Aspirin (USAN), also known as acetylsalicylic acid (/əˌsɛtəlˌsælɨˈsɪlɨk/ ə-set-əl-sal-i-sil-ik; abbreviated ASA), is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication.

Salicylic acid, the main metabolite of aspirin, is an integral part of human and animal metabolism. While much of it is attributable to diet, a substantial part is synthesized endogenously.

Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which under normal circumstances binds platelet molecules together to create a patch over damaged walls of blood vessels. Because the platelet patch can become too large and also block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, and blood clot formation in people at high risk of developing blood clots It has also been established that low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue.

The main undesirable side effects of aspirin taken by mouth are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses. In children and adolescents, aspirin is no longer indicated to control flu-like symptoms or the symptoms of chickenpox or other viral illnesses, because of the risk of Reye’s syndrome.

Aspirin is part of a group of medication called nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from them in the mechanism of action. Though it, and others in its group called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) to other NSAIDs and inhibit the same enzyme cyclooxygenase, they do so in an irreversible manner and unlike others affect more the COX-1 variant than the COX-2 variant of the enzyme For example, NSAIDs’ antiplatelet effects normally last in the order of hours, whereas aspirin’s effects last for days (until the body replaces the suppressed platelets). Hence, when physicians tell patients to stop taking NSAIDs, they usually imply aspirin as well.

Today, aspirin is one of the most widely used medications in the world, with an estimated 40,000 tonnes of it being consumed each year.^[7] In countries where Aspirin is a registered trademark owned by Bayer, the generic term is acetylsalicylic acid (ASA).^[8]

Medical uses

Aspirin is used for the treatment of a number of conditions including: fever, pain, rheumatic fever, inflammatory diseases such as rheumatoid arthritis, pericarditis, and Kawasaki disease.^[9] It is used in the prevention of transient ischemic attacks, strokes, heart attacks, pregnancy loss, and cancer.^[9]

Pain

In general, aspirin works well for dull, throbbing pain; it is ineffective for pain caused by most muscle cramps, bloating, gastric distension, and acute skin irritation. The most studied example is pain after surgery, such as tooth extraction, for which the highest allowed dose of aspirin (1 g) is equivalent to 1 g of paracetamol, 60 mg of codeine, or 5 mg of oxycodone. A combination of aspirin and caffeine, in general, affords greater pain relief than aspirin alone. Effervescent aspirin alleviates pain much faster than aspirin in tablets (15–30 min vs. 45–60 min).

Nevertheless, as a postsurgery painkiller, aspirin is inferior to ibuprofen and has higher gastrointestinal toxicity. The maximum dose of aspirin (1 g) provides weaker pain relief than an intermediate dose of ibuprofen (400 mg), and this relief does not last as long. A combination of aspirin and codeine may have a slightly higher analgesic effect than aspirin alone; however, this difference is not clinically meaningful  It appears ibuprofen is at least equally, and possibly more, effective than this combination.

According to a 1998 meta-analysis of clinical trials for menstrual pain, aspirin demonstrated higher efficacy than placebo, but lower than ibuprofen or naproxen, although maximum doses of aspirin were never used in these trials. The authors concluded ibuprofen has the best risk-benefit ratio.^[14]

Aspirin did not ease pain during cycling exercise, while caffeine, surprisingly, was very effective. Similarly, aspirin, codeine or paracetamol were not better than placebo for muscle soreness after exercise.

Headache

Aspirin is a first-line drug in the treatment of migraine, bringing relief in 50–60% of the cases. When used at a high dose of 1000 mg (as compared to 275–325 mg when used as a pain killer or 81 mg as a antiplatelet therapy), no significant differences were seen as compared to triptan medication, sumatriptan (Imitrex) and other painkillers such as paracetamol(acetaminophen) or ibuprofen. The combination of aspirin, paracetamol (acetaminophen) and caffeine (as found in the OTC brand Excedrin) is even more potent. For the treatment of migraine headache, this formulation works better than any of its three components taken separately, better than ibuprofen and better than sumatriptan. Similarly to all other medications for migraine, it is recommended to take aspirin at the first signs of the headache, and it is the way these medications were used in the comparative clinical trials.

Aspirin alleviates pain in 60–75% of patients with episodic tension headaches.It is equivalent to paracetamol (acetaminophen) in that respect, except for the higher frequency of gastrointestinal side effects Comparative clinical trials indicated metamizole and ibuprofen may relieve pain faster than aspirin, although the difference becomes insignificant after about two hours. The addition of caffeine in a dose of 60–130 mg to aspirin increases the analgesic effect in headache. The combination of aspirin, paracetamol (acetaminophen) and caffeine is still more effective, but at the cost of more stomach discomfort, nervousness and dizziness.

There is some evidence low-dose asprin has benefit for reducing the occurrence of migraines in susceptible individuals.

Prevention of heart attacks and strokes

There are two distinct uses of aspirin for prophylaxis of cardiovascular events: primary prevention and secondary prevention. Primary prevention is about decreasing strokes and heart attacks in the general population of those who have no diagnosed heart or vascular problems. Secondary prevention concerns patients with known cardiovascular disease

Low doses of aspirin are recommended for the secondary prevention of strokes and heart attacks. For both males and females diagnosed with cardiovascular disease, aspirin reduces the chance of a heart attack and ischaemic stroke by about a fifth.This translates to an absolute rate reduction from 8.2% to 6.7% of such events per year for people already with cardiovascular disease.Although aspirin also raises the risk of hemorrhagic stroke and other major bleeds by about twofold, these events are rare, and the balance of aspirin’s effects is positive. Thus, in secondary prevention trials, aspirin reduced the overall mortality by about a tenth.

For persons without cardiovascular problems, the benefits of aspirin are unclear. In the primary prevention trials, aspirin decreased the overall incidence of heart attacks and ischaemic strokes by about a tenth. However, since these events were rare, the absolute reduction of their rate was low: from 0.57% to 0.51% per year. In addition, the risks of hemorrhagic strokes and gastrointestinal bleeding almost completely offset the benefits of aspirin. Thus, in the primary prevention trials, aspirin did not change the overall mortality rate Further trials are in progress.

The expert bodies diverge in their opinions regarding the use of aspirin for primary prevention, such as can be accomplished by including aspirin in a polypill for the general population. The US Government Preventive Services Task Force recommended making individual, case by case choices based on the estimated future risk and patients’ preferences On the other hand, Antithrombotic Trialists’ Collaboration argued such recommendations are unjustified, since the relative reduction of risk in the primary prevention trials of aspirin was same for persons in high- and low-risk groups and did not depend on the blood pressure. The Collaboration suggested statins as the alternative and more effective preventive medication.

Coronary and carotid arteries, bypasses and stents

The coronary arteries supply blood to the heart. Aspirin is recommended for one to six months after placement of stents in the coronary arteries and for years after a coronary artery bypass graft.

The carotid arteries supply blood to the brain. Patients with mild carotid artery stenosis benefit from aspirin; it is recommended after a carotid endarterectomy or carotid artery stent.

After vascular surgery of the lower legs using artificial grafts that are sutured to the arteries to improve blood supply, aspirin is used to keep the grafts open.

Other uses

Although aspirin has been used to combat fever and pains associated with common cold for more than 100 years, its efficacy in this role was only recently confirmed in controlled clinical trials on adults. One gram of aspirin, on average, reduced the oral body temperature from 39.0 °C (102.2 °F) to 37.6 °C (99.7 °F) after three hours. The relief began after 30 minutes, and after six hours, the temperature still remained below 37.8 °C (100.0 °F). Aspirin also helped with “achiness”, discomfort and headache,^[36] and with sore throat pain, for those who had it. The effects of aspirin were indistinguishable from those obtained using paracetamol in any respect, except for, possibly, a slightly higher incidence of sweating and gastrointestinal side effects.

Fever and joint pain of acute rheumatic fever respond extremely well, often within three days, to high doses of aspirin. The therapy usually lasts for one to two weeks; and only in about 5% of the cases it has to continue for longer than six months. After fever and pain have subsided, the aspirin treatment is unnecessary, as it does not decrease the incidence of heart complications and residual rheumatic heart disease In addition, the high doses of aspirin used caused liver toxicity in about 20% of the treated children, who are the majority of rheumatic fever patients, and increased the risk of their developing Reye’s syndrome. Naproxen was shown to be as effective as aspirin and less toxic; due to the limited clinical experience, however, naproxen is recommended only as a second-line treatment.

Along with rheumatic fever, Kawasaki disease remains one of the few indications for aspirin use in children, although even this use has been questioned by some authors. In the United Kingdom, the only indications for aspirin use in children and adolescents under 16 are Kawasaki disease and prevention of blood clot formation.

Aspirin is also used in the treatment of pericarditis, coronary artery disease, and acute myocardial infarction

Taking aspirin before air travel in cramped conditions has been suggested to decrease the risk of deep-vein thrombosis (DVT). The reason for taking aspirin is the long period of sitting without exercise, not air travel itself. A large, randomized, controlled trial in 2000 of aspirin against placebo in 13,000 patients with hip fractures found “a 29% relative risk reduction in DVT with 160 mg of aspirin taken daily for five weeks. Although there are obvious problems with extrapolating the data to long-distance travelers, this is the best evidence we could find to justify aspirin use”.

Experimental

Aspirin has been theorized to reduce cataract formation in diabetic patients, but one study showed it was ineffective for this purpose. The role of aspirin in reducing the incidence of many forms of cancer has also been widely studied. In several studies, its use did not reduce the incidence of prostate cancer Its effects on the incidence of pancreatic cancer are mixed; one study published in 2004 found a statistically significant increase in the risk of pancreatic cancer among women, while a meta-analysis of several studies, published in 2006, found no evidence aspirin or other NSAIDs are associated with an increased risk for the disease. The drug may be effective in reduction of risk of various cancers, including those of the colon, lung, and possibly the upper GI tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract has been inconclusive. Its preventative effect against adenocarcinomas may be explained by its inhibition of PTGS2 (COX-2) enzymes expressed in them.

A 2009 article published by the Journal of Clinical Investigation suggested that aspirin might prevent liver damage. In their experiment, scientists from Yale University and The University of Iowa induced damage in certain liver cells (hepatocytes) using excessive doses of acetaminophen. This caused hepatoxicity and hepatocyte death, which triggered an increase in the production of TLR9. The expression of TLR9 caused an inflammatory cascade involving pro–IL-1β and pro-IL-18. Aspirin was found to have a protective effect on hepatocytes because it led to the “downregulation of proinflammatory cytokines”.

In another 2009 article published by the Journal of the American Medical Association, men and women who regularly took aspirin after colorectal cancer diagnosis were found to have lower risks of overall and colorectal cancer death compared to patients not using aspirin

A 2010 article in the Journal of Clinical Oncology has suggested aspirin may reduce the risk of death from breast cancer.While the information has been well-circulated by the media, official health bodies and medical groups have expressed concern over the touting of aspirin as a “miracle drug”

A 2010 study by Oxford University involving over 25000 patients showed taking a small (75 mg) daily dose of aspirin for between four and eight years substantially reduces death rates from a range of common cancers by at least a fifth and the reduction of risk continued for 20 years in both men and women. For specific cancers the, reduction was about 40% for bowel cancer, 30% for lung cancer, 10% for prostate cancer and 60% for oesophageal cancer, while the reductions in pancreas, stomach, brain, breast and ovarian cancers were difficult to quantify because there were not enough data, but other studies are in progress. However, taking aspirin doubles the annual risk of major internal bleeding that normally has a very low incidence (about 1 in 1000) in middle age, but increased dramatically after 75 years old.

[edit] Resistance

For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin resistance or insensitivity. One study has suggested women are more likely to be resistant than men, and a different, aggregate study of 2,930 patients found 28% to be resistant.A study in 100 Italian patients found that of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant.

Dosage

Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300 mg in Britain and 325 mg in the USA. Smaller doses are based on these standards; thus, 75- and 81-milligram tablets are used; there is no medical significance in the slight difference. It is of historical interest that the US 325 mg dose is almost exactly equivalent to the historic 5 grain aspirin tablet that preceded the metric dosage.

In general, for adults, doses are taken four times a day for fever or arthritis, with doses near the maximal daily dose used historically for the treatment of rheumatic fever. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, much lower doses are taken once daily.

New recommendations from the US Preventive Services Task Force (USPSTF, March, 2009) on the use of aspirin for the primary prevention of coronary heart disease encourage men aged 45–79 and women aged 55–79 to use aspirin when the potential benefit of a reduction in myocardial infarction (MI) for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage.The WHI study said regular low dose (75 or 81 mg) aspirin female users had a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause.^[74] Low dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81 mg/day) may optimize efficacy and safety for patients requiring aspirin for long-term prevention.

In children with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks.