Category:NSAIDs: Difference between revisions

The non-steroidal anti-inflammatory drugs, or NSAIDs, are among the most widely used medicines in the world. Their history is in large part the history of a single medicine, aspirin, and of the long effort to understand how it works and to build safer or more powerful relatives around it.

The story of the NSAIDs is conventionally traced to willow. A popular account holds that willow bark was used as a remedy for pain and fever in antiquity, by the Egyptians, and by the Greeks under Hippocrates. Ancient willow-as-painkiller account▲0▼ However, some historians dispute this, noting that the surviving ancient texts describe more varied uses for willow and do not clearly record it as a painkiller, and that the familiar "ancient aspirin" narrative appears only after aspirin itself was discovered.^[1] Disputed as retrospective myth▲0▼

What is well documented begins in the eighteenth century. In 1763 the English clergyman Edward Stone reported to the Royal Society that dried, powdered willow bark relieved fever; he had been struck by the bark's bitter taste, which reminded him of cinchona.^[2] Over the following decades chemists isolated the bark's active component, a substance named salicin (after Salix, the willow genus), and went on to derive from it a more potent acid, salicylic acid. Salicylic acid worked as a remedy for pain, fever, and rheumatism, but it irritated the stomach badly.^[2]

In 1897 the chemist Felix Hoffmann, working at the Bayer company in Germany, produced acetylsalicylic acid in a form suitable for commercial manufacture; Bayer marketed it as Aspirin. An impure version of the same compound had been made decades earlier, in 1853, by the French chemist Charles Frédéric Gerhardt. The credit for the Bayer synthesis is itself disputed: some historians argue that Hoffmann's colleague Arthur Eichengrün directed the work, and that his role was later written out of the record.^[1]

For the first half of the twentieth century aspirin had few rivals. That changed with a search for anti-inflammatory medicines that might be gentler on the stomach or more effective against conditions such as rheumatoid arthritis. The most successful result was ibuprofen, discovered in the United Kingdom by a team led by Stewart Adams, with a patent filed in 1961; it was first sold as a prescription medicine and later became widely available over the counter.^[3] Other NSAIDs introduced over the following decades include naproxen, diclofenac, indomethacin, and many more.

For most of aspirin's history, how it worked was unknown. The answer came in 1971, when the pharmacologist John Vane and colleagues showed that aspirin and similar medicines act by blocking the production of prostaglandins, signalling compounds involved in pain, fever, and inflammation. Vane shared the 1982 Nobel Prize in Physiology or Medicine for this and related work.^[4]

The enzyme the NSAIDs block is cyclooxygenase, or COX. It was later found to exist in more than one form: COX-1, active in many tissues including the stomach lining, where the prostaglandins it produces are protective; and COX-2, more closely associated with inflammation. Most traditional NSAIDs inhibit both. The understanding that gastrointestinal harm came largely from COX-1 inhibition, while the desired anti-inflammatory effect came largely from COX-2, suggested that a medicine selective for COX-2 might relieve pain with less stomach injury.^[5]

Selective COX-2 inhibitors, among them celecoxib and rofecoxib, were introduced in the late 1990s and were initially received with considerable enthusiasm. Within a few years, evidence accumulated that they carried an increased risk of heart attack and stroke. Rofecoxib, sold as Vioxx, was withdrawn from the market worldwide by its manufacturer in 2004 after a trial found increased cardiovascular risk with long-term use; the withdrawal led to extensive litigation.^[5] It was subsequently recognized that elevated cardiovascular risk is, to varying degrees, a property shared across the NSAID class rather than unique to the COX-2 inhibitors, and warnings to this effect were applied broadly.^[5]

NSAIDs are understood to act by inhibiting cyclooxygenase enzymes and so reducing the production of prostaglandins. The reduction of prostaglandins involved in inflammation is associated with the relief of pain, fever, and inflammation; the reduction of prostaglandins that protect the stomach lining and support kidney function is associated with the characteristic harms of the class. That NSAIDs inhibit COX is well established; the full picture relating this inhibition to every clinical effect and adverse effect, including the cardiovascular risk noted above, is more complex and remains a subject of research.

The NSAIDs include aspirin (acetylsalicylic acid), ibuprofen, naproxen, diclofenac, indomethacin, ketorolac, meloxicam, and piroxicam, among others, together with the selective COX-2 inhibitors such as celecoxib. Paracetamol (acetaminophen) relieves pain and fever but has little anti-inflammatory effect and differs in its mechanism; it is generally not classed as an NSAID. The list is not exhaustive.

The most characteristic harms of the NSAIDs are gastrointestinal: irritation, ulceration, and bleeding of the stomach and upper intestine, arising from the loss of protective prostaglandins. NSAIDs can also impair kidney function, particularly in people who are dehydrated, elderly, or who have existing kidney or heart disease, and are associated with raised blood pressure. As noted above, the class as a whole is associated with some increase in cardiovascular risk. Risk rises with higher doses and longer use, which is the basis of the common guidance to use the lowest effective dose for the shortest necessary time. Figures for these risks are population estimates that vary between studies, and individual response varies considerably between people.