Aspirin: A plant-derived pharmaceutical for the treatment of pain and inflammation

Origins of aspirin

The origins of aspirin date back over 3500 years. The Eberus papyrus (a collection of medicinal recipes dating back to the middle of the second millennium BC) describes an infusion of dried myrtle leaves used to ease the pain of rheumatism and for back problems. Juice extracted from the bark of willow trees was later used by Hippocrates, the celebrated ‘father of medicine’, in the fifth century BC to ease pain and fevers. Both of these preparations contain salicylic acid, the precursor of modern aspirin.

In the middle ages, boiled willow bark was used as a popular remedy for fever. This practice was forgotten when, to protect the budding wicker industry, the stripping of willow trees was made illegal.

In 1763 the Reverend Edward Stone of Chipping Norton near Oxford, England gave dried willow bark to 50 parishioners suffering rheumatic fever. He then described his success with this treatment in a letter to the Royal Society of London, whereupon his discovery was immediately dismissed by the leading scientists of his day.

Early aspirin chemistry

In 1826 the active ingredient was extracted from willow by two Italian chemists, Brugnatelli and Fontana, and named salicin. In 1838 salicin was also found as a naturally occurring compound in the meadowsweet flower.

Salicylic acid was made from salicin by French scientists in 1853, but found to irritate the stomach and abandoned.

A less irritating form of salicylic acid, acetylsalicylic acid (ASA – the active compound in aspirin) was apparently discovered by a French chemist named Charles Gerhardt, who first prepared it in 1853. He found it to be effective at relieving pain without producing severe stomach discomfort. It then sat on the shelf unused for almost 45 years, however, as he had no interest in commercializing his discovery.

In 1897 Felix Hoffmann, a young chemist working for the German pharmaceutical giant Bayer, was looking for a new painkiller to treat his father’s arthritis without producing the severe stomach irritation associated with the standard anti-arthritis medicine of his day. Perhaps rediscovering the work of Gerhardt, he found that adding an acetyl group to salicylic acid reduced its irritant properties. Hoffman prepared acetylsalicylic acid and patented the process for its synthesis.

Alternately, there is evidence that Hoffmann’s work was really directed by a Jewish chemist named Arthur Eichengrun, whose contribution was covered up during the Nazi era. According to Eichengrun’s account (written many years later in a Nazi concentration camp), the acetylsalicylic acid was first tested by his relative, a dentist, who found it to be quite effective in relieving pain during tooth extractions.

Aspirin gets off to a slow start

In either case, Herr Dreser (Hoffman’s superior at Bayer), held to the theory (accepted by the leading scientists of his day) that any good drug must conduct electricity. Since acetylsalicylic acid failed that test, it was originally rejected. Dresser encouraged Hoffman to continue his work on another promising new painkiller: heroin.

Eichengrun (or Hoffman) secretly gave the powder (acetylsalicylic acid was originally sold as a powder and was not available as a tablet until 1915) to different dentists and physicians who confirmed the pain-killing effectiveness of the drug. Directors of Bayer, convinced by the clinical data and seeing that these dentists and doctors appeared willing to purchase the new medication, overruled Dreser and authorized the manufacture of aspirin. Bayer registered “Aspirin” as a trademark and began selling it in 1899.

One story has it that the name “aspirin” is derived from the chemical composition, where “a” stands for “acetyl” and “spir” stands for spireic acid (a different name of salicylic acid). Alternately, “spir” might reference the spiria, a plant very similar to the willow tree in which salicylic acid is found. Some report that aspirin is actually named for Saint Aspirinus, patron saint of headaches.

Aspirin as a casualty, and prize, of war

Whatever the origins of its name, by 1914 aspirin use had grown far beyond what could have been imagined in 1899 when it was first introduced to “a few doctors.”. Aspirin was by then an essential global pharmaceutical. Aspirin was so important that the interruption of its supply from Germany with the outbreak of WWI spawned a global competition to discover a new means of producing it (won by Australian pharmacist G. R. Nicholas.)

Perhaps in part over anger at having been denied aspirin during the war years, but certainly in recognition of its value, aspirin was treated as a prize to be divided among the victors of WWI. The Treaty of Versailles (1919) required, as part of Germany’s war reparations, that Bayer to give up its aspirin trademark and patent in the U.S., Britain, France, and Russia. (Bayer’s U.S. holdings had previously been confiscated and sold to the Sterling Drug Company.) For the next 80 years none of the  “Bayer aspirin” sold in America was actually made by Bayer. It wasn’t until 1994 that the German company repurchased the right to use its own name in the United States.

Bayer fights back – early adoption of “new media” and “social marketing” brings results

In what must be the only case of a company celebrating the expiration of its own patent, Bayer was able to re-enter the aspirin market in the 1930’s when its (confiscated) patent expired and aspirin became a generic drug.  Undeterred by previous ’set backs,’ Bayer re-established its brand leadership between the two great wars. Trucks equipped with movie screens and loudspeakers were dispatched across Europe to tout the benefits Bayer aspirin. For many thousands of people, the first “moving pictures” they ever saw were images of aspirin use.

Milestones in aspirin use

In 1950, aspirin was first recognized by the Guinness Book of Records as the world’s best-selling painkiller.

In 1982 the mechanism of action for aspirin – then in use for 83 years – was confirmed as English scientist Professor Sir John Vane and two Swedish colleagues, Sune Bergström and Bengt Samuelsson. Those three shared the 1982 Nobel prize for discovering the role of aspirin in inhibiting prostaglandin production.

Aspirin turned 100 in 1999 with an estimated one trillion tablets having been consumed since its introduction.

The twentieth century was dubbed ‘the age of aspirin’ by Spanish philosopher Jose Ortega y Gasset.

The use of aspirin continues to increase, with the equivalent of 100 billion 500 mg. tablets manufactured in 2004.

Aspirin – more than just an analgesic

The list of potential applications for aspirin continues to grow. Aspirin has been shown to be effective or possibly effective in the treatment of:

• Heart attacks (and their prevention)
• Strokes
• Pregnancy complications
• Colon cancer
• Complications of diabetes
• Dementia (including Alzheimer’s)

Aspirin side effects

Unfortunately, the list of side effects associated with aspirin and other NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) also continues to grow, and now includes:

• Ulcers and gastrointestinal bleeding

  • This is the major danger with long-term use of NSAIDs and accounts for between 6,000 and 16,500 deaths, as well as 107,000 hospital admissions per year in the United States
  • There may be no warning symptoms before bleeding begins.

• Heart attacks (all NSAIDs except aspirin)

  • A Norwegian study released in April, 2005, noted that NSAID users in the study were dying at twice the rate of non-NSAID users from cardiovascular disease.
  • Risk was highest among ibuprofen users, who were nearly three times more likely to die of cardiovascular disease than non-NSAID users.
  • Aspirin was the only NSAID that did not seem to raise the risk, but the numbers of aspirin users in the study were small.
  • “To the best of our knowledge, these are the first data to support putting a box warning on NSAIDs, not just cox-2s,” said Dr. Andrew Dannenberg, a Cornell University scientist who helped do the Norway study.

• Strokes

• Congestive heart failure

• Kidney abnormalities, including kidney failure

• Liver abnormalities, including liver failure

• Potentially lethal skin disorders

• Increased blood pressure

• Dizziness

• Tinnitus (ringing in the ears)

• Headache (oddly enough)

• Depression

• Confusion or bizarre sensations (in some higher-potency NSAIDs, notably indomethacin.)

• Risk of miscarriage (Particularly if the NSAID is taken for more than a week or around the time of conception.)

• Delayed gastric emptying, which can interfere with the actions of other drugs. The elderly are at special risk.

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Aspirin is a jack of all trades, and a master of none – it has a wide range of targets, but is relatively poor at hitting any of them. This relative feebleness explains why it takes such a lot of aspirin to achieve the desired effect. Clearly, what is required is a version of aspirin that is highly effective at interfering with a given target, while leaving all its other potential targets alone.

Source:  News @Nature.com, November, 1998, “The Avatars of Aspirin.”

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[stextbox id="grey"]Explaining why a “better aspirin” is needed Philip Needleman, Ph.D., senior vice president and chief scientist at Monsanto Co. and president for research and development at G.D. Searle and Company stated, “Aspirin is alright…but if you have significant rheumatoid or osteoarthritis, you’d be shoving in handfuls of aspirin every few hours, and you probably wouldn’t get the relief you were looking for. Aspirin is not potent enough for severe disease, and it’s dangerous to push the dose.”[/stextbox]

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“Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for non-steroidal anti-inflammatory drug (NSAID) related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone. The figures for all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated.”

Source:  American Journal of Medicine, July, 1998, “Recent considerations in nonsteroidal anti-inflammatory drug gastropathy.”

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“For the average patient with rheumatoid arthritis, the chance of hospitalization or death due to a GI event (from NSAID use) is about 1.3 to 1.6% each 12 months, and about 1 in 3 over the entire course of the disease.”

Source:  Journal of Rhuematology, Supplement, March, 1991, “NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal.”

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The use of nonsteroidal antiinflammatory medications (NSAIDs) and nutraceuticals, such as glucosamine and chondroitin, is common among athletes. The use of these drugs has significant effects on pain and swelling associated with injury; however, this use does have significant risks to the gastrointestinal, hepatic (liver), and renal (kidney) organ systems.

Source:  Clinical Sports Medicine, January, 2005, “The use of NSAIDs and nutritional supplements in athletes with osteoarthritis: prevalence, benefits, and consequences.”

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The excessive use of analgesics and non-steroidal antiinflammatory agents (NSAIDs) is strongly associated with an increased prevalence of chronic renal insufficiency, some cases requiring long term replacement therapy (dialysis/transplantation). The elderly are especially susceptible and more frequently use these medications.

Source: American Journal of Medicine, July, 1998, “Should the sale of analgesic mixtures and non-steroidal anti-inflammatory agents (NSAIDs) continue to be allowed as over-the-counter (OTC) medications?”

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In the elderly in particular, the prolonged, regular use of NSAIDs should be discouraged. Patients starting NSAID therapy should be monitored regularly and drug interactions should be avoided.

Source:  Geriatric Nephrology & Urology, 1999, “Analgesic abuse in the elderly. Renal sequelae and management.”

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Hepatotoxicity (liver damage) is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals.

Source: American Journal of Medicine, 1998, “Hepatotoxicity of non-narcotic agents.”

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Acetaminophen (Tylenol) overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year. Acetaminophen produces more than $1 billion US dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. It still must be asked: Is this amount of injury and death really acceptable for an over-the-counter pain reliever?

Source: Hepatology, July, 2004, “Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure.”

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[stextbox id="grey"]Taking a low-dose aspirin every day can help prevent heart attacks in people who’ve already had one. But if you’ve never had a heart attack (or stroke), the risks of taking a daily low-dose aspirin outweigh the benefits, according to an October, 2009 U.K. report published in Drug and Therapeutics Bulletin.[/stextbox]

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