This story begins in modern times with a letter from the Reverend Edward Stone of Chipping Norton to the Royal Society in 1763. He wrote: ‘There is a bark of an English tree which I have found by experience to be a powerful astringent and very efficaceous in curing aguish and intermitting disorders.’ ‘Aguish’ means rheumatism and ‘intermitting disorders’ refers to bouts of fever. The tree was the white willow, Salix alba. Stone’s rationale for this herbal remedy was that he and his contemporaries believed that rheumatism and bouts of fever came from swamps, and that bountiful nature would provide a remedy from the same source. Willows grow on wet land. He mentions a similar but different remedy, in that case for malaria, coming from ‘Peruvian bark’ (quinine) as another example of ‘the general maxim that natural maladies carry their cures along with them’. This is fantasy but the cure works. Stone did not know that Hippocrates, Galen and Pliny were all advocates of willow bark. In the nineteenth century, chemists made an extract called salicin, and MacLagan’s Lancet paper of 1876 is called Treatment of Rheumatism by Salicin.
A vast expansion in the use of salicin followed the synthesis in 1899 by the German Bayer Company of the pure compound acetylsalicylic acid, which they named aspirin. The outbreak of the First World War in 1914 isolated Britain from the source of this wonder drug, and the government offered a prize of ?20,000 to anyone who could find an alternative synthesis. The prize was won by the Australian George Nicholas, who sold his tablets as aspro. Finally, in 1971, J. R. Vane in London showed that aspirin worked by blocking one of the pathways by which damaged cells make chemicals called prostaglandins as a crucial part of the inflammatory process.
I have told this story at some length because it shows that a crude herbal mixture was used for two thousand years, a purified extract for a century, and the precisely synthesized chemical for another 70 years before the rationale for the use of aspirin was discovered by Vane. It is intellectually satisfying to understand exactly how a remedy works, and that knowledge may lead to the development of more effective drugs. However, it is equally clear that effectiveness can be established without any idea of how or why the therapy works, or even with the wrong theory to explain its action.
Aspirin, for all its excellent properties, has its problems. Because it interrupts part of the inflammatory process, it blocks at the same time some of the beneficial parts of that process. It decreases blood clotting and is even used for that reason as a long-term low-dose preventive treatment to reduce the chances of clotting in a heart attack or a stroke. It can interrupt the normal repair process that is going on in the lining of the stomach and, in the extreme, can produce massive bleeding from the stomach.
In an attempt to overcome these dangers, every pharmaceutical company in the world has been hard at work to produce substitutes. They have produced a vast family of sons and grandsons of aspirin. They vary in potency but they all have the same problems. Distant relatives were added, such as paracetamol and di-pyrone. Because vast profits were to be made by renaming members of the same family, the public relations experts pushed aside the pharmacologists and spent giant advertising budgets persuading us to buy their brand. Television advertisements proclaim their cure as specific for aches and pains but there is hardly a jot of difference between them except in price. However, clever pharmacologists are at work to find a way to block the inflammatory pathway affected by aspirin in such a way that the bleeding does not occur. These tablets, called cyclo-oxygenase inhibitors, cox-2, are not yet available but are on their way.
Aspirin has a subtle effect on only one part of the inflammatory pathway but it reduces pain and swelling and fever. A much more vigorous approach is to use steroids, which cancel the signals that set off the whole inflammatory process. They are used in emergency situations to bring inflammation under control but their widespread side effects are also powerful. For example, inflammation is a crucial tool in our battle against bacteria by walling them off and destroying them. Steroids block that action and the bacteria can have a field day.
I have described inflammation as a sequence of actions and reactions with many components. Modern science is concentrating on this process and there are hopes that it could be controlled in a beneficial way to abolish unwanted aspects such as pain while leaving the protective, restorative functions intact. Steven McMahon in London has recently shown that a small protein that is required in the embryo for the growth of sensory nerve fibres, and is therefore called nerve growth factor, is also necessary to produce pain but not to trigger the other components of inflammation. There are therefore hopes for genuine analgesics which affect pain from the periphery but leave other parts of inflammation intact. They do not yet exist as safe, available, tested medicine. That does not mean that existing anti-inflammatory analgesics should not be used. Some people refuse to take drugs for fear of addiction, dependency, side effects or fear that their effectiveness will fade. They are usually wrong and need help to overcome their fear.
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