March 2, 2015

expert reaction to systematic review of long-term paracetamol use and cardiovascular, gastrointestinal and renal health

A review of the literature surrounding the side effects associated with the use of paracetamol has been published in the journal Annals of the Rheumatic Diseases. The authors report an increased risk of a number of side effects associated with the use of paracetamol, including those related to cardiovascular and gastrointestinal health, but state that confounding effects may play some part.

Prof. Seif Shaheen, Clinical Professor of Respiratory Epidemiology, Queen Mary University of London (QMUL), said:

“Research into the safety of paracetamol is important, given how commonly the drug is taken, and previous epidemiological studies have suggested that the drug might increase the risk of asthma, and decrease the risk of ovarian cancer. This latest study has reviewed the findings from eight cohort studies (four from the same US cohort of female nurses) which had investigated possible harmful effects of paracetamol and other analgesics on other outcomes including mortality, cardiovascular disease, hypertension and renal function. There are a number of reasons why the authors’ conclusions should be treated with caution; whilst they acknowledge limitations in their paper I found the press release (which contains some ‘cherry-picked’ results) a little misleading.

“Firstly, the UK mortality study had two main limitations: this cohort study only looked at data for prescribed paracetamol, whereas we know most paracetamol is bought and taken without prescription. Also, there was limited information about the people taking the paracetamol and their health, which meant there were confounding factors that couldn’t be accounted for in the analysis.

“Secondly, the Danish mortality study concluded that associations between paracetamol use and a variety of causes of death were largely explained by ‘confounding by indication’, which means that the apparent link between long-term paracetamol use and these health outcomes may be more likely to be explained by the conditions or symptoms for which the paracetamol is being taken.

“Thirdly, the majority of the studies showed similar associations with ibuprofen (e.g. findings for cardiovascular disease and hypertension), so the results were not specific for paracetamol.

“And fourthly, the authors do not discuss mechanisms by which paracetamol might be causally linked to the diverse outcomes studied.

“Given these limitations, this systematic review does not strengthen the weak evidence for harmful causal effects of paracetamol suggested by the component cohort studies. However, further rigorous research into possible detrimental effects of this commonly used drug would be prudent.”

Professor Nick Bateman, Honorary Professor of Clinical Toxicology, University of Edinburgh said:

“Paracetamol is one of the most commonly used medicines worldwide. It is available both on prescription and over-the-counter. In this review, small dose-related increases were shown in overall mortality, GI bleeding and renal function in different groups of patients who either reported using, or received prescriptions for, paracetamol. A large proportion of those studied were either nurses or doctors, and in several studies only prescription drug use was examined. Interpreting these results for the general population is therefore a challenge, as most people take paracetamol intermittently that they buy themselves. Based on this study the risk here is minimal.

“Retrospective studies like this show associations, but as the authors admit, other factors, such as the reason people take regular high doses of paracetamol, may be a cause of the findings. Paracetamol remains the safest analgesic available, and this study should not stop people taking it. Based on these results the lowest effective dose for the shortest necessary period is advised; this is common sense for all medicines.”

‘Paracetamol: not as safe as we thought? A systematic literature review of observational studies’ by Emmert Roberts et al. will be published in Annals of the Rheumatic Diseases at 23:30 UK time on Monday 2 March 2015, which is also when the embargo will lift. 

Declared interests

Prof Seif Shaheen has conducted research into paracetamol use and asthma.

Prof Nick Bateman has written extensively on paracetamol poisoning, but has no financial or academic conflicts.