The stomach, intestines, and digestive glands produce acid and various enzymes, including pepsin, that breaks down and digest the starch, fat, and protein in food. The stomach itself is composed mostly of protein and must be protected from the same acid and enzymes, or it too can be attacked and broken down. Ulcers develop when an imbalance occurs between the digestive juices used by the stomach to break down food and the various factors that protect the lining of the stomach and duodenum (the part of the small intestine that adjoins the stomach). A peptic ulcer is an open sore or raw area in the lining of the upper part of the small intestine (duodenal ulcer) or the stomach (gastric ulcer). In the U.S., duodenal ulcers are three times more common than gastric ulcers. Ulcers are on average between one-quarter to one-half inch in diameter.

The primary digestive juices, hydrochloric acid and pepsin, are powerful substances necessary for breaking food down for use by the body. Acid is always present in the stomach, but, except at meal times, in relatively small amounts. A common misbelief is that the acid is solely responsible for causing ulcers. Hydrochloric acid, secreted in the stomach, does indeed play a part in the development of ulcers, but it is not solely responsible. Acid output in patients with duodenal ulcers tend to be higher than normal, while in those with stomach or gastric ulcers, acid production tends to be normal or lower. Abnormally large amounts of acid secretion occur in rare situations, such as in the genetic condition known as Zollinger-Ellison syndrome, in which large amounts are stimulated by tumors located in the pancreas or duodenum. Pepsin, the other major digestive fluid, is an enzyme that breaks down whatever proteins are presented to it, including, if exposed, the stomach’s own tissues.

In order for pepsin and hydrochloric acid to cause damage to the stomach or duodenum, the stomach’s defense system must be altered or damaged. The mucous layer, which coats the stomach and duodenum, forms the first line of defense against acid and pepsin. In addition, the body secretes bicarbonate into the mucous layer, which neutralizes the acid. So while the contents of the stomach may be highly acidic, the stomach’s own tissues are normally only slightly acidic.

Other parts of the defense system are hormone-like substances known as prostaglandins, which help keep the blood vessels in the stomach dilated, ensuring good blood flow. While this is important for any organ, a lack of adequate blood flow to the stomach contributes to ulcers. Prostaglandins are also believed to stimulate bicarbonate and mucous production, which help protect the stomach.

If any of these defense mechanisms are disturbed, and acid and pepsin are allowed to attack the stomach lining, an ulcer can result.

Helicobacter Pylori (H. Pylori).
According to the Centers for Disease Control and Prevention, most healthcare consumers still believe stress causes ulcers and are unaware that the major cause of peptic ulcers is actually the bacteria Helicobacter pylori. Before the discovery of H. pylori, the stomach was believed to be a sterile environment. Now, the bacteria is seen as a major cause of or strongly associated with active chronic gastritis (inflammation of the stomach), active chronic duodenitis (inflammation of the duodenum), duodenal ulcers, and gastric ulceration. The bacterium is also strongly linked to stomach (gastric) cancer. H. pylori’s corkscrew shape is able to penetrate the mucous membrane of the stomach and attach itself there, where it is capable of causing damage in many ways. It causes changes in the immune system that allows it to survive for a person’s lifetime. It thrives in the highly acidic stomach by producing the enzyme urease, which, in turn, generates ammonia, which neutralizes the acid and ensures the survival of the bacteria. H. pylori also produces a number of toxins that cause inflammation and damage to the lining. A particularly dangerous genetic form, called chronic atrophic gastritis A (cag A), can cause damage severe enough to produce cancerous changes over time.

Studies have reported that H. pylori is present in 90% of people with duodenal ulcers and in about 80% of people with gastric ulcers. As more people are being tested and treated for the bacteria, however, some studies suggest that the bacteria may be less prevalent than was once believed. One study reported that 50% or less of duodenal ulcer patients harbored the bacteria. The risk was higher in African-American patients than white patients. It should also be noted that H. pylori is found in about 25% of people who do not have peptic ulcers. Other factors, then, must be present to actually trigger ulcers, such as genetic or other conditions, that increase susceptibility to the organism. One study indicated that coffee-drinking increases susceptibility to the bacteria. Certain strains of H. pylori may also be more virulent than others.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).
Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers. The most common NSAIDs are aspirin, ibuprofen (Advil), and naproxen (Aleve, Naprosyn), although many others are available. They are very beneficial in reducing pain and inflammation resulting from many conditions. They do this by blocking an enzyme called cyclooxygenase (COX), which is involved in the production of prostaglandins. An excess of prostaglandins causes intestinal contractions and inflammation. Because NSAIDs reduce prostaglandins, they relieve pain, but, in doing so, they also impair the defense system in the intestine and increase the danger of damaging the mucous layer and causing ulcers and gastrointestinal bleeding. Even if an NSAID is injected intravenously the drug will still reach the stomach and duodenum through the bloodstream and inhibit prostaglandins. An ulcer will form if an NSAID is taken for a long period of time and the rate of damage inflicted by the drug exceeds the rate of repair conducted by the stomach. Taking short courses of NSAIDs for temporary pain relief should not cause major problems because the stomach has time to recover and repair any damage that has occurred. In people with existing ulcers, particularly gastric ulcers, however, even short-term use might increase the risk of bleeding.

About 15% of people who take NSAIDs for longer than three months experience ulceration of the stomach. One medical center reported that between 50% and 80% of people who were hospitalized for gastrointestinal problems were taking NSAIDs. The elderly are at particular risk. The stomachs of younger, nonsmoking adults appear to adapt better to NSAIDs and have less risk for bleeding than those of older adults, particularly those who smoke. The risk for bleeding is continuous for as long as a patient is on these drugs and may even persist for about a year after taking them. No NSAIDs should be used for long-term pain relief except under physician direction.

One study ranked the sixteen most commonly used NSAIDs according to GI toxicity. Those that caused the least risk for ulcer were nabumetone (Relafen), etodolac (Lodine), salsalate, and sulindac (Clinoril). At medium risk are diclofenac (Voltaren), ibuprofen (Motrin, Advil, Nuprin, Rufen), ketoprofen (Actron, Orudis KT), aspirin, naproxen (Aleve, Naprosyn, Naprelan, Anaprox), and tolmetin (Tolectin). (Studies show, however, that short-term use of naproxen in doses similar to those expected with over-the-counter-use is twice as likely as ibuprofen to be associated with hospitalization from GI bleeding.) The highest risk is for users of flurbiprofen (Ansaid), piroxicam (Feldene), fenoprofen, indomethacin (Indocin), meclofenamate (Meclomen) and oxaprozin. Others not compared in this analysis are diflunisal (Dolobid) and ketorolac (Toradol). A gel containing ibuprofen can be applied to sore joints directly and may have less risk for gastrointestinal side effects. Buffered aspirin, which is coated with an antacid, is not protective against ulcers. A combination of diclofenac and misoprostol (Arthrotec) has now been approved that may reduce the risk for gastrointestinal bleeding.

Zollinger-Ellison Syndrome.
The third, and least common, major cause of peptic ulcer disease is the Zollinger-Ellison syndrome. In this condition, a tumor in the pancreas produces excessive amounts of gastrin, a hormone that stimulates gastric acid formation.

Emergency Symptoms.
Tarry, black or bloody stools, vomiting of blood, or vomiting of a substance that has the appearance of coffee grounds could be the sign of a serious hemorrhage. Severe abdominal pain, even without vomiting or external bleeding, could indicate a perforated ulcer. Persons who experience any of these symptoms should go to the emergency room immediately.

Nonemergency Symptoms.
Peptic ulcer disease usually makes itself known through pain that can be either localized or diffuse. Sometimes it radiates to the back or to the chest behind the breastbone, where it can be experienced as heartburn. The most common symptom is dyspepsia, a burning, gnawing, or aching pain in the upper abdomen; others describe the pain as a stabbing feeling penetrating through the width of the gut. Some people feel hungry or empty an hour or two after meals. Sometimes there is no pain at all, but only a feeling of indigestion or nausea. Eating a meal usually relieves the pain of a duodenal ulcer, but for a gastric ulcer there may be no change, or the pain may become worse. It is best to consult a physician if any of these symptoms appear. Peptic ulcer disease can also occur without symptoms. Symptoms may also arise when there is no ulcer – a condition known as nonulcer dyspepsia.

Bleeding and Perforation.
Although peptic ulcers are rarely lethal, the disease can be very serious if it progresses to the point of hemorrhage or perforation of the stomach or duodenum. Of the people who get ulcers up to 15% will experience some degree of bleeding. Bleeding is more apt to occur with ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) than those caused by the bacteria H. pylori. NSAIDs cause bleeding in 1% to 2% of people who are taking them. NSAID-related stomach problems may be responsible for 76,000 hospital admissions and over 7,000 deaths in the United States annually. Because there are usually no symptoms until bleeding begins, physicians cannot predict which patients taking these drugs will develop bleeding, although elderly patients and those with serious conditions, such as congestive heart failure, are at greatest risk. The risk for a poor outcome in a patient with bleeding is increased by the presence of one or more other factors, including ongoing bleeding, abnormal blood-clotting tests, low systolic blood pressure, mental instability, and the presence of another serious, unstable medical condition.

Obstruction.
Ulcers that form where the small intestine joins the stomach can swell and scar, resulting in a narrowing or closing of the intestinal opening. In such cases, a patient will vomit the entire contents of the stomach and emergency procedures are necessary.

Stomach Cancer.
Between 30% and 90% of stomach, or gastric, cancers are linked to H. pylori, and people with stomach ulcers from the bacteria are at twice the risk for stomach cancer than those without such ulcers. Those with duodenal ulcers, however, appear to be at lower risk for stomach cancer. Studies are now helping to define why H. pylori affects stomach and duodenal ulcers differently, and, furthermore, how the infection in the stomach may lead to gastric cancer. In developing countries where the rate of H. pylori in children is very high, the risk of stomach cancer is six times higher than in America. In the U.S., where H. pylori infects older individuals, less than 1% of people with H. pylori develop stomach cancer.

If H. pylori infects a child, by early adulthood the individual may develop a precancerous condition called chronic atrophic gastritis (CAG), in which the infection inflames areas in the stomach and destroys patches of glands that secrete protein and acid. New cells replace those destroyed but have less acid to protect against carcinogens; over time, stomach cancer can develop. Infection of H. pylori in adults may still cause CAG, but stomach ulcers or cancer would develop from this condition so much later that the patient would probably die of other causes first. It should be noted that other factors, particularly diets low in fresh fruits and vegetables, might also influence the increased risk for stomach cancer reported in population studies of people with high rates of stomach cancer.

Heart Disease.
Some (but not all) research has reported a very high rate – up to 84% – of H. pylori infection in men with coronary artery disease. Some experts are focusing on a particularly virulent genetic form of H. pylori called chronic atrophic gastritis A (cagA), which they believe may be the culprit in this process. H. pylori also increases levels of a blood-clotting factor called fibrinogen, which is a risk factor for heart attacks. It should be stressed that H. pylori is also common in people without heart disease, and other studies, including a recent, extensive one, have found no association between the two conditions.

Migraine Headaches.
A recent study has found that H. pylori may also be responsible for some cases of migraine headaches in people who also have gastrointestinal problems. Eliminating the bacteria in such people often appears to also relieve headaches.

Impaired Quality of Life.
Researchers report that pain and sleeplessness caused by peptic ulcers have a dramatic and adverse impact on quality of life, particularly reducing social functioning.

Ten percent of males and 4% of females develop a duodenal ulcer in their lifetime. Although H. pylori is known to be the major player in ulcers not caused by nonsteroidal anti-inflammatory drugs, other conditions increase susceptibility. There seems to be an increased incidence of ulcers in people who have Type O blood. Peptic ulcer disease affects all age groups, including children. Other risk factors thought to play contributory roles include alcohol abuse, and stress, although some studies have not confirmed any additional risk from these factors.

Risk Factors for H. Pylori.
About 50% of the general population has H. pylori, and it occurs almost universally in people who live in crowded, unsanitary conditions. Almost 25% of children in the U.S. and about half in developing countries harbor H. pylori. Some people are concerned that, because it is a bacteria, it may be contagious, but little is yet known about its transmission. It may be that young adults and children can be infectious if they have the bacteria, but many experts do not believe adults can easily transmit H. pylori to each other. It is possibly spread by sewage-contaminated water or by fecal-oral transmission (caused, for instance, by touching food with hands that weren’t washed after a bowel movement). Although experts do not know exactly how the bacterium is transmitted, some postulate that the common housefly may be an important agent in transmission.

Family History.
Some evidence indicates that genetic factors may be involved in making some people susceptible to peptic ulcer disease triggered by H. pylori. Identical twins have a similar risk for developing ulcers, and duodenal ulcers seem to be two to three times more likely in relatives of people with ulcers. Various inborn abnormalities such as high levels of acid production, weaknesses in the mucosal layer, or production of types of mucous that are not as protective may make someone susceptible to peptic ulcer disease. Inherited ulcers, however, are far less common than ulcers caused by NSAIDs or those associated with lifestyle factors that may increase a person’s vulnerability to the ulcer-producing effects of H. pylori.

Caffeine, Cigarettes, and Alcohol.
Caffeine. Coffee (both caffeinated and decaffeinated), soft drinks, and fruit juices with citric acid induce increased stomach acid production. Although no studies have proven that any of these drinks contribute to ulcers, consuming more than three cups of coffee per day may increase susceptibility to H. pylori infection.

Smoking. Results of studies on the effect of smoking on ulcers are mixed. Smoking does, however, increase acid secretion, reduces prostaglandin and bicarbonate production, and decreases mucosal blood flow. Some evidence suggests that smoking delays the healing of gastric and duodenal ulcers. One study reported that after ulcers healed, about half of nonsmokers relapsed after a year, but that all heavy smokers relapsed after three months. Other studies have found no increased risk for ulcers in smokers, and smoking does not appear to increase susceptibility to H. pylori or inhibit treatments for it – but this should not give smokers any comfort about the dangers of smoking.

Alcohol. Alcohol, too, has mixed reports. Some studies have shown that alcohol may actually protect against H. pylori. Drinking alcohol may, however, intensify the risk of bleeding in those who also take NSAIDs. In any case, everyone should avoid excessive use of alcohol.

Stress and Psychological Factors.
A recent survey reported that 88% of Americans still believe that stress causes ulcers. A host of studies have attempted to establish a correlation between the formation of ulcers and various types of occupations, stressful life events, lower educational or socioeconomic status, personality traits, and the ability to cope with stress. It makes intuitive sense that stress probably plays some role in exacerbating peptic ulcer disease, but the results of these studies have generally indicated that no relationship exists.

Medical History.
The physician will ask for a thorough report of symptoms, any present and past drug use – especially chronic use of NSAIDs – family members with ulcers, and drinking, and smoking habits.

Trial of Acid-Blocking Medication.
Before proceeding to expensive and possibly needless testing in patients who are suffering a first attack of symptoms, physicians often recommend a four-week course of acid-suppressing medication. In such cases, the ulcer may heal. If symptoms persist, then further testing is needed.

Testing for H. Pylori.
Now that it is well-established that H. pylori is a proven cause of peptic ulcers that can be eradicated with antibiotics, the questions facing clinicians are which individuals should be tested for H. pylori and what tests should be performed. Many individuals harbor the bacteria, but it causes ulcers in only 20% of those infected. A panel of the National Institute of Health has issued guidelines recommending testing for H. pylori only for individuals with strong indications for ulcers, such as those with clear symptoms and patients who have a history of active ulcers. One German study reported that screening workers for infection with H. pylori bacteria might prevent illness and reduce lost productivity. Simple breath and blood tests can now detect H. pylori with a fairly high degree of accuracy. The more invasive test, gastroscopy, which allows a biopsy of stomach tissue, is the most accurate test. Studies have indicated that if a patient with dyspepsia has a positive blood test result for the bacteria, antibiotic treatment is warranted without going through an expensive endoscopy to confirm that a diagnosis of ulcers. It should be noted, however, that there is also concern in the medical community about the increase in bacterial strains resistant to common antibiotics, generally due to the overprescribing of antibiotics.

Breath Test. A simple breath test may significantly reduce the need for endoscopy. In order to qualify for the test, a patient must be off all antibiotics and not have taken any Pepto Bismol for one month before the test. The patient must also not eat or drink six hours before taking it. The patient is asked to swallow a special fluid or capsule containing urea that has been treated with carbon atoms. If H. pylori is present, it converts the urea into carbon dioxide, which is then exhaled by the patient into the device. This test is proving to be very accurate for both initial detection of the bacteria and for checking recurrence after antibiotic treatment, when it should be performed at least four weeks after therapy. Studies have found that the test can identify 95% of people who have H. pylori. The test can also be used to detect any residual bacteria after treatments for ulcers.

Gastroscopy. Gastroscopy with biopsy has been the standard for diagnosing H. pylori, but it is invasive and expensive. Gastroscopy (also often called by its general name, endoscopy) may be performed either in a hospital or in a doctor’s office. The physician administers a local anesthetic using an oral spray and an intravenous sedative to suppress the gag reflex and to relax the patient. The physician then places an endoscope – a thin, flexible plastic tube – into the patient’s mouth and down the esophagus into the stomach. A tiny camera in the endoscope allows the physician to see the surface of the esophagus (food pipe), stomach, and duodenum to search for abnormalities. The physician will take about ten small tissue samples (biopsies) which will be used to test for H. pylori. Recently, studies report that simply testing gastric juices obtained using endoscopy can detect H. pylori infection. The bacteria is likely to be present in over 90% of patients with high activity of urease, the enzyme produced by H. pylori. The biopsy can also be used to detect the presence of gastric cancer, which is a risk for 5% of people with gastric ulcers.

Blood Tests. Blood tests, which are much less expensive than either the breath test or gastroscopy, measure antibodies to H. pylori with results available in minutes; some are reporting accurate diagnosis of between 80% and 90%. The tests, however, are not useful for treatment follow-up, since even after successful therapy. Although antibody levels may drop, they still remain in the bloodstream.

Other Tests for H. Pylori. Other tests are under investigation including a saliva test and one known as polymerase chain reaction (PCR) that uses cells from gums or stools and makes multiple copies of the DNA, or genetic material, of H. pylori until the bacteria is detectable.

Upper GI Series.
The upper GI (gastrointestinal) series has been the traditional mainstay of ulcer diagnosis to date. It is already being supplanted to a great extent by simpler tests for H. pylori. When taking this test, the patient drinks a solution containing barium, then x-rays are taken which may show inflammation, active ulcer craters, or deformities and scarring due to previous ulcers. Endoscopy is more accurate, although more invasive and expensive.

Other Laboratory Tests.
Stool tests may show traces of blood that are not visible, and blood tests may reveal anemia in those who have bleeding ulcers. A test that measures sucrose in the urine shows great promise in revealing gastric ulcers. An endoscopy would still be needed to confirm the diagnosis, but the test is simple and inexpensive and could be used to track people taking NSAIDs long-term. If Zollinger-Ellison syndrome is suspected, blood levels of gastrin should be measured.

General Guidelines for Combination Therapy for the Eradication of H. pylori.
Candidates for Antibiotic Treatment. Combination drug treatment that includes antibiotics is now the recommended treatment for ulcer patients in whom H. pylori is detected, including those who also take NSAIDs. People with NSAID-related ulcers, who do not have the bacteria should not be given this regimen. Some experts suggested that in patients with symptoms who have a history of recurring ulcers, no indication of excessive stomach acid, and no history of taking NSAIDs or antibiotics, the presence of H. pylori is so strongly suggested that they should receive the antibiotic regimen even without confirming tests.

Eradication of H. pylori infection using antibiotic regimens may also lower the risk for developing precancerous changes in the stomach, although one study found that if such changes have already developed, eliminating the bacteria has little effect. Another study, however, found the eradicating H. pylori in people treated for initial-stage stomach cancer helped prevent recurrence of the disease, and eliminating the bacteria may cure a rare, low-grade gastric lymphoma known as MALT (mucosa-associated lymphoid tissue).

In spite of the proven high cure rates using antibiotic therapy to eradicate H. pylori and the possibility of reducing the risk of stomach cancer, half of physicians are still giving patients with ulcers the acid-blocking drugs called H₂ blockers without testing for H. pylori. In one study, less than half of elderly peptic ulcer patients who were proven to harbor the bacteria were given antibiotics to eradicate it. Patients with ulcers caused by the bacteria should question their doctors if they are not receiving drugs to eradicate H. pylori. On the other side of the argument, however, is the danger in overuse of antibiotics particularly with the risk of developing bacteria that become resistant to them.

Drug Regimens. A number of effective drug combinations are being used with success rates as high as 90% although cost varies widely. Most use two antibiotics and an acid suppressor, usually omeprazole (Prilosec). A typical triple-drug regimen consists of omeprazole, clarithromycin (Biaxin), and amoxicillin. Other effective regimens substitute metronidazole (Flagyl) for clarithromycin or amoxicillin. Three-drug regimens using these medications are well tolerated, effective, but very expensive. A less costly regimen using omeprazole, Bismuth (Pepto Bismol), and tetracycline is effective, although side effects can be very distressing and many patients cannot tolerate it. Another uses Biaxin and a newly developed drug that combines ranitidine with bismuth citrate (Tritec). Two-drug regimens are being developed that use omeprazole and one antibiotic or two antibiotics, but so far, they are slightly less effective than taking three drugs. Nevertheless the two-drug regimens are still more effective and less expensive than older acid-blocking therapies that treat only symptoms. Most regimens need to be taken for at least 14 days; only the three-drug combination Prilosec, Biaxin and Flagyl requires just seven days, and, in one study, taking them for only three days appeared to be effective. [For descriptions of these drugs, see Specific Drugs Used to Treat H. Pylori, below.]

Side Effects and Noncompliance. Although antibiotic treatment is very effective against both gastric and duodenal ulcers, patient compliance is poor. The triple-drug regimens are complicated and require many pills a day. Side effects from one or more of these drugs occur up to 30% of patients. Cases of severe diarrhea have occurred during treatment. One study indicates that the long term side effects of treatment include weight gain and an increased risk for gastroesophageal reflux esophagitis (a cause of severe heartburn).

Long-Term Success. Studies are indicating that, at least in developed countries, once the bacteria is eliminated the ulcers do not recur. (Reinfection with the bacteria may be possible, however, particularly in areas where the incidence of H. pylori is very high and sanitary conditions are poor.)

Specific Drugs Used to Treat H. Pylori.
Antibiotics. For treating H. pylori, amoxicillin or tetracycline are effective drugs and either can serve as a second antibiotic. H. pylori is very sensitive to both. Amoxicillin can cause diarrhea and allergic reactions. Tetracycline may cause staining of the teeth, which can be permanent in children. It should not be given to pregnant women. Clarithromycin (Biaxin) is an antibiotic that is similar to erythromycin but more effective against H. pylori. It causes changes in taste that might be unpleasant and is the most expensive of the antibiotics used against H. pylori. Resistance to this drug is already between 2% and 3% and researchers fear that this rate will increase as usage against H. pylori increases. Ciprofloxacin (Cipro) is another potentially effective antibiotic.

Metronidazole. Metronidazole (Flagyl) was the mainstay in initial combination regimens, but resistance to the drug is very high (about 25% of H. pylori bacteria). Consuming alcohol while taking the drug can cause flushing and severe gastrointestinal problems, so should be avoided during therapy and for three days afterward.

Bismuth. Compounds that contain bismuth destroy the cell walls of the H. pylori bacteria and are an effective addition to the regimen. The only available bismuth compound available in the US has been bismuth subsalicylate (Pepto-Bismol). A drug combination of the H₂ blocker ranitidine and bismuth citrate (Tritec) has recently been released. High doses can cause vomiting and depression of the central nervous system, although the doses given for ulcer patients rarely cause side effects.

Proton-Pump Inhibitors. Omeprazole (Prilosec) and lansoprazole (Prevacid) are known as proton-pump inhibitors. They work by inhibiting the so-called gastric acid pump that is required for the stomach’s cells to secrete acid. They are very effective suppressers of acid production. Either drug can be used as part of the triple-drug regimen. These drugs do not eradicate H. pylori, but they reduce the acidity in the intestinal tract, thereby increasing the effectiveness of the bacteria-fighting drugs being used in the regimen. Side effects are uncommon but may include an allergic reaction, headache, stomach pain, and diarrhea. These drugs are also useful in the treatment of ulcers caused by Zollinger-Ellison syndrome and may benefit long-term NSAID users [see below]. One study also reported that in people whose ulcers were not cured by H. pylori therapy, lansoprazole helped maintain remission after temporary ulcer healing for more than a year. Proton-pump inhibitors should not be used unless necessary by pregnant women or nursing mothers. There is some concern that long-term use of proton-pump inhibitors can increase the risk of stomach cancer by causing chronic atrophic gastritis, in which acid secretion is reduced, thereby impairing protection against carcinogens in the stomach. Such a risk, however, appears to occur only if H. pylori is present. Eradicating the bacteria should eliminate this risk, although if such precancerous changes already exist, the danger may persist.

Older Treatments for Ulcers Cause by H. Pylori.
Elderly patients with ulcers caused by H. pylori but who cannot tolerate the side effects of the antibiotic therapy may continue to benefit from H₂ blockers, the older treatments for peptic ulcer. Some experts recommend H₂ blockers for people who test positive for H. pylori but have symptoms only of dyspepsia and no sign of peptic ulcers. Their argument is based on reducing costs; young people who meet this criteria but who have other risk factors for ulcers should discuss options with their physician. Some researchers are also concerned that eradicating H. pylori may not be effective against bleeding episodes from existing ulcers and that H₂ blockers will remain important for treating this condition. By decreasing acid production, the body has the opportunity to heal itself. H₂ blockers temporarily heal up to 95% of ulcers after eight weeks, but they do not prevent recurrence of ulcers. One study, for example, showed that long-term therapy with the H₂ blockers ranitidine (Zantac) significantly prevented recurring bleeding in people who had experienced severe hemorrhaging from non-NSAID-induced ulcers. [For information on H₂ blockers see What Are Treatment for Ulcers Caused by NSAIDs? below.]

Vaccines and Experimental Treatments.
There is some urgency in pursuing development of alternative treatments to antibiotics, because strains of the bacteria are emerging that are resistant to many common antibiotics. Vaccines, including an oral form called Ora Vax, are showing promise in producing an immune response against H. pylori although availability is still years away.

Researchers have recently analyzed the entire genetic sequence of H. pylori. This means that eventually they may be able to develop drugs that block proteins that are essential for bacterial growth.

A drug being tested is a carbohydrate-based drug called NE-0800 that attaches to H. pylori. Early trials are showing lower bacterial activity but the long-term safety of the drug is not yet known. Laboratory studies using vitamin C report that high doses inhibit H. pylori growth. (Taking vitamin C supplements, however, has no proven benefits against peptic ulcers.)

Alternatives to NSAIDs.
Arthrotec. A combination of the NSAID declofenac and misoprostol (Arthrotec) has now been approved that may reduce the risk for gastrointestinal bleeding. One study found that patients taking Arthrotec had 65% to 80% fewer ulcers than those who took NSAIDs alone.

Acetaminophen. Acetaminophen (Tylenol, Anacin-3, Panadal, Phenaphen, Valadol, and other brands) is the most common alternative to NSAIDs, although many patients report less pain with acetaminophen than with an NSAID; acetaminophen is not an anti-inflammatory agent. Acetaminophen can be used alone or in combination with NSAIDs with some success. Liver and kidney damage are potential serious side effects of acetaminophen. Alcohol use with acetaminophen increases the risk for liver damage. Experts recommend taking no more than eight extra-strength tablets each day. If NSAIDs are needed, taking them with food buffers acidity and helps reduce the risk.

COX-2 Inhibitors. New, aspirin-like drugs, including celecoxib (Celebra) and another (Vioxx), are being developed to target a specific prostaglandin-producing enzyme called cyclooxygenase 2 (COX 2) without affecting COX 1, another enzyme that generates stomach-protective prostaglandins and which other NSAIDs block. Such drugs may allow high doses without accompanying gastrointestinal side effects.

Specific Drugs Used for Treating Ulcers Caused by NSAIDs.
Proton-Pump Inhibitors. Omeprazole (Prilosec), a proton-pump inhibitor, is proving to be very effective, particularly for NSAID-users who have large gastric ulcers. One study suggested that taking omeprazole with NSAIDs can both heal and help prevent ulcers. In fact, an interesting study reported that using antibiotic regimens and omeprazole to eradicate H. pylori before initiating NSAID treatment reduced the occurrence of NSAID-induced peptic ulcers in people harboring the bacteria. In comparison study between omeprazole and misoprostol [see below], the two drugs were about equally effective in the short term, but after eight weeks of maintenance therapy, omeprazole was superior. It was also more effective than the H₂ blocker ranitidine. It wasn’t compared to famotidine, an H₂ blocker with some proven effectiveness against NSAID-induced ulcers. [For detailed information on this drug, see Specific Drugs Used to Treat H. pylori, above, and Famotidine and Other H₂ Blockers, below.]

Famotidine and Other H₂ Blockers. H2 blockers block or antagonize the actions of histamine, a chemical found in the body that encourages acid secretion in the stomach. H2 blockers were the standard treatment for peptic ulcers until the development of antibiotic regimens against H. pylori. They cannot cure or prevent ulcers, however. Nevertheless, at least some of these drugs still may have value for preventing and treating ulcers caused by NSAIDs. Four H₂ Blockers are currently marketed in the U.S. and are available over the counter: famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac) and nizatidine (Axid). All have few side effects and good safety points.

Famotidine (Pepcid AC) is the most potent H₂ blocker and the only one to date found to be effective for NSAID-induced ulcers. The most common side effect of famotidine is headache, which occurs in 4.7% of people who take it. Famotidine is virtually free of drug interactions. A trial of NSAID-users who took 40 mg of famotidine (Pepcid AC) twice a day reported that only 8% of patients taking the drug developed stomach ulcers and 2% developed duodenal ulcers, compared to 20% of patients who didn’t take famotidine developing stomach ulcers and 13% duodenal ulcers. In one study of NSAID-users who had existing ulcers, the ulcers healed in 82% of patients who took famotidine, even though they continued taking the NSAIDs. After six months, the ulcers had recurred in only 25% of the patients who took famotidine compared to recurrence in over half of those who did not. It is not known whether the drug is effective in people whose ulcers have developed to the point that they are causing symptoms. Some experts are concerned that although famotidine appears to prevent and perhaps even heal ulcers, the use of acid-blocking drugs may actually increase the risk for serious complications including perforation, internal bleeding, and possibly even stomach cancer. In cases of patients taking NSAIDs for long periods, some experts advise acid-blocking drugs only for those who are at risk for ulcers (e.g., if they have a history of ulcers, are over 70, or are also taking corticosteroids).

The other common acid blockers, ranitidine, cimetidine, and nizatidine, have not been proven to be effective for NSAID-induced ulcers. Still, they do heal ulcers and may have benefits for people whose ulcers are caused by H. pylori but fail antibiotic treatment. Cimetidine (Tagamet), the first H₂ blocker, was one of the widest-selling drugs in the world. It has few side effects; approximately 1% of people taking cimetidine will experience mild temporary diarrhea, dizziness, rash or headache. Because cimetidine interacts with a number of commonly used medications such as phenytoin, theophylline, and warfarin, however, patients should always inform the physician of any drugs they are taking. Long-term use of excessive doses (more than 3 grams a day) of cimetidine may also cause impotence or breast enlargement; these problems resolve after the drug is discontinued. Ranitidine (Zantac) was the second H₂ blocker to be introduced. Ranitidine’s advantage over cimetidine is that it interacts with very few drugs. Even so, the physician must always be aware of any other drugs a patient is taking. In a recent study, ranitidine provided more pain relief and healed ulcers more quickly than cimetidine in people under 60 years old, but there was no difference in older patients. A common side effect associated with ranitidine is headache, which occurs in about 3% of the people who take it. Nizatidine (Axid) is the latest H₂ blocker and is nearly free of side effects and drug interactions.

Misoprostol. Misoprostol (Cytotec) increases prostaglandin levels in the stomach lining, thus conferring protection against the major intestinal toxicity of NSAIDs. Misoprostol can reduce formation of ulcers in the upper small intestine by two thirds and in the stomach by three quarters. It does not neutralize or reduce acid, however, and so, although the drug is used for preventing NSAID-induced ulcers, it is not generally used to heal existing ulcers. Diarrhea and other gastrointestinal problems are side effects that are severe enough to cause 20% of patients to stop taking the drug. Taking the misoprostol after meals should minimize these effects; one study indicated that taking the drug two or three times a day instead of the standard regimen of four times may prove to be just as effective and cause fewer side effects. Misoprostol can induce abortion or cause birth defects and should not be taken by pregnant women. If pregnancy occurs during treatment, the drug should be discontinued at once and the physician contacted immediately.

Sucralfate. Sucralfate (Carafate) seems to work by adhering to the ulcer crater and protecting it from further damage by stomach acid and pepsin. It also promotes the defensive processes of the stomach. Through these dual mechanisms, sucralfate has proven to have a duodenal ulcer healing rate similar to that of H₂ blockers. Other than constipation, which occurs in 2.2% of patients, the drug has few side effects. Sucralfate does interact with a wide variety of drugs, including warfarin, phenytoin and tetracycline. It is not approved for gastric ulcers.

Antacids. Many antacids are available without prescription and are the first drugs recommended to relieve heartburn and other mild ulcer symptoms. They are best used alone for relief of occasional and unpredictable episodes of heartburn. All of the many brands available rely on various combinations of three basic ingredients and work by neutralizing the acid in the stomach. It has recently been suggested that they may also stimulate the defensive processes of the stomach, causing increases in bicarbonate and mucous secretion. There are three basic salts used in various antacids: magnesium, calcium, and aluminum. Magnesium salts are available in the form of magnesium carbonate, magnesium trisilicate, and most commonly, magnesium hydroxide (Milk of Magnesia). The major side effect of magnesium salts is diarrhea. Calcium carbonate (Tums, Titralac, and Alka-2) is a potent and rapid-acting antacid. It can cause constipation. There have been rare cases of hypercalcemia (elevated levels of calcium in the blood) in people taking calcium carbonate for long periods of time. This can lead to kidney failure and is very dangerous. The most common side effect of antacids have this side effect of antacids containing aluminum salts (Amphogel, Alternagel) is constipation. People who take large amounts of antacids that contain aluminum may also be at risk for calcium loss and osteoporosis. Long-term use also increases the risk for kidney stones. Combination products (Mylanta and Maalox) contain both aluminum and magnesium salts, which balances the side effects of diarrhea and constipation.

It is generally believed that liquid antacids work faster and are more potent than tablets, although some evidence suggests that both forms work equally well. Antacids can interact with a number of drugs in the intestines by reducing their absorption. These drugs include tetracycline, ciprofloxacin (Cipro), propranolol (Inderal), captopril (Capoten), and the H₂ blockers ranitidine (Zantac) and famotidine (Pepcid). These interactions can be voided by taking these other drugs one hour before or three hours after taking the antacid.

Bleeding stops spontaneously in about 70% to 80% of people with bleeding ulcers. Initial care usually involves administration of fluids and, if necessary, blood; diagnostic procedures to detect causes; and any other necessary medical treatment. Diagnosis is confirmed using endoscopy, which involves tubes that are passed down into the stomach. Physicians are able to detect signs of bleeding that include active spurting or oozing blood from arteries, swollen but nonbleeding blood vessels, and nearby blood clots. Depending on the intensity of the bleeding, patients can be released from the hospital within a day or kept up to three days after endoscopy. Patients who have the H. pylori bacteria, even if NSAIDs caused the bleeding, should be treated with antibiotic therapy to eradicate the bacteria. People on NSAIDs should discontinue them if possible.

Surgical Treatment for Bleeding Ulcers.
Those who show signs of continued or recurrent bleeding require immediate emergency treatment, most often using endoscopy. Endoscopic treatment f bleeding involve using a probe passing through the endoscopic tube that applies electricity or heat to coagulate the blood and stop the bleeding. An injection f ethanol, saline, or epinephrine (commonly known as adrenaline) directly into the ulcer may be used in addition to or instead of endoscopic treatments. Epinephrine plus a combination of blood clotting factors termed fibrin glue are proving to be even more effective than epinephrine alone. Mortality has been high after emergency operations, although the risk of death can be significantly reduced if patients are first given endoscopic therapy to stop bleeding. In spite of improved surgical techniques, bleeding episodes have increased because of high NSAID usage and a larger elderly population, so the mortality rate has remained steady at between 6% and 10% for 50 years.

With the advent of antibiotic therapies for H. pylori, major surgery for prevention of bleeding ulcers is now very uncommon except for life-threatening situations from perforated ulcers. Procedures include vagotomy, which cuts the vagus nerve and interrupts messages from the brain to the stomach that stimulate acid secretion. Antrectomy removes the lower part of the stomach that manufactures the hormone responsible for stimulation of digestive juices. Pyloroplasty enlarges the opening into the small intestine so that stomach contents can pass in to it more easily. Surgery does not cure upper GI ulceration due to chronic NSAID use.

Medical Treatments for Bleeding Ulcers.
Researchers are looking at alternatives to surgery for bleeding ulcers that could lower the mortality rate. The proton-pump inhibitor omeprazole is showing promise. In one study, it significantly reduced recurrent bleeding in patients with evidence of clots or swollen blood vessels (although it had no benefit in cases where overt bleeding was evident). More research is needed. Somatostatin is a hormone that is used to prevent bleeding in people with cirrhosis. Octreotide (Sandostatin) is a drug that resembles somatostatin. Both drugs have reduced persistent peptic ulcer bleeding or the risk of recurrence in half of patients studied.

Diet.
It was common in the past to restrict people suffering from peptic ulcers to frequent intake of small amounts of bland foods and milk. Exhaustive research conducted since then has shown that a bland diet is not effective in reducing the incidence or recurrence of ulcers, and that frequent small meals throughout the day are no more effective than consumption of three meals per day. (Large amounts of food should still be avoided because stretching or swelling of the stomach can result in painful symptoms.) Milk was found to actually encourage the production of acid in the stomach, although moderate amounts (two to three cups a day) can be drunk without harm. Coffee may increase susceptibility to H. pylori, and, in any case, cutting down on coffee (both decaf and caffeinated) and carbonated beverages may help reduce stomach acid.

The good news is that a diet rich in fiber may cut the risk of developing ulcers in half and speed healing of existing ones. Fiber found in fruits and vegetables is particularly protective; vitamin A contained in many of these foods may increase the benefit. In one study, apples and yams appeared to be especially helpful. Apples, celery, cranberries, onions, red wine, and green and black tea are also high in natural chemicals known as flavonoids, which appear to inhibit H. pylori growth and have many other health benefits.

Studies conducted on spices and peppers have yielded conflicting results. The rule of thumb is to use all these substances moderately, and to avoid them if they irritate the stomach.

Other Lifestyle Changes.
Some evidence exists that exercise may help reduce the risk for ulcers. Stress relief programs have not been shown to promote ulcer healing, but they may have other health benefits.

National Digestive Diseases Information Clearinghouse
Call (301-654-3810)

American Gastroenterological Association
Call (301-654-2055 or toll-free 800-NO-ULCER)
or on the Internet (http://www.gastro.org)

American Society for Gastrointestinal Endoscopy
Call (978-526-8330), fax (978-526-8330)
or on the Internet (http://www.asge.org)

Helicobacter Pylori Foundation
On the Internet (http://www.helico.com)

Centers for Disease Control and Prevention
Call toll-free (888-MY-ULCER)

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Modified April 24, 1999 - Four M Engineering, Inc

(Well-Connected, Report #45, September 30, 1998)