Dolobid

The Down Side of NSAIDs

Millions of people take NSAIDs, more potent relatives of aspirin, to alleviate the pain or reduce the inflammation caused by such common conditions as arthritis, sore muscles, tendinitis, headaches, or menstrual discomfort. Most of these nonsteroidal antiinflammatory drugs, to give them their full name, are prescription items. But in 1984 ibuprofen (Motrin, Advil, Midol, and others) was licensed for sale over the counter, and since then it has become one of the most widely taken drugs in the United States. Along with the prescription NSAIDs, it has contributed greatly to pain relief and healing from inflammatory ailments. Recent reports, however, have reaffirmed the risks that NSAIDs pose, particularly to older people and those with impaired kidney function or vulnerable stomach linings.

NSAIDs, commonly pronounced "en-seds," are the first line of treatment for arthritis because they have a broad ability to inhibit the synthesis of prostaglandins. Although prostaglandins are not the primary cause of inflammation leading to pain and joint destruction, they are critical mediators of the process. They are small signaling molecules, somewhat like hormones. Unlike hormones, however, prostaglandins do not circulate in the bloodstream; instead they diffuse short distances from one group of cells to another, so as to influence the behavior of the target cells.

The antiinflammatory drugs, unfortunately, limit the body's ability to produce not only the inflammatory prostaglandins but also the beneficial ones. In the kidney prostaglandins play a crucial role in maintaining the flow of blood; in the stomach they help protect the lining from being attacked by the acid of digestive fluid.

Kidney function

When stressed by disease or dehydration, the body restricts the amount of blood it permits to circulate in peripheral tissues. The kidneys, however, must maintain their circulation so as to continue clearing the blood of wastes. They can at least partially override a general reduction in blood flow by secreting prostaglandins, which dilate their internal vessels and thereby preserve adequate flow.

The elderly, who are particularly susceptible to arthritis and are therefore likely to receive NSAIDs, are also particularly susceptible to reduced kidney function. In a study of 114 elderly men and women who had recently begun taking NSAIDs, mostly ibuprofen, researchers at the Hebrew Rehabilitation Center for Aged and the Beth Israel Hospital in Boston found that 13% showed signs of reduced kidney function.

Although kidney function quickly returned to its previous level after the drug was stopped, some physicians fear that many elderly patients with existing kidney damage are not being monitored while they use NSAIDs and may therefore be at risk of more serious impairment. "The symptoms of kidney failure can be silent until the condition is quite advanced," says Dr. Jerry H. Gurwitz, who led the study. "Without monitoring, we can't tell how many people may be experiencing such effects." In a recent study at the Johns Hopkins University School of Medicine, 3 of 12 patients with asymptomatic, mild but stable chronic renal failure had to interrupt courses of ibuprofen when they showed evidence of yet further impairment.

The risk seems greater with high doses of NSAIDs (equivalent to 2,400 milligrams a day, or 12 tablets of over-the-counter ibuprofen), but even recommended doses (1,200 milligrams, or 6 tablets) can produce evidence of reduced kidney function in susceptible people. "Patients with normal kidney function who are taking adequate amounts of fluid should not be at risk," says Dr. Andrew Whelton, who led the Hopkins research. "People with silent kidney disease, though, may run into trouble even while taking the upper limit of the recommended over-the-counter dose."

These findings have rekindled a debate on package labeling for over-the-counter NSAIDs. After the Food and Drug Administration approved ibuprofen for nonprescription sale, the National Kidney Foundation responded by calling for stronger warning labels directed toward the elderly and people who have kidney disease, heart failure, very high blood pressure, or cirrhosis. Patients taking diuretics must also be at least somewhat cautious. When combined with furosemide (Lasix) or bumetanide (Bumex), the so-called loop diuretics, NSAIDs appear to be yet more likely to limit kidney function than when taken alone. The new studies reinforce a large number of case reports describing adverse effects, according to Dr. Gurwitz, who adds, "We should be using the lowest doses possible and watching out for people at special risk."

Stomach irritation

Like aspirin, NSAIDs in high doses can injure the lining of the stomach. Although the damage typically takes the form of multiple small, superficial patches of erosion, large ulcers can also result. The cause of this damage is, again, loss of prostaglandin production. Prostaglandins secreted by cells in the stomach lining stimulate production of mucus to cover the surface exposed to digestive fluid; they also promote secretion of bicarbonate, which neutralizes acid, into the mucus. Additionally, prostaglandins seem capable of speeding the rate at which cells of the stomach lining repair acid damage. Taken together, these functions make prostaglandins a crucial link in the stomach's defense against self-digestion.

When NSAIDs were introduced, there was some hope that they would irritate the stomach lining less than aspirin does. On the whole, that has not been the case, although some NSAIDs are believed to be less irritating than others. Patients who must take NSAIDs for persistent inflammation can partially protect their stomachs by taking their medication with food and using antacids. Currently, though, gastric complications from these drugs are rampant.

Researchers at Stanford University School of Medicine report that hospitalization for gastrointestinal problems is over six times greater for elderly patients taking NSAIDs to treat rheumatoid arthritis than for similar patients not using these drugs. Extrapolating from their data, the authors of this report estimate that gastric bleeding from NSAIDs is the most frequent and severe drug side effect in the U.S., causing 20,000 hospitalizations and 2,600 deaths each year just in patients with rheumatoid arthritis.

Not all bad

NSAIDs, like aspirin, have not been found to pose a significant risk to young, healthy people using them for relatively short periods. (Nor is there any reason to believe that people taking a single aspirin a day, or every other day, to prevent a heart attack or stroke are risking either kidney damage or injury to the stomach lining. Their blood is, however, less capable of clotting, which puts them at somewhat increased risk of abnormal bleeding.)

Even chronic users of NSAIDs are not necessarily at high risk - according to one estimate, only 1 in 6,000 of these medications for NSAIDs will lead to gastrointestinal bleeding in elderly users. But the more of these medications one takes, the higher one's cumulative risk of having such a complication. People who are already at high risk, principally those at later ages, must walk a tightrope between pain relief and the potential risks of kidney damage or gastrointestinal bleeding if they take NSAIDs on a regular basis.

Keeping the balance has been made somewhat easier by a new drug, misoprostol (Cytotec), which mimics a prostaglandin. Recently approved for use in the United States, misoprostol is a close chemical relative of the prostaglandin that helps to maintain the stomach's defenses against acid. It has been shown to help heal ulcers of both the stomach and the duodenum and to counteract the diffuse damage caused by NSAIDs. Nausea, loss of appetite, or similar discomfort due to NSAIDs is not relieved by misoprostol, however. Misoprostol itself can cause abdominal discomfort (diarrhea, cramping, or flatulence) arising from its tendency to stimulate intestinal activity. Misoprostol has the potential to precipitate contractions of the pregnant uterus; women of childbearing age should not take it unless they are using contraceptive measures, and a woman who becomes pregnant while taking misoprostol should immediately discontinue it.

Since it was approved for use in this country, misoprostol has been very heavily promoted. It is, however, quite expensive. The drug is best prescribed for people who have a known tendency to form ulcers or bleed from the stomach and who must take an NSAID. Protection has been documented over periods of two or three months. Whether it will work as well for people taking NSAIDs for years on end remains to be seen.

Table : Common NSAIDs

COPYRIGHT 1990 Copyright by President and Fellows of Harvard College. All Rights Reserved
COPYRIGHT 2004 Gale Group