Suggested Learning

More than a century after the discovery of aspirin and paracetamol, we are still learning about the risks and benefits of these two analgesic mainstays.

Last October, recruitment began in the UK of 11,000 people with bowel, breast, oesophageal, prostate or stomach cancer. Those selected will take a drug for five years that, researchers hope, will cut the chance that their malignancy will recur.

The drug isn’t some expensive targeted treatment controlling an esoteric checkpoint in the cell cycle. It isn’t a pharmacologically sophisticated antibody or an exotic genetically engineered immunotherapy. It’s aspirin.

Meanwhile, a recent study raises questions about the nonhepatic safety of another of the world’s favourite analgesics: paracetamol.

On August 10 1897, Felix Hoffmann, a young chemist working at Bayer, added salicylic acid to acetic acid, creating pure and stable acetylsalicylic acid. Bayer launched acetylsalicylic acid as Aspirin in 1899. The rest, as the cliché goes, is history.

Over the years, researchers wrote numerous new chapters in aspirin’s history. In 1948, for example, Lawrence Craven, a GP in California, reported that none of 400 men to whom he had prescribed daily aspirin suffered heart attacks over two years. Craven suggested that men might avoid “dying a horribly painful death if they would take a couple of aspirins daily for the rest of their lives”.1

Unfortunately, few doctors noticed his findings and it wasn’t until 1989, when the Physicians’ Health Study showed that aspirin cuts heart attack risk2, that aspirin was used to prevent countless myocardial infarctions and strokes. And, as the new study will investigate, growing evidence suggests that aspirin might be a useful chemoprotective drug in a range of cancers.

Aspirin – still full of surprises

New discoveries

Aspirin isn’t the only old drug that is proving to have previously unsuspected actions. A few years before Hoffmann’s experiments, Arnold Cahn and Paul Hepp at the University of Strasbourg were investigating naphthalene as a treatment for intestinal worms. Naphthalene proved a poor antiparasitic but one patient, who had several concurrent conditions, showed a marked reduction in fever. In this case, however, the pharmacist had mistakenly dispensed acetanilide.

For many years, acetanilide was a cheap, widely used antipyretic, despite inactivating haemoglobin (methaemoglobinaemia). Bayer made and marketed a safer derivative called phenacetin. Then, in 1889, researchers realised that acetanilide and phenacetin shared a major urinary metabolite – paracetamol – and in 1893, Joseph von Mering, a leading German physiologist, confirmed paracetamol’s antipyretic and analgesic actions. However, von Mering believed paracetamol caused methaemoglobinaemia (an impurity was probably responsible).

Paracetamol remained in limbo until 1948, when pharmacologists Julius Axelrod and Bernard Brodie reported that paracetamol accounted for acetanilide’s antipyretic and analgesic actions. A minor metabolite, aniline, caused methaemoglobinaemia. In 1953, Sterling-Winthrop launched paracetamol.

Asthma risk?

Paracetamol’s hepatic effects are now well known but, recently, several studies have linked paracetamol to an increased risk of developing asthma. (Aspirin, of course, can also trigger asthma in susceptible people.) A new Norwegian study “is by far the largest” linking prenatal and infant paracetamol exposures with asthma.3

Researchers evaluated 53,169 and 25,394 children for current asthma at three and seven years of age respectively and 45,607 for dispensed asthma medications at seven years. Of these 27.9 per cent of children were exposed to paracetamol only during pregnancy, 15.5 per cent only during the first six months of infancy and 19.1 per cent during both pregnancy and infancy.

Overall, 5.7 and 5.1 per cent of children had current asthma at three and seven years respectively and 4.8 per cent received asthma medicines.

After adjusting for confounders, prenatal paracetamol exposure and use during infancy were associated with increases of 13 and 29 per cent respectively in asthma risk at three years compared to unexposed. The risk was 27 per cent higher in those exposed prenatally and during infancy.

Prenatal and infant paracetamol exposure were associated with increases of 27 and 24 per cent respectively in asthma risk at seven years. The risk was 49 per cent higher in those exposed prenatally and during infancy. Prenatal exposure, using paracetamol during infancy and both were associated with increases of 17, 27 and 26 per cent respectively in the likelihood of receiving asthma medicines at seven years.

Further investigation

Children born to women who experienced pain during pregnancy, but did not use paracetamol, were 47 per cent more likely to have asthma at three years. However, this was the only statistically significant association at any time for the three indications examined – pain, respiratory tract infections/influenza (RTI) and fever – that emerged in both those exposed to paracetamol and the unexposed.

The link requires further investigation but pain could increase maternal stress, which previous studies suggest increases asthma risk. Against this background, the associations between paracetamol and asthma “could not be fully explained by confounding by indication.” For example, children born to women who used paracetamol for RTI, fever or pain during pregnancy were 51, 58 and 73 per cent more likely to have asthma at three years.

In other words, the study “provides evidence that prenatal and infant paracetamol exposure have independent associations with asthma development.” Such a link seems biologically plausible. Other studies suggest that paracetamol could increase oxidative stress, enrich the number of Th2 cells or mediate non-eosinophilic inflammation, all of which can contribute to asthma.

But the thought occurs: if we are still learning about the risks and benefits of aspirin and paracetamol despite more than a century’s worth of research and billions of patient-years of use, how much do we really know about all the other drugs that are prescribed, dispensed, and used each day?

References

  1. Tex Heart Inst J 2007; 34:179-186
  2. N Engl J Med 1989; 321:129-35
  3. Int J Epidemiology Doi:10.1093/ ije/dyv366

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