the University of Michigan College of Pharmacy. However, there may be some differences in rapidity of effects and in the subset of patients with moderate to severe disease. In clinical studies, lansoprazole (Prevacid, TAP), rabeprazole (Aciphex, Eisai/ Janssen), and esomeprazole (Nexium, AstraZeneca) appear to relieve symptoms faster than omeprazole (Prilosec, AstraZeneca). That is, they bring relief within a few days after initiation of treatment, she explained.

Table 2
A comparison of PPIs

"All this is helpful," said Berardi. "But what we're really looking for is differences in clinical outcome, such as heartburn relief and esophageal healing." So far, all five agents are similarly effective at healing the esophagus and relieving symptoms. In studies of omeprazole compared with esomeprazole, for example, the drugs are basically equally effective. However, in patients with moderate to severe symptoms and esophagitis, esomeprazole seems to have an edge. In this group of patients, the 40-mg strength of esomeprazole was superior to omeprazole in all studies.

Among the makers of PPIs, competition is fierce. Because PPIs are essentially identical in pharmacology, manufacturers are looking for idiosyncratic differences that may give one product an edge over the others. They are also seeking ex- panded indications.

Rabeprazole is comarketed by Eisai and Janssen. The two companies announced in February that the product is now approved for the treatment of heartburn and other symptoms, such as regurgitation and belching, associated with GERD. The new indication was approved based on results of two clinical trials in patients with NERD. When compared with placebo, rabeprazole significantly relieved symptoms and reduced antacid use in these patients.

TAP Pharmaceutical Products submitted an SNDA (Supplemental New Drug Application) to the Food & Drug Administration in February, seeking approval for pediatric labeling of lansoprazole (Prevacid). TAP is hoping Prevacid will be the first PPI approved for patients ages one to 11. The company already markets an oral suspension formulation of the drug, and it has another SNDA pending for a quick-dissolve tablet.

While Ponte doesn't see many kids in his practice, he suspects that acid reflux is probably a fairly common problem, especially in newborns. Harland Winter, M.D., a pediatric gastroenterologist, confirmed Ponte's suspicion. "GERD is a common condition that may occur in childhood but can be overlooked," he said. Children may not be able to describe their symptoms, and the symptoms may be confusing. Most often, kids experience chest or abdominal pain and difficulty swallowing. They may also show decreased interest in eating or refuse food altogether. More vague symptoms include hoarseness and wheezing.

Diagnosing acid reflux in children may be more difficult than it is in adults. While older kids may be able to describe their symptoms, babies and toddlers cannot. In infants, the occurrence of cyanotic episodes may be a tip-off, Ponte said. If reflux is, in fact, the cause, it can be treated with nondrug methods (e.g., positioning changes) or H₂ antagonists. Prokinetics, such as metoclopramide, may also be used.

While there are no new drugs for GERD on the immediate horizon, researchers are looking into a new class of drugs called acid-pump antagonists. These would inhibit acid secretion by directly antagonizing the acid pump. In the meantime, excitement is building about the possibility of generic omeprazole reaching the market in the near future. Several generic companies are prepared to produce omeprazole and are challenging AstraZeneca's patents on the drugs. One of these, Andrx Pharmaceuticals, received final market approval from the FDA in November 2001 and is awaiting the resolution of the patent suit. The company hopes to launch generic omeprazole by the end of this year.

An OTC version of omeprazole may also be in the works. AstraZeneca and its comarketing partner Procter & Gamble have filed an application for an OTC version of omeprazole. Berardi is aware of this development also, and she is hopeful the product will be available to consumers sometime this year. Both this and the generic Rx product should help cut costs, a very welcome development for patients and third-party payers.

Nocturnal acid breakthrough

Although PPIs are quite effective, they do not always provide complete relief. Some patients experience periods of acid breakthrough, particularly in the evening or at bedtime. This has been termed nocturnal acid breakthrough (NAB). Comparison studies of the PPIs suggest the newer drugs, namely, pantoprazole and rabeprazole, may allow less NAB than the older ones. This has yet to be proven, however.

Berardi cautioned that NAB does not always result in GERD symptoms. Those patients who do experience symptoms may be helped by OTC antacids, although the effects of these are short-lived. Another solution, Ponte said, is twice-daily dosing of a PPI. For some patients, though, that still doesn't do the trick. Some physicians are prescribing H₂ receptor antagonists (H₂RAs) at night, in addition to twice-daily PPIs to relieve NAB.

According to Berardi, though, the evidence to support H₂RA supplementation is inconclusive so far. Furthermore, some resistance to these drugs has been observed in clinical studies. This is a controversial practice, she said, and should not be encouraged.

The pharmacist's role

Experts believe pharmacists have a real opportunity to help patients with acid reflux disorders. Here's where those questions about OTCs can lead to effective pharmacist interventions. Talking to people seeking heartburn and other gastrointestinal remedies can help identify those with long-term or recurring problems. Pharmacists can recommend short-term therapy (antacids, H₂ blockers) and direct them to physicians for diagnosis and treatment.

The OTCs are good for dyspepsia or short-term GERD treatment, said Takiya. However, it's important to be aware of the different ingredients in OTC antacids. Not all products are the same, even within the same brand name. For example, many liquids contain aluminum and magnesium, while the tablets of the same brand may actually contain calcium.

There are other things to keep in mind, too, Takiya said. Antacids work best when taken after meals, while the H₂RAs should be administered 15 to 50 minutes before meals. Drug interactions are more common with antacids than with H₂RAs (except cimetidine). Too much of an antacid can lead to electrolyte abnormalities, a particular danger in patients with renal failure or certain heart conditions (e.g., arrhythmias). Too much calcium carbonate may lead to kidney stones. And pregnant patients may take calcium products but should avoid famotidine, ranitidine, and nizatidine, which are all in pregnancy category C.

"When counseling patients who desire OTC medications, it is important for the patient to understand that the OTC medications [at the OTC doses] may be effective in treating symptoms but not effective in healing structural changes or preventing other complications," said Takiya. "Therefore, if a patient truly has GERD, the OTC medications should be used as temporary treatment until the patient can see his or her prescriber for more definitive treatment."

Takiya also noted that patients using OTCs for longer than two weeks with no relief should be referred to their primary care providers. Likewise, people presenting with chronic cough, hoarseness, pharyngitis, dysphagia, painful swallowing, bleeding, or weight loss should also be referred to their physicians. If GERD is the cause, it is important to remind them that they need continual and long-term evaluation with their physicians.

If prescribed PPIs, patients will need to know a few things about these medications as well, said Berardi. All of the PPIs are acid labile and, therefore, enteric coated. None of them should be chewed or crushed. While lansoprazole is the only product with a formulation made for suspension, esomeprazole, lansoprazole, and omeprazole capsules contain enteric-coated granules, which can be sprinkled over food (e.g., applesauce) or mixed with juice. Another option is to dissolve the granules with sodium bicarbonate for administration via nasogastric tubes. Pantoprazole is available in IV form.

If patients complain that the medication is not working, ask a few questions before sending them to their physicians for a change in therapy. According to Berardi, noncompliance is a major reason for treatment failure. The timing of PPI dosing is critical. In order to achieve maximum intragastric pH effects, she said, the drug should be present when the stomach is actively secreting acid. Because acid is secreted in response to food, the best time to take the PPIs is 15 to 30 minutes before breakfast. If the patients don't normally eat breakfast, have them substitute coffee, tea, or juice for the meal. For patients on twice-daily dosing, the second dose should be taken 15 to 30 minutes before dinner. PPIs should not be taken at bedtime.

Patients should also know that it might take a few months to achieve maximum efficacy with PPIs. This is especially true for patients with atypical disease. These folks may need higher than usual doses of PPIs, and they will need to take these doses for at least three to six months.

People may be especially concerned that the chest pain they are having is heart-related. According to Ponte, this is not unfounded, as heartburn pain is very similar to angina. "Probably the most common cause of noncardiac chest pain is reflux," he said. Confusion over the source of the pain brings a lot of people to the emergency room. One of the easiest ways to rule out heartburn is to administer a GI cocktail—a mixture of lidocaine, pink bismuth, and diphenhydramine liquids. This concoction will relieve heartburn, not angina.

"If you read the literature with respect to reflux, it really affects the person's quality of life," said Ponte. Relieving the symptoms of GERD, NERD, and EE will help improve quality of life immediately, and healing erosion will decrease the chance of complications in the future. Unfortunately, therapy doesn't cure reflux, he said. If treatment is stopped, the reflux usually returns. "Reflux is a chronic disorder—you have to treat it long-term."

Jillene Magill-Lewis, R.Ph.

The author is a clinical writer in the Seattle area.

FAST FACTS ABOUT ACID INHIBITORS

• Worldwide sales for products in the acid inhibitor category were $17.4 billion in 2000. Sales in the United States were almost $11 billion in the year from March 2000 to March 2001.

• This class has led the world in sales for 10 years and is second only to cholesterol reducers in the United States. Omeprazole is the No. 1 selling drug worldwide; it reached $6.1 billion in sales in 2000. Lansoprazole is the No. 2 seller.

• Nearly 102 million prescriptions for acid inhibitors were dispensed in this country between March 2000 and March 2001. That was a 10% increase over the previous year.

Source: IMS

 

Jillene Lewis. GERD: BEYOND THE ESOPHAGUS. Drug Topics 2002;8:62.