This apparently scandalous story was brought to my attention this week. The story was about what seemed to the reporters to be a massive coverup of the toxicity of acetaminophen, which is the US spelling of paracetamol. It is remarkable for a number of reasons, not least of which was the fact that it took 2 reporters a couple of years and $750,000 to do it. The toxicity of paracetamol is well-known in medical circles, and is certainly familiar to the majority of people who use it a lot. Strangely enough I still think paracetamol can justifiably be called a safe drug. Bear with me and you’ll see why I say this.
Paracetamol produces mild to moderate analgesia in a relatively short time frame by a mechanism that is still not determined. It also acts to reduce fever, so stopping the production of some of the peptides that promote both pain and fever would seem the likeliest way for it to work. . It is metabolised into non-toxic, inactive molecules by the liver using a couple of different pathways which cope just fine with doses in the recommended range. At doses above the recommended range however, the usual pathways get backed up, and a third pathway comes into play to deal with the excess. Paracetamol metabolized by this 3rd pathway (the cytochrome 450 system) comes out as a different breakdown product, which unlike those produced by the usual pathways is toxic to the liver cells. This process is unpredictable because the liver has variable stores of a peptide called glutathione which deactivates the toxic byproduct.
Glutathione is a powerful antioxidant which can neutralise the toxic paracetamol product. Once your liver uses more than around 30% of your total store though, you ain’t in Kansas anymore and things get rough for the liver cells. Glutathione levels can be depleted by fasting, malnutrition or chronic disease, and it is slow and very difficult to replenish by direct supplementation. Glutathione is made up of 3 amino acids, of which 2 are plentiful in the body, and one is rare. The rare one is called cysteine and has to be sourced from foods rich in it. Increasing the amount of cysteine in the body has been shown to rapidly increase glutathione stores. Hence, the main treatment for a paracetamol overdose is to give intravenous cysteine replacement to help the liver protect itself while the toxic metabolites of paracetamol are leaving the building. If no treatment is given, and damage has already occurred, the process can’t be stopped, and overdose victims then have an agonizing wait for several days to see if enough liver cells will survive to avoid complete liver failure, and the need for a transplant. Death, if it comes before a transplant, is prolonged and very uncomfortable.
Overdoses of paracetamol are relatively common, with a recent paper showing over 2,000 a year in Victoria alone over the last 7 years. The rate seems to be declining, and 85% of those overdoses were deliberate self-harm attempts. Just over 2,000 Victorians were admitted to hospital over 7 years with accidental overdoses. There were a total of 26 deaths, none of whom were under the age of 15. A paper from Iceland covering a similar period showed rates of paracetamol overdose with broadly similar trends. In general, while severe overdoses continue to occur, the death rate is quite low and the risk is mainly in people who are deliberate overdose takers. Even in the ProPublica investigation, they admit that only around 150 people in the US die each year, out of a population of over 300 million.
Outside of overdoses, there are very few reports of paracetamol toxicity in the literature. When taken in the recommended doses, you have to be very malnourished or otherwise unwell to be unable to cope with it. When balanced against its benefits, should we be worried about paracetamol being so freely available? It has a massive track record of safety and modest effectiveness despite being the most widely used painkiller. As always, the situation is complicated.
A previous article on this very website has highlighted what I think may be the most insidious danger from paracetamol. People with poorly treated severe pain are desperate, and numerous studies now confirm that having severe pain tends to inhibit the usual critical thinking faculties, known as executive function. It appears many of the inadvertent cases of severe toxicity have occurred where the doses involved may have been right on or only just been over the upper end of the recommended dose. if this is sustained over several days the results can be as bad as a single big overdose. Another concern (one of the best points to come out of the American article above) is that paracetamol is often mixed with other drugs as in cold and flu tablets or stronger analgesics like codeine. Consumers in a fog of pain or ill-health may find it quite easy to lose track of how much paracetamol they have had if they are taking multiple products.
It’s hard to see how regulators and public health types can respond to this. Millions of doses of paracetamol are taken every day in Australia without causing severe toxicity, so compared to the number of doses taken and the wide availability of the drug, it’s still reasonable to say it’s a safe and modestly effective drug. Consumers need to be savvy about what they are taking, but the evidence would suggest they overwhelmingly are already. How far can packaging, warnings and education campaigns go before they become too restrictive and expensive? Attempts at addressing the problem in the US and UK by reducing the dose size in pills from 500mg to 325mg have not been clearly successful at reducing overdose rates or death rates, and in any case (in Victoria at least) these are coming down without the dose or packet size being reduced.
Here’s my groat’s worth of wit as to what we should do about paracetamol.
(1) Target education about weight-related dosing in children to new parents via child health nurses and parents’ groups. (2) Have a public health advertising campaign with the message to be aware of paracetamol-containing products adding up, and also not to push on taking paracetamol if it’s not working. It is, after all, only effective in mild or moderate pain. (3) Link this campaign to a change in the labelling of paracetamol-containing products along the lines of a ‘percentage of recommended daily intake’ score. Consumers can then easily tell if they’re near the edge of the dosing envelope by looking at the containers of what they’ve taken and doing a simple addition. (4) Fund these changes from donations (I’ll be generous and assume that the pharma companies will voluntarily want to help with this problem their products create) from the OTC medicines industry. A levy or some other statutory fee on paracetamol-containing products would do if they won’t be reasonable.
There you go. Not too expensive or bureaucratic, paid for by the industry which is creating the problem and targeted to the paracetamol toxicity victims who can be easily prevented from needing hospital care. It also capitalises on the good job that consumers are already doing at managing the use of paracetamol day to day by making it easier for them to avoid the pitfalls we’ve now discovered. The large numbers of self-harm attempts with paracetamol I’m afraid is quite another problem. To bring that down substantially would require the sort of investment in mental health services that no political party is currently contemplating.