By Shauna S. Roberts

As any good son would, Felix Hoffmann hated to see his father suffering from arthritis and the severe side effects of the sodium salicylate used to treat it. But unlike most sons, Hoffmann had the means to help. A chemist at the Farbenfabriken Friedrich Bayer in Germany, Hoffmann began tinkering with salicylic acid in hopes of preserving its inflammation-fighting properties while easing its harsh effects on the stomach. The result, in 1897, was acetylsalicylic acid, which Bayer began marketing in 1899 under the trade name Aspirin.

In the century since, a throng of other nonsteroidal anti-inflammatory drugs (NSAIDs) has emerged. Even so, aspirin has become the most widely consumed drug in the world, with Americans gulping down 29 billion pills a year.

Many of these billions are taken to ward off heart and artery disease. The FDA has approved the use of aspirin (1) to reduce the risk of

• a second stroke in people who’ve already had one ischemic stroke, caused by blockage in a blood vessel that supplies the brain, or a transient ischemic attack, a ministroke;
• a second heart attack in people who’ve already had one or have unstable angina, chest pain caused by unpredictable impairment of blood flow to the heart;
• death in people having a heart attack; and
• heart attack in people who have stable angina, predictable chest pain caused by impaired blood flow to the heart, such as after exercise.

New century, new uses
Aspirin is clearly no longer just a pill to pop when your head aches. But research under way suggests we don’t yet know the half of what aspirin can do.

Cancer. Aspirin looks especially promising for preventing certain cancers. In 1983, researchers published case studies of four people whose gastrointestinal polyps regressed when they were put on the NSAID Sulindac (2). Since then, scientists have explored whether NSAIDs can reduce the odds of suffering from cancer. Researchers have found increased levels of the enzyme cyclooxygenase-2 (COX-2) in some tumors, and aspirin’s ability to inhibit this enzyme might help suppress tumors.

Experiments show that some NSAIDs, including aspirin, inhibit various cancers in rats and mice. In several studies in which people with and without colorectal cancer were queried about their medical history, the risk of colon cancer was much lower in those who were regular NSAID users. Other studies started with NSAID users and nonusers and followed them to see which cancers they got. Most found lower rates of colorectal cancer in the NSAID users. These studies suggest that regular NSAID use cuts colorectal cancer risk by 40–50%. If these results are confirmed, aspirin and other NSAIDs may have a role as cancer preventives for people at high risk for colon cancer (3).

Heart. Aspirin may have additional cardiovascular uses. In the U.S. Physicians’ Health Study (as reviewed in 1, 3–5), aspirin use reduced first heart attacks by 44% among healthy men. But before advocating widespread use, trials are needed to determine the relative benefits and risks of this use for the general public.

Stroke. Research to determine whether aspirin can prevent not just a second but also a first stroke is further along. Evidence suggests that aspirin may help some people at high risk for strokes. Studies show that aspirin reduces the risk of first strokes in people who have atrial fibrillation, a disturbance in heart rhythm that quintuples the risk of ischemic stroke (6). But the Physicians’ Health Study, studying mostly low-risk subjects, found that aspirin did not lower the risk of stroke and may have actually raised it (as reviewed in 3, 7).

Other. Studying patients who had suffered hip fractures or had undergone hip or knee replacement surgery, some of whom had taken aspirin for five weeks, the Pulmonary Embolism Prevention trial found another benefit. Researchers found that for aspirin-receiving patients, the risk of developing pulmonary embolism (an artery blockage in the lung) and deep-vein thrombosis (a clot in a deep vein) was reduced by more than one-third compared with subjects taking a placebo (8).

Mixed results have plagued research on other potential uses. There is evidence for and against aspirin’s ability to prevent cataracts, preeclampsia (a pregnancy complication), and dementia. Also, various small studies suggest sundry other uses, from treating gum disease to preventing osteoporosis and acute mountain sickness.

Aspirin’s dark side
But aspirin’s benefits come at a cost. The biggest problem remains its harshness on the stomach—with effects ranging from pesky (nausea and heartburn) to perilous (bleeding ulcers). The latter effect is especially dangerous because only one-fifth of the sufferers have warning symptoms. In the United States, more than 100,000 people with osteoarthritis or rheumatoid arthritis are hospitalized every year for gastrointestinal problems caused by NSAIDs—and at least 16,500 of them die from these side effects (9, 10).

In many cases, aspirin’s side effects are part and parcel of its promoted effects. For example, aspirin reduces second heart attacks and ischemic strokes because it decreases platelet aggregation, inhibiting clotting. This action may also explain why aspirin seems to raise the risk of hemorrhagic strokes, which are caused by bleeding in the brain.

Despite some of its serious side effects, aspirin is comparatively safe. In cases involving individuals with a history of myocardial infarction, it is estimated that for every 1000 patients who take aspirin each year, 40 subsequent heart attacks are prevented and there is only one episode of bloody vomiting (11).

The future
In an effort to fight fire with fire, researchers have tried to counter the gastrointestinal effects of aspirin and other NSAIDs with other drugs. While histamine receptor antagonists such as cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac) can tame the milder side effects such as upset stomach, research to date shows they have little ability to prevent ulcers and other serious side effects. By contrast, proton-pump inhibitors such as omeprazole (Prilosec) look more promising in that they may both treat symptoms and prevent ulcers. The drug misoprostol (Cytotec) also can prevent ulcers, but it has many side effects and doesn’t ease NSAID-induced stomach upset.

Another approach is to eschew aspirin in favor of less-irritating NSAIDs. Older NSAIDs inhibit both forms of cyclooxygenase. However, it is believed that only COX-2 plays a role in inflammation and only COX-1 is involved in maintaining the stomach lining. In the case of aspirin, the inhibition of COX-1 is 10–100 times greater than its inhibition of COX-2. Thus, drugs that primarily inhibit COX-2, such as celecoxib (Celebrex) and rofecoxib (Vioxx), should calm inflammation and not irritate the stomach—although possibly at the cost of slower healing.

Other new drugs are still under development, such as NSAIDs combined with agents that protect the stomach. Some researchers have modified aspirin molecules by adding side chains that release nitric oxide. The release of nitric oxide counteracts the loss of prostacyclin, preserves the blood flow that protects gastric mucosa, and increases gastric mucus synthesis (12).

But swapping one drug for another is not always an option. For people wishing to prevent a second heart attack or stroke, aspirin remains the drug of choice. Other NSAIDs have not been shown to have aspirin’s benefits to the circulatory system. However, unlike the high doses needed to treat arthritis pain, cardiovascular benefits occur at even low doses and thus produce fewer side effects. For example, the risk of ischemic stroke is cut by the same 15% regardless of whether the daily aspirin dose is 50 mg or 1500 mg (13).

Aspirin stands poised to remain as important in the 21st century as it was in the 20th. But the transition from a therapeutic to a preventive medicine requires thoughtful balancing of risks and benefits. The perception of aspirin as innocuous—exemplified by the advice to “take two aspirin and call me in the morning”—must give way to a respect for its potency.

An ancient remedy meets modern science Felix Hoffman Salicylates have been used medicinally for millennia. An Egyptian papyrus scroll from 1550 B.C. recommended the use of dried myrtle leaves to treat pain. Other salicylate-rich plants such as wi Figure 1. The synthesis of acetylsalicylic acid from salicylic acid. By using acetic anhydride to acetylate the hydroxyl group of slicylic acid (left), Felix Hoffmann syntehsized acetylsalicylic acid (right), improving on the work of Charles Gerhardt. llow and poplar were also used therapeutically in the ancient world, meriting mentions in the works of Hippocrates, Pliny the Elder, and Galen. In the 1830s, chemists succeeded in extracting salicin from willow and converting it to salicylic acid for use in treating fevers. In the 1870s, researchers discovered that salicin derivatives also relieved pain and inflammation. Sodium salicylate became the preferred form for treating arthritis. When Felix Hoffmann began experimenting with salicylic acid in the 1890s, he started with the assumption that acidity was responsible for its gut-wrecking effects. Hoping to moderate this acidity, Hoffmann uncovered the long-ignored synthesis of acetylsalicylic acid in 1853 by Charles Gerhardt, who acetylated the hydroxyl group of sodium salicylate at position 1 of the benzene ring. But Gerhardt hadn’t pursued acetylsalicylic acid because its synthesis proved difficult. Hoffman devised a better way to produce acetylsalicylic acid—aspirin—by choosing acetic anhydride as the acetylating agent instead of Gerhardt’s use of acetyl chloride (see Figure 1). But it wasn’t until the 1970s that researchers discovered exactly how aspirin worked, netting pharmacologist John Vane the Nobel Prize in Physiology or Medicine in 1982. Aspirin inhibits the enzyme cyclooxygenase. By doing so, aspirin blocks the synthesis of prostaglandins (a family of hormones) and so impedes their actions, which include causing redness and fever after tissue injury, inhibiting stomach acid secretion, and moderating blood clotting.