Take two aspirin and call the doctor in the morning" may not have been such bad advice. On its 100th anniversary, that little white pill keeps on coming up with new uses.
Well beyond its traditional roles for killing pain, reducing fever and controlling inflammation, aspirin has proved to be a potent medication for a wide variety of ailments, from halting heart attacks to preventing strokes. The National Library of Medicine has logged more than 23,000 scientific papers on aspirin, with 880 published this year alone on various aspects of its use. Aspirin can soothe migraine headaches, stop premature labor in some pregnant women and control lung inflammation caused by a common respiratory virus that is a major hazard for premature infants.
Aspirin is one of the most widely used medications in the world. Each year, 58 billion doses of aspirin are swallowed, sipped in fizzling concoctions or taken in suppositories, according to the Bayer Company, one of the largest manufacturers. Americans pop 80 million aspirin tablets daily -- 29 billion per year -- a figure that works out to 117 aspirin tablets annually for every man, woman and child in the country, according to Joe Graedon, author of "The Aspirin Handbook."
Experts say yearly aspirin consumption could rise even higher in its second century as researchers uncover new applications. The latest scientific findings suggest that aspirin can help in preventing colon cancer and in treating Alzheimer's disease and other forms of senility. It might even play a role in preventing cataracts. "It's mind-boggling how many new applications this simple drug has," said Paul Lietman, professor of pharmacology at the Johns Hopkins Medical Institutions in Baltimore. "It seems that each year we hear of a new therapeutic application for the drug." Prostaglandin Is the Key
Acetyl salicylic acid is one of the original members of a group of more than four dozen chemical compounds called non-steroidal anti-inflammatory drugs (NSAIDs). Among the better-known NSAIDs are ibuprofen, such as Advil and Motrin; and sodium naproxen, sold as the prescription drug Naprosyn and the over-the-counter medication Aleve. Another popular pain killer, acetaminophen, most often sold as Tylenol, is not an NSAID.
As a group of drugs, NSAIDs help to control fever, swelling and pain. How well they exert these effects -- and with what number of complications -- varies from drug to drug. But "aspirin is still the gold standard that all the others are compared to," said Lietman.
Researchers did not begin to understand how aspirin exerts its powerful effects until the 1970s, although there were many intriguing clues beforehand. Kidney researchers had found that low doses of aspirin blocked the production of uric acid in the kidneys. Pharmacologists had research proving that aspirin reduced pain by acting on tissues and nerves throughout the body instead of working like morphine to block nerves in the brain that transmit pain signals.
Evidence also showed that aspirin lowered fever by affecting key centers in the hypothalamus rather than by affecting blood vessels throughout the body. In the blood, aspirin halted platelet function and blood clot formation as well as causing salt and water retention. It also caused indigestion and in a small number of people and could produce nasal polyps.
But there was no common thread to explain these varied effects until British pharmacologist John Vane wove them all together with the discovery that aspirin halts production of a potent group of chemicals in the body called prostaglandins. "At long last, the salicylate story seemed to have found a beginning, middle and end," noted New York University rheumatologist Gerald Weissman in a 1991 article on aspirin published in Scientific American.
Prostaglandins, which are synthesized from fatty acids, are manufactured in every cell of the body except red blood cells. They are key ingredients in a host of essential body reactions from muscle contraction to ovulation. But unlike other hormones such as insulin that are released from organs, prostaglandins are released when cells are injured or otherwise stimulated. They, in turn, can cause tissue damage.
Vane found that aspirin was able to halt the release of prostaglandins. The linchpin in this process, Vane and his colleagues at the Royal College of Medicine later found, was aspirin's ability to regulate an enzyme called cyclo-oxygenase-2 or COX-2. The discovery about prostaglandins won him a Nobel Prize in Medicine in 1982 and led to an explosion of scientific research on aspirin. Uses Include a Host of Possibilities'
"Aspirin now has a whole hst of possibilities that were never envisioned," said Charles Hennekens, chief of the Physicians Health Study, an ongoing research project at Harvard that has examined aspirin use closely. "It really has the extraordinary potential to have benefits on a wide range of disease."
As researchers learn more about the many actions of aspirin in the body, new and unexpected possible benefits are emerging. "Aspirin has spawned a huge amount of research into the mechanisms of the inflammatory response," said Lee Simon, associate professor of medicine at Harvard Medical School and chairman of the committee on education for the American College of Rheumatology. "It has been an incredible field of development."
Among some of the key findings in recent years:
Heart Disease. Low doses of aspirin -- as little as 81 milligrams per day, or the amount found in one chewable baby aspirin -- can reduce the risk of repeat heart attacks by about 20 percent in those who have already experienced one. In people who suffered from unstable chest pain, the use of aspirin cuts the risk of second heart attacks by 50 percent. The Food and Drug Administration approved aspirin for this use in 1985, but the practice is still underused, according to Hennekens, who estimates that 30 percent of heart attack survivors are not taking daily aspirin. "We could save as many as 10,000 premature deaths per year," he said.
In 1996, aspirin took on a new role in heart disease. The FDA proposed that death rates could be cut by nearly a quarter if physicians would give one half of a regular strength aspirin tablet during a heart attack and continue administration of the tablet in affected patients for 30 days.
Henneken's study of physicians found that even among healthy men aged 50 and older, taking one 325 milligram tablet every other day reduced the risk of heart disease by 44 percent.
Strokes. Two Canadian studies found that taking a 325-milligram aspirin tablet reduced by half the risk of death and stroke in people who had experienced a mini-stroke, also known as a transient ischemic (TIA) attack. The FDA approved the use of aspirin among men for this purpose in 1980.
Alzheimer's disease. Aspirin may be helpful for preventing Alzheimer's disease and other forms of senility. The Baltimore Longitudinal Study of Aging, involving nearly 1,700 participants, reported earlier this year that aspirin users had a significantly lower risk of Alzheimer's disease than people who took acetaminophen. A 1995 study of 210 patients treated at the Johns Hopkins Alzheimer's Disease Research Center found that patients who took aspirin on a daily basis showed less decline in speaking, spatial recognition and orientation than patients who did not take aspirin.
"The findings support other recent studies' suggestions that NSAIDs may serve a protective role in Alzheimer's disease," the researchers noted in a paper published in the journal Neurology.
Colon cancer. Large epidemiological studies have found a 40 to 50 percent reduction in the death rate from colorectal cancer in people who took aspirin or other NSAIDs on a regular basis. A 1996 study of nearly 10,000 people in Finland found a significantly lower colorectal cancer rate among people with rheumatoid arthritis who regularly took aspirin or other NSAIDs. Animal studies by researchers at Vanderbilt University, the University of Texas Health Science Center and the University of Michigan, among others, suggest that aspirin may inhibit key enzymes in the intestine, which are also linked to the development of pre-cancerous polyps.
Preventing premature labor. Because prostaglandins help contract the uterus during childbirth, aspirin and its new derivatives may also be used one day to help prevent premature labor and to treat preeclampsia. This use is still experimental as current recommendations are for women to avoid aspirin use during the third trimester of pregnancy because of potential bleeding problems. Heavy Use Can Cause Serious Side Effects
But aspirin does have its dark side. High doses of aspirin have been linked to the risk of gastrointestinal ulcers and bleeding, and some aspirin users consume it in high doses: 20 percent of the users consume 80 percent of the drug.
"About 2 to 4 percent of people will develop important complications of aspirin and other NSAID use," Simon said. In a study involving nearly 9,000 participants, Simon and his colleagues found that 1 to 2 percent of aspirin users experience the worst bleeding complications. "There are about 2,600 excess deaths due to gastrointestinal complications from NSAID use and about 20,000 hospitalizations annually," Simon said. "It's not an inconsequential problem."
Aspirin use can also be a problem for about 10 percent of people who have asthma. Studies have found that in this group of asthmatics the drug can trigger attacks, may cause facial swelling and may produce polyps -- small benign growths -- in the nasal passages. High doses of aspirin -- a dozen or more regular strength tablets taken over several days -- have also been linked to ringing in the ears.
Most importantly, aspirin is not recommended at all for children aged 16 and younger because of its link to an often fatal neurological problem called Reye syndrome that can develop after a child has a viral infection. No one knows exactly what causes this condition, but researchers at the federal Centers for Disease Control and Prevention in Atlanta found that the number of cases declined markedly from 1980 to 1985 after public health warnings about the link between Reye syndrome and use of aspirin in children.
The challenge is to develop preparations that retain aspirin's beneficial effects while decreasing its complications.
Recent studies by Vane in England and by Philip Needleman of the chemical company Monsanto have found that the COX enzymes may hold the key to reducing aspirin complications. COX-1 is linked to the greatest amount of bleeding complications. Under development are new aspirin derivatives that produce COX-2 enzymes, which appear to cause less bleeding or ulcers in the stomach and intestines.
Three new drugs are already approved in Europe and are under study in the United States. "The beauty of the selective COX-2 inhibitors is that they do not rot the stomach," Vane said. However, initial studies have shown that these compounds are not as effective in protecting the heart.
As aspirin marks its first century, experts rank the drug as one of the most useful available and one of the best bargains around. Aspirin still costs just pennies per dose. "If aspirin were half as effective and 10 times more expensive, we would take it far more seriously," said Hennekens of Harvard.
"Considering how many people use it, which numbers in the millions, and the low level of toxicity, it is a pretty good drug," said Simon, who prescribes aspirin regularly to his patients at Harvard.
"It has stood the test of time." From Tablet to Suppository
Aspirin is popular around the world. But there are important cultural differences in how aspirin is taken.
Americans prefer aspirin tablets that can be swallowed or chewed, according to Joe Graedon, author of the Aspirin Handbook. Italians like to down their aspirin in a fizzy liquid, similar to drinking Alka-Seltzer. The British most often choose aspirin powders that are dissolved in water, while the French use more aspirin suppositories than pills.
Among some other overlooked facts about aspirin:
Pop two aspirin and figure it takes between 20 to 30 minutes for the drug to begin entering the bloodstream. Food will slow its absorption. Peak levels of aspirin generally occur about two hours after the drug has been taken. Don't take aspirin with milk. Many people think that milk helps "coat" the stomach, thereby reducing the risk of developing ulcers. Not so, according to Lee Simon, associate professor of medicine at Harvard Medical School in Boston. The lactic acid in milk actually accentuates the natural acidity of aspirin.
Never give aspirin to children age 16 and younger without checking with your doctor. Aspirin use in youngsters has been linked to a rare, and usually fatal, neurological complication called Reye syndrome. Acetaminophen is a safer choice for controlling fevers in children.
Don't try to short-circuit a hangover by taking aspirin with alcohol. Debra Bowen, from the U.S. Food and Drug Administration's Center for Drug Evaluation and Research, said aspirin "enhances the irritation effect in the gastrointestinal tract," and increases the risk of gastrointestinal bleeding.
-- Sally Squires Personal Interest Motivated Researcher
It was 100 years ago -- August 10, 1897 -- that a 29-year-old German chemist named Felix Hoffmann figured out how to chemically alter salicyclic acid, an age-old pain relief compound extracted from willow bark, so that it would be kinder to the stomach. By adding one acetyl molecule to salicylic acid, he launched a new medicine that would change millions of lives.
Hoffmann had a professional and a personal interest in improving salicylic acid, which, in its pure form, is very irritating to the stomach. In those days, chemists generally mixed a compound of sodium salicylic acid, which helped mute some of the gastric side effects but was still very irritating.
As an employee of the Frederich Bayer Company, Hoffman was part of a team charged with looking for new drugs to control pain. But the problem of chronic pain and inflammation also hit home for Hoffmann. His father was severely disabled by agonizing joint pain. Hoffmann's father developed chronic stomach ulcers and bleeding from taking high doses of the medicine.
Medical historians differ on how Hoffmann made his discovery. Some say he synthesized it through trial and error in his laboratory. Others contend that he "rediscovered the wheel," after reading a scientific paper by a German scientist, Charles Frederic von Gerhardt, who had first extracted acetyl salicylic acid from willow bark in 1853. Von Gerhardt's compound, which was difficult to synthesize, was largely ignored for the next 50 years. According to this version of the story, Hoffmann improved upon that extraction process, making it easier and faster to manufacture the drug.
However the discovery occurred, the finding kindled interest in the drug by Bayer officials. They sought a patent for this new version of salicylic acid, but were denied it. They then took another tack and registered acetyl salicylic acid under the trade name Aspirin. "A" stood for acetyl, "spir" came from the German word Spirsaure, an old synonym for salicylic acid and "in" was a common suffix for drug names.
By 1899, Bayer was distributing a powdered form of aspirin to physicians for use by patients with arthritis.
The use of aspirin quickly caught on as physicians found that the drug was effective at controlling fevers, relieving pain and reducing all types of inflammation. As medical historian Jan R. McTavish noted in a 1987 paper on aspirin published in the journal Pharmacy in History, the drug "was soon the preferred treatment for headache, toothache, and other minor pains, especially in influenza, the common cold or alcoholic indisposition.' "
By 1900, aspirin became the first drug available in a water-soluble tablet, which cut the cost in half. By 1906, aspirin was Bayer's best-selling drug and by 1914, it was one of the most widely used medications in the world, according to McTavish. The following year, aspirin became available without a doctor's prescription, widening its use even more.
Drug manufacturers jockeyed to gain control of this burgeoning market. But because Bayer held the trademark on the name aspirin, the company was able to successfully press claims that any doctor who prescribed aspirin prescribe the Bayer brand. Even today, in Germany and 70 other countries, the name Aspirin is a trademark that belongs exclusively to Bayer AG. CAPTION: OVER-THE-COUNTER PAIN RELIEVERS ASPIRIN COMMON BRAND NAMES Bayer, Empirin, St. Joseph, Ecotrin (enteric-coated to dissolve in the intestine rather than the stomach), Anacin (with caffeine), Bufferin (buffered), Alka-Seltzer (with sodium bicarbonate and citric acid), Excedrin (with acetaminophen and caffeine). USE relieves pain, reduces fever, lessens swelling and stiffness of inflammation. RECOMMENDED ADULT DOSE 325 to 650 milli-grams (one or two regular-strength pills) every four hours. SIDE EFFECTS stomach upset, mild stomach bleeding, heartburn, indigestion, burns on mucous membranes if placed directly on teeth or gums. ESPECIALLY GOOD FOR inflammation, especially rheumatoid arthritis (enteric-coated products are recommended for long-term use), Under a doctor's supervision, may be used in low doses to reduce risk of second heart attack or stroke caused by blood clots. WHO SHOULD NOT TAKE children and young adults with chickenpox or flu symptoms, which if treated with aspirin could lead to Reye's syndrome, a potentially fatal swelling of the brain; people who have ulcers, other gastrointestinal problems, a vitamin K deficiency, a history of gout, asthma, acute liver or kidney disease, or aspirin sensitivity; women in the last trimester of pregnancy; people scheduled for surgery in the next five days; hemophiliacs; heavy drinkers. ACETAMINOPHEN COMMON BRAND NAMES Tylenol, Aspirin-Free Anacin, Aspirin-Free Excedrin (with caffeine), Tempra, Midol, Pamprin, Alka-Seltzer Advanced Formula (with calcium carbonate, potassium and sodium bicarbonates and citric acid), Bromo-Seltzer (with sodium bicarbonate and citric acid). USE relieves pain, reduces fever. RECOMMENDED ADULT DOSE 325 to 650 milligrams (one to two tablets) every four hours. Special caution advised against taking overdoses. SIDE EFFECTS possible liver damage, especially in older adults, if more than recommended dose is taken or if taken continuously for more than 10 days or with heavy alcohol use. ESPECIALLY GOOD FOR children, because it comes in palatable children's liquid formulas and does not have a potential Reye's syndrome hazard; people with ulcers or other stomach problems; people with aspirin sensitivity, asthma or hemophilia or others who can't take aspirin because of bleeding problems; people taking gout medicine or anti-coagulants. WHO SHOULD NOT TAKE people with liver problems; those needing to reduce inflammation, such as from rheumatoid arthritis or sprains; heavy drinkers. NAPROXEN Brand name Aleve (no generic available). USE pain relief, fever reduction, relief of swelling and stiffness of inflammation. RECOMMENDED ADULT DOSE 200 milligrams (one tablet) every eight to 12 hours or 400 mg (two tablets) initially, followed by 200 mg 12 hours later. Those over 65 should take no more than one tablet every 12 hours. SIDE EFFECTS stomach upset, nausea, indigestion but less than with aspirin. ESPECIALLY GOOD AS bedtime medicine because it has longer-lasting pain relief of up to eight hours, and for menstrual cramps, after dental surgery or childbirth, for migraines not being treated with prescription drugs and for people who cannot get enough pain relief from aspirin or acetaminophen. WHO SHOULD NOT TAKE Children under 12; people with a history of ulcers, kidney disease or asthma; those with sensitivity to aspirin or ibuprofen; women in the last three months of pregnancy; heavy drinkers. IBUPROFEN COMMON BRAND NAMES Advil, Nuprin, Motrin-IB. USE relieves pain, reduces fever and inflammation. RECOMMENDED ADULT DOSE 200 to 400 milligrams (one to two tablets) every four to six hours for pain relief, 300 to 600 mg every four to six hours for reducing inflammation. People over 60, particularly those with decreased liver function, should take lower doses. SIDE EFFECTS possible stomach upset, nausea and indigestion but less than with aspirin; may decrease kidney function and cause retention of salt and water. ESPECIALLY GOOD FOR menstrual cramps, pain after dental surgery, postpartum pain, inflammation such as from arthritis, and migraines not being treated by prescription drugs, and for people who do not get enough pain relief from aspirin or acetaminophen or those who want longer pain relief of up to six hours. WHO SHOULD NOT TAKE people with congestive heart disease, ulcers, kidney disease, asthma or aspirin sen-sitivity; women in the last three months of pregnancy; heavy drinkers.
-- Sandra Evans CAPTION: 400 BC: Hippocrates prescribes willow bark and leaves to relieve pain and fever. Willow bark contains salicylic acid, a key ingredient of aspirin. 1853: German chemist Charles Frederic von Gerhardt synthesizes a crude form of salicylic acid from the bark of a willow tree.
1869: Karl Johann Kraut develops a purer form of acetyl salicylic acid, but the compound is not developed as a drug. 1897: German chemist Felix Hoffmann, an employee of the Bayer Company, finds an improved way to make acetyl salicylic acid, a compound that proves helpful in controlling pain of arthritis. Unable to get the drug patented, the company registers a trade name for the new medicine, aspirin. 1900: Aspirin becomes available in water-soluble tablets -- a new way of taking medicine. 1915: Aspirin becomes a nonprescription drug. 1920: Use of aspirin expands to include treatment of rheumatism, lumbago and neuralgia or nerve pain. 1948: California physician Lawrence Craven notes that 400 men to whom he prescribed daily doses of aspirin have not suffered heart attacks. He proposes a possible protective effect of aspirin for the heart. 1952: Food and Drug Administration (FDA) approves acetaminophen elixir for prescription use. 1960: A non-aspirin painkiller, acetaminophen elixir, approved for nonprescription use. 1974: Ibuprofen, a pain reliever related to aspirin, approved as a prescription drug. 1975: Acetaminophen becomes available in extra -- strength pills. 1976: Naproxen sodium, another pain reliever related to aspirin, is approved as a prescription drug in the United States. 1980: FDA approves the use of aspirin to reduce the risk of stroke after a so-called mini-stroke, or transient ischemic attack, in men. 1984: FDA approves the use of ibuprofen as a nonprescription drug. 1985: FDA expands the use of aspirin to include prevention of heart attacks in people who have suffered one heart attack or who experience chronic, unstable chest pain. 1988: FDA requires warning label on all aspirin products for children because of the increased risk of the rare, but often fatal Reye Syndrome when taken with symptoms of flu or chicken pox. 1990: FDA requires all oral and rectal aspirin products to include a label warning against use during the last three months of pregnancy without a doctor's approval. 1994: Naproxen sodium is approved for use as a nonprescription painkiller by the FDA. 1995: FDA approves ibuprofen for use without a prescription in children. 1996: FDA approves the use of aspirin during a suspected heart attack.
1997: FDA committee recommends approval of aspirin for the prevention of stroke in women who have had a mini-stroke as well as for use after a minor stroke. FDA committee also recommends aspirin for use in doses lower than previously recommended. CAPTION: At the turn of the century, pharmacists often mixed individual remedies for customers. Aspirin was the first drug available in a water-soluable tablet.