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Poppy Juice and Willow Bark: Advances in their use for the 21st Century

Dr J C D Wells

"Purify and pulverise the skin of a watersnake. Pour water over it and over the amamashdubkaskal plant, the root of myrtle, pulverised alkali, barley, powdered fir resin, the skin of the kushippu bird; boil; let the mixture's water be poured off; wash the ailing organ with water; rub the tree oil on it; let shaki be added".

This is the first known medical prescription for pain. It comes from a Babylonian clay tablet from 4,000 years ago. We may laugh at the ingredients but who knows, watersnake skin might contain endorphin enhancers or prostaglandin inhibitors.

Aspirin is said to be 100 years old. In 1899, Felix Hofmann, a chemist for Beyer, acetylated sodium salicylate to produce acetylsalicylic acid, which he gave to his father, who was crippled with arthritis. Further experiments followed and the name "aspirin" was coined - "a" standing for acetyl, "spir" for the spiraea plant and "in" just for good measure.

When it was first used by Wilthauer and Wohlgemut it was pointed out that it was not of greater therapeutic effect than the old salicin derivatives, but it was more pleasant to taste and less irritable to the lining of the patient's stomach! This seems to be what the new COX2 antagonists are saying about themselves and the present NSAIDS!!

During the First World War, the British Government offered a prize for anyone who could re-formulate aspirin, due to their supplies from Germany having been cut off! A Melbourne chemist, George Nicholas, synthesised an even purer form and called his product "Aspro". Aspro swept the world, penetrating the outback of Australia where it was sometimes delivered by camel and spreading throughout Asia and then Europe and Africa. However, patients continued to experience marked gastric side-effects and in the '30s calcium aspirin was investigated. Unfortunately it decomposed rapidly.

In 1938, Reckitt and Colman started work on this project, and after periods of research, periods of blanks and periods of serendipitous discovery, launched Disprin in 1948.

However, all of these developments ignored the fact that the magical power of willow leaves had been known to herbalists for a long time. Hippocrates, 2,400 years previously, recommended a brew of willow leaves to ease childbirth. Celcus, in the first century AD, boiled them in vinegar to treat a prolapsed uterus. Pliny recommended a paste of burned willow bark for treating corns, and Galen used the leaves for treating bloody wounds and ulcers. Use is also recorded in Japanese and Chinese herbal remedies, 2000 years ago.

In April 1763, the Reverend Edward Stone from Chipping Norton wrote to the President of the Royal Society, the Earl of Macclesfield, to tell him of his use of the bark of an English tree. He described willow bark extract as being effective for curing rheumatism and fever. As a believer in the doctrine of signatures, his finding that the tree delighted in moist or wet soil, where rheumatic complaints abound, suggested to him that he should use it for these conditions. He reported his 5 year experience, albeit not double-blind or placebo-controlled, but certainly showing that good clinical observation could tell a genuine ingredient - salicylic acid - from a placebo ("salix" is Latin for "willow").

The doctrine of signatures came from a Neapolitan called Giambattista della Porta. According to him, places where various plants grew offered information as to their therapeutic properties. Plants common to a particular region would cure the afflictions of its inhabitants, the theory being that the local climate was responsible both for the diseases and their cures; della Porta lived in the 16th century, 200 years before Stone, but certainly influenced not only Stone but many other people who were looking to herbalism to cure nature's afflictions.

The meadowsweet, spiraea ulmaria, was used by Pagenstecher, who was a Swiss pharmacist. He was a disciple of Paracelcus, the great 16th century scientist who preached the doctrine of signatures. He suggested that each herbal remedy must contain one active ingredient put there by nature specifically to work on one human disease. Pagenstecher's extract, aldehyde of meadowsweet, was modified by Löwig, a German chemist, in 1835 to produce spirs&ure, which was in fact salicylic acid. Gerhardt acetylated the compound in 1953, and formed aspirin, but the procedure was so tedious and time-consuming that he rated the new substance as of no further significance.

Dr T J MacLagan in Dundee used salicin in 1875. He was able to obtain salicin from salix alba, or spiraea ulmaria. He published in the Lancet on 4th March 1876, reporting the use of salicin for rheumatism and rheumatic fever. Following this report, he received a letter from Dr Ensor at the Cape of Good Hope, stating that the Hottentots in Africa had used willow tree bark for many years to treat rheumatic diseases. Dr MacLagan did very well and so did salicin. The price rose from 2/- to 12/- an ounce. He built up a substantial practice in London, became a Fellow of the RSM and doctored the Duchess of Albany and Thomas Carlisle.

"Take of opium, of the juice of the unripe mulberry, of hyoscyamus, of the juice of hemlock, of the juice of the leaves of mandragora, of the juice of the wood-ivy, of the juice of the forest mulberry, of the seeds of lettuce, of the seeds of the dock which has large round apples, and of the water hemlock: each an ounce; mix all these in a brazen vessel and then place in it a new sponge; let the whole boil until the sponge consumes it all and it is boiled away in it.

As oft as there shall be need of it, place the sponge in hot water for an hour, and let it be applied to the nostrils of him who is to be operated on, until he has fallen asleep, and so let surgery be performed".

This was the sleeping sponge used by surgeons in the 13th century to anaesthetise the patient. This mixture had already been in use for 400 years by this time. Hugh de Lucca, the most renowned surgeon of the 13th century, used this sleeping sponge, but still tied down the patient with 3 straps, rather like one of my anaesthetics before I took up pure pain medicine. Mandrake, hemlock and henbane all contain hyoscine so the Omnipon and Scopolamine of our anaesthetic teachers were not very advanced in terms of history. Lettuce also appears to be soporific (Beatrix Potter, 1909 - also Galen).

Opium must rank with aspirin as being the most widely-used drug of all time. It not only induces lethargy and sleep, it also relieves pain - although for more than 5000 years nobody understood why.

The first reference to opium, contained in the juice of a poppy, seems to have been an inscription carved on a tablet by members of the Sumerian tribe around 4000 years BC. Five hundred years after that, in Egypt, it was mixed into a paste with flies' excrement and given to children to stop them from crying. Assyrians and Greeks were quite familiar with its analgesic and soporific properties, and the poppy goddess was worshipped in the Minoan civilisation in Crete, 3½ thousand years ago. Four hundred years BC, Hippocrates described poppy wine as medicine.

Galen was born in Pergamum, the capital of Asia Minor, in AD130. He started studying medicine at the age of 16 and lived to AD200. He contributed much to our understanding of pain, and described the nervous system and its links with the brain. He was centuries ahead of his time, but as he refused to accept that the soul was immortal he was considered anti-Christian and, as the practice of medicine was in the hands of the fathers of the Christian church, his work was largely suppressed for hundreds of years.

The Romans knew a lot about opium, both from Galen and from Dioscorides, an army surgeon in Nero's time, who described opium as a sedative and painkiller. Poppy juice was widely distributed by quacks and thousands of Romans became addicted before this drawback was recognised.

The Persian physician, Avicenna (Abu-Ali Al-Husain Ibn Abdullah Ibn Sina Avicenna) practiced in the 11th century. He wrote a book called The Canon of Medicine, in which he positioned the main receptors for pain in the anterior ventricle. He described 15 varieties of pain and inflammation. The Arabs had spread the use of opium after the fall of Rome, to Persia, India and Malaysia. Avicenna used it for his patients, but unfortunately also used it for himself and died in 1037 from opium intoxication.

Opium was widely used throughout the Middle Ages, and explorers and travellers who visited Asia Minor often brought it back to their own countries. One of these was Marco Polo, who was suspected to utilise the drug for its psychic properties.

Opium may have been introduced to Britain by the Romans, but certainly the Crusaders of the 11th to 13th centuries brought some back with them from the Middle East, while other supplies were imported by the explorers. Opium was taken for pleasure during the 18th and 19th centuries, and freely used. It was cheap and readily available. It was drunk instead of hard liquor such as gin, and even given to children. George IV was treated for stomach irritation with it; Clive of India died an addict, and William Wilberforce, Coleridge and Wilkie-Collins all took it regularly for long periods (without any apparent deterioration in performance).

Charles Dickens was an occasional user, and describes an opium den in The Mystery of Edwin Drood ? In Oliver Twist, Nancy drugs Bill Sykes with laudanum. Arthur Conan Doyle was also a user and wrote this in as a characteristic of Sherlock Holmes.

Poets were also users. Byron took it when his marriage broke up. Shelley took it for headache, Lamb for colds, Crabbe for vertigo and Keats for fun.

Opium tends to be associated with the Chinese, but it seems they were only introduced in the 9th century through their trade with the East Indies. The British farmed opium throughout the world in the 18th century and introduced it in large quantities to China towards the end of that century. It was used to pay for the China tea that was imported into Britain. The Chinese called it "foreign black mud" and tried to legislate against its importation and usage. By 1833 the British were earning 12 million dollars a year for their opium - huge sums in those days. In 1838 the Chinese tried to stop this trade, but a war started, won by the British Navy; by 1842 the Chinese had to pay compensation for the opium stocks they had destroyed and open their ports freely to opium trade.

Salicyl has been used for 2000 years. Observation supported its efficacy, but also its side-effects were recognised. The formulation of aspirin in 1899 was an important breakthrough. Perhaps in 1999, before the new Millenium, the COX2 antagonists represent a further breakthrough of equal significance.

Opioids have enjoyed use and abuse over more than 4000 years. Fashions have changed; sometimes the drug has been suppressed and at other times used freely. Neither can be right, but again, as we move into the new Millenium, hopefully we can use the drug appropriately. Voltaire said "Doctors pour drugs of which they know little, into patients of whom they know less, for diseases of which they know nothing".

In the 21st century we need to know a lot more about the diseases that cause our patients pain. We need to find out more about our patient than just his complaint of pain. We need to thoroughly research drugs, both old and new, so that we can give the right drug to the right patient.

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