Aspirin

Aspirin is one of the oldest, simplest, cheapest, most pervasive, and most versatile drugs in the world. Chemical precursors of aspirin have been used for thousands of years; aspirin itself has been used for over 100 years by millions of people and has been marketed, alone or in combination with other drugs, under hundreds of brand names. Its primary use is as a pain reliever (an analgesic) for mild to moderate pain, but it is also effective in controlling fever as well as in reducing inflammation, and it is the prototypical non-steroidal anti-inflammatory drug. Aspirin also inhibits platelet aggregation and has found great utility in the prevention of arterial and venous thrombosis. It is deservedly called a "wonder drug." It is one of the few medicines to have been taken to the moon, and continues to hold an integral place in almost every household's medicine cabinet.

Aspirin tablets. Source: Medpedia Contributors

Other Names

Aspirin is sometimes abbreviated by physicians and pharmacists as ASA, an acronym for acetylsalicylic acid (the compound's chemical name, equivalent to 2-acetoxybenzenecarboxylic acid). ECASA is an acronym for enteric-coated aspirin; the coating helps slow down the tablet's disintegration until it has left the stomach so as to avoid some of the stomach upset that can accompany use of the drug.

Aspirin appears as the only active ingredient in many over-the-counter and prescription medications.

• Adprin B Tri-Buffered Caplets
• Aggrenox|(aspirin and dipyridamole)
• Alka-Seltzer (Effervescent Pain Reliever and Antacid, Extra Strength Effervescent Pain Reliever and Antacid, and Flavored Effervescent Pain Reliever and Antacid) is a trade name for effervescent tablets containing aspirin, citric acid, and sodium bicarbonate
• Anacin is a trade name for aspirin mixed with caffeine.
• Ascriptin (Arthritis Pain Caplets, Enteric Adult Low Strength, Enteric Regular Strength, Maximum Extra Strength Caplets and Regular Strength)
• Aspergum is chewing gum containing aspirin, intended to relieve sore throat pain.
• Bayer (Aspirin with Calcium Regimen Caplets, Aspirin Arthritis Pain Regimen Extra Strength Caplets, Aspirin Caplets, Extra Strength Caplets, Aspirin Extra Strength Gelcaps, Aspirin Extra Strength Tablets, Aspirin Gelcaps, Aspirin Plus Buffered Extra Strength Caplets, Aspirin Regimen Adult Low Strength, Aspirin Regimen Children's Chewable, Aspirin Regimen Regular Strength Caplets, Aspirin Tablets, and Arthritis Strength Caplets)
• BC Powder contains aspirin, caffeine, and salicylamide, which works in the same way as aspirin.
• Bufferin (Enteric Low Dose Caplets, Extra Strength, and Tablets) is a trade name for aspirin mixed with an antacid agent to reduce heartburn
• Darvon Compound Pulvules
• Easprin
• Ecotrin (Ecotrin, Adult Low Strength, and Maximum Strength), which is an enteric-coated form of aspirin
• Empirin with codeine is a trade name for aspirin mixed with codeine, a stronger narcotic analgesic.
• Endodan
• Excedrin (Extra-Strength Caplets, Extra-Strength Geltabs, Extra-Strength Tablets, Migraine Caplets, Migraine Geltabs, and Migraine Tablets) is a trade name for aspirin mixed with caffeine and acetaminophen. (Some preparations of Excedrin contain no aspirin.)
• Gelpirin
• Genacote (Genacote and Maximum Strength)
• Goody's (Body Pain Powders, Extra Strength Headache Powders, and Extra Strength Tablets)
• Halfprin
• Magnaprin ("Arthritis Strength" and "Improved")
• Norwich (Aspirin and Aspirin Maximum Strength)
• PC-CAP
• Percodan (Percodan and Percodan-Demi)
• Roxiprin
• St. Joseph Aspirin Adult Chewable
• Supac
• Sureprin
• Talwin Compound Caplets
• Vanquish Caplets
• ZORprin
• Alka-Seltzer Plus Cold & Sinus Medicine Effervescent (aspirin and phenylpropanolamine bitartrate)
• Anacin Caplets, Anacin Maximum Strength, and Anacin Tablets (aspirin and caffeine) , a trade names for aspirin mixed with caffeine. The combined preparation may be especially useful at relieving headaches caused by causing blood vessels in the brain to tighten, thus reducing blood flow.
• BC Powder and BC Powder Arthritis Strength (aspirin, caffeine, and salicylamide)
• Butalbital Compound (aspirin, butalbital, and caffeine)
• Cope (aspirin and caffeine)
• Damason-P (aspirin and hydrocodone bitartrate)
• Equagesic (aspirin and meprobamate)
• Fiorinal (aspirin, butalbital, and caffeine)
• Fiorinal with Codeine (aspirin, butalbital, caffeine, and codeine phosphate)
• Fiortal (aspirin, butalbital, and caffeine)
• Fortabs (aspirin, butalbital, and caffeine)
• Micrainin (aspirin and meprobamate)
• P-A-C Analgesic (aspirin and caffeine)
• Stanback Powder (aspirin, caffeine, and salicylamide)
• Synalgos-DC (aspirin, caffeine, and dihydrocodeine bitartrate)

Uses

Aspirin's main use is as a treatment for many kinds of pain—headaches, toothaches, muscle pain, menstrual cramps, the joint pain from arthritis, and aches associated with colds and flu. It is also used to reduce the risk of several types of cardiovascular disease.

Relief of pain

Aspirin is most useful in relieving mild to moderate pain such as headaches, muscle aches, and joint pains; it is not as useful at relieving pain arising from the viscera (the internal organs) such as the liver or intestine. Long-term use does not lead to tolerance or addiction.

Heart attack

The appropriate dose of aspirin for the prevention of cardiovascular disease has recently been reviewed.^[1] Dosages more than 75 to 81 mg/d, which are commonly recommended, are associated with increased risks of gastrointestinal bleeding and do not lower the risk of cardiovascular disease.

Despite the well-established benefits of aspirin in reducing cardiovascular disease and the impressively low cost of aspirin compared to statins (and the cost savings associated with avoiding Heart attacks), aspirin remains underutilized in the prevention of cardiovascular disease.^[2]

Prevention of colorectal and other cancers

Regular use of aspirin reduces the risk of colorectal cancer. In particular, the risk of colonic adenomas (a lesion that is thought to precede colon cancer) in randomized controlled trials was reduced by 18%, by 13% in case–control studies, and by 22% in cohort studies^[3], but aspirin has not been formally approved for this purpose in most countries.

Alzheimer disease and related dementias

The value of aspirin in reducing the risk of Alzheimer disease (AD) became apparent in the mid-1990s, with large epidemiological studies that demonstrated a lower incidence of AD among patients receiving aspirin for rheumatoid arthritis.^[4] After the initial observations were published, several long-term studies in human volunteers were conducted, primarily with NSAIDs available without a prescription such as aspirin and ibuprofen, that confirmed the initial observations and estimated the benefits. An analysis of nine studies estimated the relative risk of AD among users of NSAIDs as 0.72 (95% confidence interval 0.56 to 0.94), representing a 28% reduction in risk of developing AD compared to non-NSAID users.^[5] There is little if any benefit in treating patients who already have AD with aspirin, however.^[6] There are probably multiple mechanisms by which aspirin exerts its beneficial effects, some of which are specific to AD pathology and some of which relate to aspirin's effects on blood vessels and platelets.

Kawasaki disease

Kawasaki disease is a potentially fatal inflammatory disease that can damage several different organ systems, especially the heart and larger blood vessels. It affects children more often than adults. It is usually treated with a combination of aspirin to control the associated fever and inflammation and high doses of intravenous immunoglobulins.^[7]

How Aspirin Is Taken

Aspirin is available in many forms, most commonly as tablets containing either 325 mg or 81 mg; however, it is also available in suppositories, chewing gum, as a powder, and as topical (applied directly to the skin) preparations. Taking aspirin just after eating may reduce epigastric discomfort, though it does not prevent the development of possibly serious gastroenteric side effects such as gastruodenal ulcers, bleeding or perforation. In case of surgical procedures the low dose aspirin taken to reduce ischemic risk should be interrupted 6-7 days before the procedure to recover the clotting ability. Whenever it is clinically appropriate, aspirin may be substituted by other blood thinner or anti-thrombotic drugs.

How It Works

Aspirin interferes with the body's production of prostaglandins, which are versatile molecules involved in pain, fever, and in production of the redness and swelling (inflammation) that can accompany injuries. By lowering the level of prostaglandins, aspirin reduces pain and fever. In particular, aspirin slows the production of prostaglandins E2 and I2, which reliably cause pain in a variety of settings.^[8] Aspirin accomplishes this by binding to and irreversibly inhibiting the enzyme COX-1, also known as cyclo-oxygenase or prostaglandin synthase.^[9]

Risks

Gastrointestinal

Gastrointestinal side effects, especially at higher doses, are the most prominent risk of aspirin use; these include the formation of stomach ulcers and stomach bleeding.^[10]

Auditory

Tinnitus (ringing in the ears) is another noted risk of aspirin and results from mild chronic intoxication. If tinnitus is present, it often occurs with other symptoms such as headache, dizziness, visual disturbances, and occasionally diarrhea.

Reye's Syndrome

Aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox, due to the risk of Reye's syndrome, a rare but sometimes fatal problems related to the liver and central nervous system. Although a direct cause-and-effect relationship has not been established, there is a strong epidemiological association leading to the recommendation that aspirin and other salicylate-containing drugs should not be used in children with chickenpox or influenza.^[11]

Kidney Injury

Excessive use of NSAIDs is strongly associated with an increased prevalence of renal injury. The elderly are especially susceptible and more frequently use these medications. ^[12]

History

Willow tree, a source of aspirin precursors. Source: USDA-NRCS PLANTS Database.

Discovery

In 1763, the first clearly documented description of the use of willow bark and leaves was written by the Rev. Edmund Stone in a letter to the president of the Royal Society. The related compounds salicin and salicylic acid were isolated in their chemically pure forms in 1829 and 1836, respectively, and by 1874, salicylic acid was being produced industrially and used to treat fever (especially rheumatic fever), and gout. However, salicylic acid has an unpleasant taste and quickly damaged the stomach lining, making sustained or routine use difficult.

In the late 1800s, Felix Hoffman, a chemist at Bayer Laboratories, was asked by his father (who was suffering from severe rheumatoid arthritis at the time) to form a less irritating drug than sodium salicylate. Hoffman based his work on earlier studies by the French chemist, Gerhardt, who had placed two additional carbons (an acetyl group) on salicylic acid in 1853. The resulting compound, acetylsalicylic acid, apparently had a more favorable side effect profile than the parent compound. Hoffman's work with acetylsalicylic acid resulted in Bayer's testing the drug in animals by 1899—the first time that a drug was tested on animals in an industrial setting—and quickly moved forward with human studies and marketing.^[14]

Popularization

By 1900, Bayer was distributing aspirin powder to physicians to give to their patients. Aspirin quickly became the world's most widely-used medicine. In 1915, aspirin became available without a prescription and was provided in tablets as well as powder.

In 1948, Dr. Lawrence Craven noted a surprisingly low incidence of heart attacks among patients to whom he had prescribed aspirin, and began recommending it to all patients and colleagues to reduce cardiovascular problems.^[15] In the early 1970s, the effect of aspirin on inflammation-causing prostaglandins became the focus of investigations into aspirin's mechanism of action. By 1988, the FDA recommended use of aspirin to reduce the risk of recurrent heart attack, and prevent the first heart attack, in patients with unstable angina. The FDA also approved aspirin for the prevention of recurrent transient-ischemic attacks or "mini-strokes" and made aspirin standard therapy for previous strokes. In addition to its role in heart attack and stroke prevention, research continues to explore aspirin's possible role in prevention of colon, esophageal cancer and other diseases.

In the late 1980s, large studies were undertaken to determine whether aspirin taken by otherwise healthy individuals would lower the incidence of heart attacks. A large benefit was found, and the study was terminated early due to a profound 44% reduction in the risk of a first heart attack. ^[16] Dr. Charles Hennekens, one of the leaders of the study, later published a meta-analysis describing an overall 32% reduction in cardiovascular events.^[17]

In 1998, results of the Thrombosis Prevention Trial confirmed the effectiveness of aspirin in the prevention of MI in persons having cardiovascular risk factors.^[18]

Aspirin was featured in the Treaty of Versailles (1919, at the end of World War I), which required Bayer (as part of Germany's war reparations) to give up its aspirin trademark in the U.S., Britain, France, and Russia. Although "Bayer" aspirin was sold in the U.S. for the next 80 years, it was not made by Bayer until 1994, when the German company bought back the right to use its own name in the United States.

In 1950, the Guinness Book of Records recognized aspirin as the world's best-selling painkiller.

In 1982 the mechanism of action for aspirin—inhibition of prostaglandin synthesis—was confirmed by John Vane (UK), Sune Bergström, and Bengt Samuelsson (Sweden), who later were awarded the Nobel prize for their work.

The use of aspirin continues to increase, with the equivalent of 100 billion 500 mg. tablets manufactured in 2004. The inhabitants of the US consume more than 9000 tons of aspirin each year (the equivalent of about 44 million tablets every day). ^[19]

Name

Aspirin's name is derived from the meadowsweet plant, Spiraea ulmaria, which contains considerable amounts of salicylates (the chemical precursors of aspirin). The "a" derives from from the two-carbon acetyl group, "spir" is taken from the spirea plant, and "in" is a common suffix for medications.

Some people attribute aspirin's name to "St. Aspirinus, the patron saint of headache sufferers." This is not true; the patron saint of headache sufferers is St. Teresa of Avila, who was canonized in 1622.^[20]

Controversy

(begin verbatim clip from http://www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Salix/index.html) Perhaps a piece of judiciary history is needed here. Aspirin was a patented name by Bayer, but this German company had conflicts with France and Great Britain, who fought against Germany in World War I and did not acknowledge that patent. Australia also began its own production when aspirin could not be supplied there. A legal battle ensued when Monsanto in the United States began its own production in 1917, and this eventually reached the U.S. Supreme Court, which ruled that "aspirin" had become so widely advertised and common that Bayer no longer owned the name. Hence, aspirin is now a vernacular name, which is why large companies of other products now aggressively take anyone to court when a popular product name is unlawfully used. (end verbatim snip)

Alternatives

Other NSAIDs

Other drugs share aspirin's anti-inflammatory characteristics and are also known as non-steroidal anti-inflammatory agents. They are also effective pain relievers.

• Ibuprofen is available without a prescription as Motrin, among other names.
• Acetaminophen is widely known as Tylenol and is available without a prescription.
• Other NSAIDs

Other analgesics

For pain that does not resolve with aspirin or other NSAIDs, stronger analgesics such as opiates represent another option, but with the increased risk of addiction.

Other coagulation inhibitors

Clopidogrel, marketed as Plavix, is a prescription drug to reduce platelet aggregation. In a secondary prevention study published in 1996 of patients with recent ischemic stroke or heart attack, clopidogrel was found to reduce the risk of additional ischemic strokes, heart attacks, or vascular-related deaths by almost 9% more than aspirin.^[21] When only additional heart attacks were considered, the improvement gained by switching from aspirin to clopidogrel jumped to 19%.^[22] However, clopidogrel is much more costly than aspirin, and a 2002 analysis using computer models comparing the cost-effectiveness of population-level interventions came out in favor of aspirin, concluding that clopidogrel is only cost-effective for aspirin-intolerant patients.^[23]

• Warfarin
• Heparin

Statistics

How many pills have been taken to date? How many every day?

• In 2004, Americans took 29 billion tablets of aspirin. ^[24]

Research

Many research efforts are aimed at creating safer and more effective drugs based on aspirin. Some examples include versions of aspirin that release nitric oxide or hydrogen sulfide, which are gases with favorable effects on the body.^[25]

Interesting Facts

• Lawrence Craven, an ear, nose, and throat doctor who practiced in California in the 1940s and 1950s, gave aspirin-containing gum to his tonsillectomy patients. He noticed that patients who chewed large amounts of the gum tended to bleed more and, acting on a hunch, started his older male patients on aspirin and eventually accumulated data on more than 8,000 patients, none of whom experienced a heart attack. This led to his observation that aspirin lowers the incidence of heart attacks. His data remained underappreciated—partially because he published them in obscure medical journals and partially because he died of a heart attack in 1957.

• Aspirin tablets in the US contain either 81 or 325 mg of the active ingredient; in the rest of the world, tablets contain 50, 75, or 150 mg of aspirin. The difference can be traced to previous use of "grains" in American pharmacies, where 1 grain weighs 64.8 milligrams. A 325 mg tablet contains about five grains' worth of aspirin.

References

1. ↑ Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA. 2007 May 9;297(18):2018-24. Abstract | Full Text | PDF
2. ↑ Stafford RS, Monti V, Ma J. Underutilization of aspirin persists in US ambulatory care for the secondary and primary prevention of cardiovascular disease. PLoS Med. 2005 Dec;2(12):e353. [1] | Full Text | PDF
3. ↑ Dubé C, Rostom A, Lewin G, et al. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007 Mar 6;146(5):365-75. Abstract | Full text | PDF
4. ↑ Breitner JC, Gau BA, Welsh KA, et al. Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. Neurology. 1994 Feb;44(2):227-32. Abstract
5. ↑ Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ. 2003 Jul 19;327(7407):128. Abstract Full Text PDF
6. ↑ AD2000 Collaborative Group, Bentham P, Gray R, Sellwood E, Hills R, Crome P, Raftery J. Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial. Lancet Neurol. 2008 Jan;7(1):41-9. [2]
7. ↑ Wolff AE, Hansen KE, Zakowski L. Acute Kawasaki disease: not just for kids. J Gen Intern Med. 2007 May;22(5):681-4. Abstract | Full Text | PDF
8. ↑ Ferreira SH. Peripheral analgesia: mechanism of the analgesic action of aspirin-like drugs and opiate-antagonists. Br J Clin Pharmacol. 1980 Oct;10 Suppl 2:237S-245S. Abstract | PDF
9. ↑ Vane SJ. Aspirin and other anti-inflammatory drugs. Thorax. 2000 Oct;55 Suppl 2:S3-9. Citation | PDF
10. ↑ Lee M, Feldman M. The aging stomach: implications for NSAID gastropathy. Gut. 1997 Oct;41(4):425-6. Abstract | PDF
11. ↑ Hall SM. Reye's syndrome and aspirin: a review. J R Soc Med. 1986 Oct;79(10):596-8. Citation | PDF
12. ↑ Lindeman RD. Should the sale of analgesic mixtures and non-steroidal anti-inflammatory agents (NSAIDs) continue to be allowed as over-the-counter (OTC) medications? Geriatr Nephrol Urol. 1999;9(1):3-4. Abstract
13. ↑ Rainsford KD, "History and Development of the Salicylates." Chapter 1 in Aspirin and Related Drugs, Rainsford KD, ed. Taylor & Francis, London, 2004.
14. ↑ Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation. 1994 Jan;89(1):432-49. Abstract
15. ↑ Craven LL. Acetylsalicylic acid, possible preventive of coronary thrombosis. Ann West Med Surg. 1950 Feb;4(2):95. Citation
16. ↑ Buring JE, Hennekens CH. Prevention of cardiovascular disease: risks and benefits of aspirin. J Gen Intern Med. 1990 Sep-Oct;5(5 Suppl):S54-7. Abstract
17. ↑ Manson JE, Tosteson H, Ridker PM, et al. The primary prevention of myocardial infarction. N Engl J Med. 1992 May 21;326(21):1406-16. Citation
18. ↑ [No authors listed] Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet. 1998 Jan 24;351(9098):233-41. Abstract
19. ↑ Gossop M. Living With Drugs. Ashgate, 2007. ISBN 0754649199, 9780754649199, 246 pages.
20. ↑ St. Teresa at Catholic.org
21. ↑ CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996 Nov 16;348(9038):1329-39. Abstract
22. ↑ Cannon CP; CAPRIE Investigators. Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE trial). Am J Cardiol. 2002 Oct 1;90(7):760-2. Citation
23. ↑ Gaspoz JM, Coxson PG, Goldman PA, et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med. 2002 Jun 6;346(23):1800-6. Abstract
24. ↑ World's Wonder Drug With Many Benefits, 50,000 Tons Of Aspirin Are Sold Worldwide CBS News
25. ↑ Wallace JL. Building a better aspirin: gaseous solutions to a century-old problem. Br J Pharmacol. 2007 Oct;152(4):421-8. Abstract | Full Text | PDF