Heartburn is a common complaint reported frequently by individuals in the general population. It has been estimated that 40% of the population report at least one episode of heartburn per month, and up to 20% report heartburn several times per week.
Heartburn is typically described as a sensation of warmth or burning that occurs below the sternum and may radiate to the neck. It generally occurs when contents of the stomach are refluxed through the lower esophageal sphincter (LES) into the esophagus. The esophagus appears not to have the elaborate mucosal defense mechanisms of the stomach and duodenum, and thus is prone to mucosal injury.
The spectrum of heartburn can range from symptoms that occur occasionally and cause nothing more than an annoyance to symptoms that occur on a daily basis and are very disabling for patients. Damage to the esophagus may range from minimal irritation to more severe complications such as inflammation, ulceration, stricture, and Barrett’s esophagus.
The severity of heartburn symptoms does not always correlate well with the severity of esophageal injury. Thus, patients with relatively mild heartburn may have significant mucosal injury and patients with more severe symptoms may have a lesser degree of injury. The terms erosive esophagitis and gastroesophageal reflux disease (GERD) are frequently used to describe esophageal mucosal damage. Erosive esophagitis refers to inflammation and ulceration of the esophagus that is secondary to gastric contents that are refluxed into the esophagus. GERD is a more inclusive term and refers to the spectrum of clinical symptoms (ie, heartburn) and esophageal damage that can occur due to refluxed materials; gastroesophageal reflux disease lesions can range from minimal inflammation to very severe ulceration.
Table 1 shows the various physiologic processes that facilitate gastroesophageal reflux and may result in heartburn. Reflux is a process that occurs to some extent in all adults. However, heartburn occurs only when refluxed materials are in the esophagus in sufficient amounts and for sufficient time to produce injury that is extensive enough to produce pain. Processes that result in large amounts of refluxed material and / or inhibit the clearance of refluxate from the esophagus can result in heartburn. In some patients, several of these processes interact. Perhaps the most important process that leads to the development of heartburn and gastroesophageal reflux disease is dysfunction of the LES. Reflux is facilitated when the lower esophageal sphincter has a low resting pressure or spontaneously relaxes. Patients are more prone to heartburn when they are in the recumbent position (as compared with sitting or standing), since the gravitational forces that inhibit reflux are not operative.
Table 1. Physiologic Factors Related to Heartburn and GERD
| Factor | Mechanism or Condition | Result |
| Reduced lower esophageal sphincter (LES) pressure | LES has reduced resting pressure or relaxes at inappropriate times. | Allows for increased reflux of stomach contents into the esophagus. |
| Decreased esophageal clearance | Reduced esophageal motility slows clearance of refluxed material. | Allows refluxed material to be present in esophagus for longer periods of time, thereby increasing potential for mucosal damage. |
| Delayed gastric emptying | Reduced gastric motility slows emptying of stomach contents into duodenum. | Stomach contents are more available for reflux, as they remain in the stomach for a prolonged period of time. |
| Increased gastric volume | Consumption of large amounts of food results in increased gastric contents. | Greater amounts of stomach contents and acid are available for reflux. |
| Increased intra-abdominal pressure | Conditions such as pregnancy, obesity, and pressure on stomach, particularly when in recumbent position. | Increased pressure on stomach facilitates reflux of contents. |
Dietary factors frequently play a role in the development of heartburn. Overeating can increase gastric volume, and various dietary components can result in reduction of LES tone. Substances such as coffee and alcoholic beverages can produce heartburn by further damaging injured esophageal mucosa, as can foods with high acid content such as citrus juices and tomato products. Spicy foods can produce heartburn in some individuals.
Medications may also exacerbate heartburn by lowering lower esophageal sphincter tone; some commonly implicated drugs are included in Table 2. Thus, when evaluating a patient’s heartburn, his or her drug regimen should be carefully examined to identify drugs that may exacerbate heartburn. Whenever possible, offending drugs should be eliminated or substituted with appropriate alternative agents.
Table 2. Drugs, Substances, and Conditions That Decrease LES Tone
| Alcohol |
| Anticholinergic drugs |
| Beta-agonists |
| Caffeine |
| Calcium channel blockers |
| Chocolate |
| Esophagitis |
| Fatty diet |
| Nitrates |
| Onions and garlic |
| Peppermint and spearmint |
| Pregnancy |
| Progesterone |
| Theophylline |
| Tobacco (smoking) |
Gastroesophageal reflux disease is a common condition in patients with asthma. It may worsen during an acute asthmatic episode and also may serve as a trigger for an attack. Management of GERD in asthmatics is made more difficult by the effects of theophylline and beta-agonist drugs in lowering LES tone.
Managing Heartburn and GERD
Appropriate management of heartburn by the physician includes nonpharmacologic as well as pharmacologic approaches.
Lifestyle Modification
Table 3 lists several lifestyle modification measures that are used to manage heartburn and gastroesophageal reflux disease. These nonpharmacologic approaches work by producing beneficial alterations in the various physiologic mechanisms causing heartburn. When used consistently, they are capable of relieving symptoms in those with mild, intermittent symptoms of heartburn. Proper use of these lifestyle modifications can prevent the need for drug therapy or allow for less intensive therapeutic regimens.
Table 3. Lifestyle Modifications Useful in the Management of Heartburn and GERD
| Avoid substances that decrease LES pressure; whenever possible, eliminate offending medications or change to alternatives. |
| Avoid substances that irritate esophageal mucosa (eg, cit-rusjuices, tomato products, coffee, alcohol, spicy foods). |
| Stop smoking. |
| Avoid tight-fitting clothes. |
| Elevate head of bed on 6- to 8-inch blocks. |
| If overweight, lose weight. |
| Eat smaller meals and avoid bedtime snacks. |
Pharmacologic Approaches
A wide spectrum of pharmacotherapeutic agents can be used in the management of heartburn and gastroesophageal reflux disease. In Table 4, the various drug types are characterized, describing the mechanisms of action, clinical uses, and key points to consider when using each agent.
Table 4. Synopsis of Drug Therapy Used in the Management of Heartburn and GERD
| Drug or Drug Class | Mechanism of Action | Clinical Uses | Key Points To Consider Wheh Using |
| Alginic Acid | — Floats on surface of acid and buffers its effects, especially during the day | — Similar to antacids | — Similar to antacids — Most effective for daytime heartburn |
| Antacids | — Neutralize acid to prevent caustic effects on esophageal mucosa | — Used as needed to relieve occasional mild heartburn | — Provide quick relief from heartburn — Short duration of action — Not effective in healing erosive esophagitis |
| Metoclopramide | — Stimulates cholinergic receptors and blocks dopamine receptors — Increases LES (lower esophageal sphincter) tone (less effect with severe esophagitis) — Increases gastric emptying |
— Treatment of mild to moderate heartburn | — Efficacy varies greatly from patient to patient — Slightly increased efficacy when combined with H2 antagonists or proton pump inhibitors — may notjustify added cost — Frequent adverse effects including extrapyramidal side effects, anxiety, restlessness, and insomnia |
| OTC H2 Antagonists1 | — Inhibit H2 receptors, thus reducing acid secretion so that refluxed stomach contents are less acidic | — Occasional use in treating mild heartburn*— Can be used to prevent heartburn when administered prior to consumption of food previously shown to produce heartburn3 | — Slower onset of action than antacids — Longer duration of action than antacids — Minimal effect on healing erosive esophagitis — Should not be used continuously at maximum dosage for more than 2 weeks without physician supervision |
| Prescription H2 Antagonists1 | — Inhibit H2 receptors, thus reducing acid secretion so that refluxed stomach contents are less acidic — Only decrease acid reflux 30%-50% because gastrin and acetylcholine receptors not blocked |
— Treatment of mild to moderate heartburn — Healing of mild to moderate erosive esophagitis |
— Little effect on healing in severe cases of erosive esophagitis— May be used for maintenance therapy in patients with healed erosive esophagitis4
— Slightly increased efficacy when combined with metoclopramide — Cimetidine may inhibit the elimination of various hepatically metabolized drugs. Excessive serum levels resulting in clinically significant adverse effects have been observed when cimetidine was concomitantly administered with theophylline, phenytoin, warfarin, and lidocaine |
| Proton Pump Inhibitors5 | — Inhibit the final common pathway of acid secretion, potassium-hydrogen ATPase enzyme, thus reducing acid secretion by 80%-90% | — Treatment of moderate to severe heartburn — Healing of moderate to severe gastroesophageal reflux disease lesions |
— Most effective agents for healing erosive esophagitis and management of complicated GERD (strictures, ulcers, and Barrett’s)— Slightly increased efficacy when combined with metoclopramide — may notjustify added cost
— May be used for maintenance therapy in patients with healed erosive esophagitis6 |
| Sucralfate | — Protects esophageal mucosa through undefined mechanisms | — Treatment of mild to moderate heartburn7— Healing of mild to moderate erosive esophagitis7 | — Efficacy similar to prescription H2 antagonist drugs — Contact with esophageal mucosa is necessary for drug effect; therefore must be administered as a suspension |
- It is the opinion of the authors that all the H2 blockers are similar when used at the appropriate OTC and prescription doses and can be used interchangeably.
- Only cimetidine, ranitidine, and famotidine (Pepcid AC, Merck) are FDA-approved for this indication.
- Only famotidine (Pepcid AC, Merck), nizatidine (Axid AR, Whitehall-Robins), and cimetidine are FDA-approved for this indication.
- Only ranitidine is FDA-approved for this indication.
- It is the opinion of the authors that all the proton pump inhibitors are similar when used at appropriate doses and can be used interchangeably.
- Only omeprazole (Prilosec, AstraZeneca), lansoprazole (Prevacid, TAP Pharmaceuticals), and rabeprazole (Aciphex, Eisai / Janssen) are FDA-approved for this indication.
- Indication is not FDA-approved.
Antacids, alginic acid and low-dosage histamine (H2) antagonist products are the 3 classes of over-the-counter (OTC) drugs that are useful in managing heartburn on a short-term basis. Antacid products provide rapid relief because they act by neutralizing existing acid in the stomach and esophagus, with effects lasting for 1 to 2 hours. Liquid antacid products are more effective than tablets, as they make contact with the esophagus while passing into the stomach and do not require a dissolution step.The many available antacid products vary greatly in their ability to neutralize acid, and efficacy in relieving heartburn is directly related to acid-neutralizing capacity; thus, the more concentrated products may provide more effective relief of symptoms due to their increased acid-neutralizing capacity.
Alginic acid forms a foamy “raft-like” barrier after contact with stomach acid, thereby protecting the esophageal mucosa. It is more effective in relieving daytime heartburn. Otherwise, it is very similar to antacids.
Both the prescription and OTC H2 antagonist products (see Table 5) have asomewhat different efficacy profile from antacid products. The H2 antagonist products have a slower onset and longer duration of action. Taken before meals, the various H2 antagonist products are effective in preventing heartburn resulting from overeating or consumption of specific foods that produce heartburn in a given individual. H2 antagonist products also produce relief of heartburn symptoms; however, patients should be advised that relief may not occur for 30 to 60 minutes.
Table 5. Dosage Regimens for Heartburn and GERD
a) Prescription Drugs
| Generic Name | Trade Name / Manufacturer | Dosage Regimens for Heartburn | Dosage Regimens for Erosive Esophagitis |
| H2 Antagonists | |||
| Cimetidine | Tagamet / SmithKline Beecham, various | 400 mg qid | 400 mg qid |
| Famotidine Nizatidine | Pepcid / Merck Axid / Eli Lilly | 20 mg bid150 mg bid | 20-40 mg bid150 mg bid |
| Ranitidine | Zantac / Glaxo Wellcome, various | 150 mg bid | 150 mg qid |
| Mucosal Protectant | |||
| Sucralfate 1 | Carafate / Aventis, various | 1 g qid2 | 1 g qid2 |
| Proton Pump Inhibitors | |||
| Lansoprazole Pantoprazole | Prevacid ATAP Pharmaceuticals Protonix / Wyeth-Ayerst | 15-30 mg qd40 mg qd | 15 mg qd330 mg qd
40 mg qd |
| Omeprazole | Prilosec / AstraZeneca | 20 mg qd | 20 mg qd |
| Rabeprazole | Aciphex / Eisai-Janssen | 20 mg qd | 20 mg qd |
| Prokinetic Agent | |||
| Metoclopramide | Reglan / Robins, various | 10-15 mg qid | 10-15 mg qid |
b) OTC H2 Antagonist Products
| Generic Name | Trade Name / Manufacturer | Tablet Dose | Dosage Regimen |
| Cimetidine | Tagamet HB / SmithKline Beecham | 200 mg | 200 mg bid |
| Famotidine | Pepcid AC / J&J-Merck | 10 mg | 10 mg bid |
| Nizatidine | Axid AR / Whitehall-Robins | 75 mg | 75 mg bid |
| Ranitidine | Zantac 75 / Glaxo Wellcome | 75 mg | 75 mg bid |
- Suspension product must be used for effectiveness in treating heartburn and erosive esophagitis.
- Dosage listed is taken from the pharmaceutical and medical literature for non-FDA-approved indication.
- Dosage of 30 mg is for healing erosive esophagitis; 15 mg is for maintenance therapy.
Over-the-counter (OTC) antacid, alginic acid, and H2 antagonist products, taken either singularly or in combination, are excellent choices for the management of occasional heartburn symptoms; however, more persistent heartburn may be indicative of more clinically significant disease processes. Patients should be instructed to make their physician aware of heartburn that is not relieved by OTC products, requires OTC therapy for more than 2 consecutive weeks, or is accompanied by dysphagia, weight loss, or evidence of bleeding.
Substernal burning due to coronary heart disease (ie, angina pectoris) and gastroesophageal reflux often have similar clinical presentations. Thus, heartburn that does not rapidly resolve with OTC treatment may require a cardiac as well as a gastrointestinal workup. In addition, severe gastroesophageal reflux disease, if untreated, may ultimately result in hemorrhage, esophageal strictures, or Barrett’s esophagus that can progress to esophageal cancer.
Effective management of moderate to severe heartburn and GERD centers primarily around drug therapy to suppress gastric acid production. These drugs do not alter motility of the esophagus or improve LES pressure, so gastric contents continue to be refluxed into the esophagus. However, the refluxed contents are less caustic and thus produce less irritation and damage to the esophageal mucosa than if gastric acid suppression was not initiated.
The limited mucosal defense mechanisms in the esophagus make healing of esophagitis and ulcerations difficult to achieve. Even if the high-dose H2 antagonist regimens shown in Table 5 are used, only 50% to 75% of patients with moderate to severe GERD will have their lesions healed. By producing more profound acid suppression, the proton pump inhibitors are much more effective in treating severe heartburn and esophageal lesions. Omeprazole and lansoprazole can achieve overall healing rates of approximately 90%, and can produce healing in many patients refractory to H2 antagonists.
Rabeprazole and pantoprazole are two additional proton pump inhibitor drugs that have become available in the last year. Their efficacy and safety are similar to those of omeprazole and lansoprazole.
Sucralfate, presumably acting by protecting the esophageal mucosa, has been somewhat effective in healing esophageal lesions. In fact, its efficacy appears to be similar to that of the prescription-strength H2 antagonists. The suspension form of sucralfate must be given to enable contact with the esophageal mucosa and healing of gastroesophageal reflux disease lesions.
The prokinetic drug metoclopramide acts by improving lower esophageal sphincter (LES) tone and enhancing gastric and duodenal motility, thus reducing the amount of reflux and improving esophageal clearance of refluxed material. Monotherapy with metoclopramide appears to be comparable in effectiveness to the prescription H2 antagonists and is useful in mild to moderate heartburn and GERD; it may be particularly helpful in patients with documented gastric and esophageal dysmotility. Metoclopramide may be added as a second agent to the regimens of patients who do not completely respond to H2 antagonists or proton pump inhibitors.
Cisapride, another prokinetic agent, was recently removed from the market due to cases of toxicity leading to arrhythmias and deaths. It is metabolized by the cytochrome P450 3A4 isozyme. Decreased metabolism can result in high serum levels resulting in serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. This has been frequently seen when cisapride was coadministered with a variety of other drugs that inhibit this enzyme, thus resulting in the various reported cardiac arrhythmias.
Cisapride will remain available under a limited-access program to patients for whom other medications have failed.The prescribing physician must be a gastroenterologist or the patient must be under the care of a gastroenterologist by consultation. Institutional review board approval, signed informed consent, baseline and serial laboratory tests, and electrocardiograms are required.
Effective maintenance therapy to prevent recurrence of healed esophageal lesions may be difficult to achieve. Patients often relapse even while on high-dose H2 antagonist therapy, metoclopramide, or proton pump inhibitors. Concern has subsided about the carcinogenic potential of proton pump inhibitors. Omeprazole, lansoprazole, and rabeprazole are FDA-approved for GERD maintenance therapy.
Surgery
Surgical management of heartburn and gastroesophageal reflux disease centers around procedures designed to reduce the hiatal hernia and increase LES tone, thus reducing reflux. Some recent clinical studies have shown surgery to be at least equivalent in efficacy to long-term drug therapy in selected patients with severe, persistent GERD. Obviously, the results of such surgery will vary with the skill of the surgeon performing the procedure. Paradoxically, patients who are the best candidates for surgery are those responding well to acid suppression, but requiring lifelong therapy where the medication may be very expensive or have unknown long-term side effects.
Other indications include patients with persistent regurgitation after adequate acid control and, possibly, those with complicated gastroesophageal reflux disease cases. Skilled surgeons can now perform this operation laparoscopically with a short hospital stay and rapid return to normal activity. The overall efficacy of antireflux surgery initially is about 85% to 90%, but this may deteriorate over time to 60% to 70%. The more severe the reflux disease (ie, stricture, Barrett’s esophagus, large nonreducible hiatal hernia), the less successful the antireflux operation.
All patients prior to surgery require extensive physiologic testing, best done by a gastroenterologist.These tests will usually include endoscopy, barium x-rays of the esophagus, esophageal manome-try and 24-hour esophageal pH testing, especially if the patient does not have esophagitis. Gastric emptying studies should be considered if nausea, vomiting, or bloating are associated problems.
Heartburn, GERD, and Pregnancy
Gastroesophageal reflux and heartburn are reported by 45% to 85% of women during pregnancy* Most cases result from decreased lower esophageal sphincter pressure, the result of hormonal changes occurring during pregnancy. Increased progesterone levels appear to mediate smooth muscle relaxation in LES, although estrogen may serve as a primer to initiate this reaction. Mechanical factors such as increased intragastric pressure (due to the gravid uterus) and delayed gastrointestinal transit time may also be factors in some patients. Fortunately, symptoms usually resolve after delivery.
Treatment should follow a systematic, step-by-step approach. (See Figure.) Mild cases can be treated by reassuring the patient that reflux is commonly encountered during a normal pregnancy. Lifestyle and dietary modifications may be all that are required. (Table 3) In more symptomatic cases, nonsystemically absorbed medications, including antacids or sucralfate, may be offered with little if any risk to the unborn fetus.
During pregnancy, systemic therapy with H2 antagonists or metoclopramide should be reserved for patients with more severe symptoms. Proton pump inhibitors are not recommended during pregnancy, except for severe and intractable cases of gastroesophageal reflux or possibly prior to anesthesia during labor and delivery. Use of the least possible amount of drug needed to ameliorate the patient’s symptoms is clearly the best choice for therapy. Informed consent should be obtained prior to using any systemic drugs. If symptoms are intractable or atypical, endoscopy can be safely performed with conscious sedation and careful monitoring of the mother and fetus.
Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.