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Strong Medicine, Pain relief -- at a price.

Until about 30 years ago, there were few drugs available to ease the crippling pain and swelling of arthritic diseases. So when a new class of medicines called non-steroidal antiinflammatory drugs (NSAIDs) was developed in the 1960s, it was a godsend for people with rheumatoid arthritis, osteoarthritis, and gout.

A person's choice was limited to indomethacin (Indocin) and a handful of other drugs until 1974, when ibuprofen (Motrin) came on the scene. Five years later, the Food and Drug Administration approved Motrin for menstrual cramps, pain following surgery, and soft tissue injuries. The drug developed such a following among women with menstrual pain that an informal black market sprang up in offices across the country where the treasured tablets were dispensed to friends and colleagues.

In 1984, ibuprofen was approved for over-the-counter sales in a reduced-strength version. In just over a decade, the drug (sold as Advil, Motrin IB, Nuprin, and generic forms) has surpassed aspirin to become the second bestselling nonprescription pain reliever after acetaminophen (Tylenol).

Although NSAIDs have become the most widely prescribed class of drugs in the industrialized world, their benefits-like most things in life-come at a price. High doses of these medications can cause not only stomach pain but also bleeding from gastritis or ulcers. And because NSAIDs decrease renal blood flow, they have been linked to kidney failure in some patients, particularly in elderly people and those with preexisting kidney damage.

"In the last three to five years there has been more of an appreciation that the risk/benefit ratio of long-term NSAID use is not as favorable as we thought 10 years ago," says rheumatologist David Trentham, associate professor of medicine at Harvard Medical School.

Although gastrointestinal hemorrhage is infrequent, occurring in only about 1 to 2 percent of patients, and fatalities are even rarer (one-tenth of a percent), there is no way to predict when or whom they will strike because, Trentham says, people are generally free of symptoms until the event. NSAID-induced stomach problems are estimated to be responsible for 76,000 hospitalizations and 7,600 deaths in the United States each year.

High Dose Dangers
More than 20 different NSAIDs are available by prescription in this country. Over-the-counter forms include generic and branded ibuprofen as well as naproxen sodium (Aleve) and two new brands of ketoprofen, Orudis and Actron. Aspirin is also considered to be an NSAID, although it existed long before the 1960s, when the newer drugs were developed and the acronym was coined.

All medications in this class work by blocking the production of prostaglandins, chemicals that cause inflammation and trigger transmission of pain signals to the brain. NSAIDs were specifically dubbed "nonsteroidal" to differentiate them from the corticosteroids, which also reduce the production of prostaglandins but have side effects that are far more dangerous. When taken in high doses for long periods of time, corticosteroids may cause hypertension, diabetes mellitus, osteoporosis, immune system impairment, and severe mental disturbances.

People who use over-the-counter NSAIDs for occasional aches and pains, and even those who have had high doses of ibuprofen (1,600 mg to 2,400 mg) prescribed for a few days to relieve the pain of dental surgery or menstrual cramps, run little risk of gastrointestinal harm.

Strong MedicineIt is the people who take high doses for prolonged periods of time who are in greatest danger. "There's good evidence to show that the injury from these drugs in the G.I. tract is dose-related," says gastroenterologist Frank L. Lanza, clinical professor of medicine at Baylor College of Medicine in Houston. "The more you take, the more likely you are to have damage and complications."

Common sense dictates that the smallest amount of medication needed to control pain is what should be taken, says Lanza. He believes that NSAIDs are both overprescribed by doctors and overused by people with osteoarthritis and mild rheumatoid arthritis.

In fact, there is little evidence showing that an NSAID is more effective than acetaminophen (Tylenol) for osteoarthritis, a disease that destroys joint cartilage through overuse, age, and other factors. Although this tends to be a noninflammatory condition, osteoarthritis is sometimes accompanied by inflammation. A 1991 study published in the New England Journal of Medicine found that four grams per day of acetaminophen was as effective as either 1,200 mg or 2,400 mg a day of ibuprofen in mitigating the pain of osteoarthritis of the knee.

For years, doctors have recommended acetaminophen over NSAIDs for noninflammatory conditions because the drug has generally been thought to be safer. However, a shadow has been cast on this old standby.

Some doctors recommend that people with mild to moderate arthritic conditions take acetaminophen during the day and about 400 mg to 600 mg of ibuprofen after dinner (to reduce the chances of stomach irritation). NSAIDs are most appropriate for acute inflammatory arthritis or the chronic pain and swelling of systemic rheumatic disease.

Pick and Choose
Doctors find that selecting the most appropriate NSAID for an individual patient is more of an art than a science. While people seem to respond differently to different drugs, both in terms of pain relief and adverse reactions, few clinical trials have examined why this occurs.

Some studies that have asked people to compare one NSAID to another found few strong preferences. But other surveys show that patients favor specific medications. It is not clear, however, whether there is some pharmacologic basis for this or if it is a result of chance or of a placebo effect. Because these drugs work in much the same way, choosing one NSAID over another may depend more on cost or other factors. A one-month supply of NSAIDs can range in price from less than $5 for eight aspirin a day to about $100 for three 75-mg tablets of ketoprofen a day.

People who are allergic to aspirin should be wary of other NSAIDs because they may also provoke an allergic response. Gout patients should avoid salicylates (a subgroup of NSAIDs that includes aspirin) because these drugs may hasten or prolong an attack of joint pain.

Gastrointestinal damage is the leading adverse effect of NSAIDs. Although high doses of any NSAID increase the risk of bleeding and ulcers, more research is needed to pin down exactly how the risks differ among drugs. Two 1994 studies published in the Lancet suggested that ibuprofen was the least toxic to the gut of six frequently used NSAIDs. But, while kinder to the stomach, the drug may be among the worst offenders when it comes to damaging the kidneys.

Indeed, a growing body of evidence points to a link between heavy NSAID use and renal failure. One study, published in the December 22, 1994, issue of the New England Journal of Medicine, found that prolonged NSAID therapy (more than 5,000 pills in a lifetime) appeared to increase a person's risk of developing kidney failure. The investigators, however, found no such association with aspirin. And despite the accumulating evidence, some experts believe that data on renal disease may be flawed because they come exclusively from interviews with patients about the types and amounts of medication they've used over the years. It is possible that sick people recall their habits differently than do healthy individuals in control groups, they argue.

Other side effects of NSAIDs may include dizziness, anxiety, drowsiness, and confusion when the drug is first started. These usually disappear with further use. Tinnitus, a ringing or buzzing in the ears, sometimes results from high doses of aspirin. This usually dissipates when the medication is stopped. There is also some evidence that NSAIDs may reduce the effectiveness of beta-blockers and other antihypertensive drugs, probably by promoting fluid retention.

Finally, questions have been raised about the effect of NSAIDs on joint cartilage since reports in the 1960s found that some arthritis patients experienced hip joint destruction after taking high doses of indomethacin. Although two subsequent investigations debunked the connection, some researchers point to more recent experimental studies in animals indicating that high doses of NSAIDs do, in fact, damage cartilage cells.

Using NSAIDS Safely
Clearly, NSAIDs are powerful drugs with the potential for harm as well as for good. While they can be dangerous if taken with abandon, it doesn't make sense to shun them in low doses where they do a lot of good with little risk of injury.

At the same time, doctors have recently begun to emphasize the importance of strengthening muscles as one way people with arthritic diseases can reduce joint pain and lessen their reliance on NSAIDs. One study found that older people with osteoarthritic changes in their knees, hands, and spine who engaged in vigorous running and other aerobic activities actually had greater mobility than a group of non-exercisers who had the same arthritic changes.

"The admonition to avoid activity is clearly not in the cards anymore," says David Trentham. A mixture of rest, moderate exercise, and prudent use of NSAIDs may in fact be the best medicine of all.


Reprinted from The Harvard Health Letter. Copyright 1995 President and Fellows of Harvard College. All rights reserved. For subscription information, write Harvard Health Letter, P.O. Box 420300, Palm Coast, Florida 32142-0300, or contact "pbibbins@warren.med.harvard.edu".


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