February 7, 2022

expert reaction to study looking at regular, long-term paracetamol use and blood pressure, in people with high blood pressures

A study, published in the journal Circulation, looked at regular, long-term paracetamol use and blood pressure, in people with high blood pressures.

This roundup accompanied an SMC Briefing. 

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This clinical trial uses a standard trial design and generally standard statistical methods.  It provides pretty firm evidence that, when people who already have high blood pressure take paracetamol regularly over a period of two weeks, in the amounts that people might take for chronic pain, that causes their blood pressure to increase.  As a statistician, I can’t comment on the clinical consequences of increases in blood pressure of the size that were found in the trial.  The results don’t apply to people who take paracetamol for fairly brief periods to deal with headaches, fevers and the like.

“The researchers report that there has been previous evidence that taking paracetamol is associated with increases in blood pressure, but (apart from one small randomised clinical trial in a very particular group of patients) the evidence all comes from observational studies, where people just behaved as they normally would in deciding whether to take paracetamol.  The problem with studies like that is that there will inevitably be other differences between the people that take and don’t take paracetamol, apart from whether they take paracetamol, and those other differences could be the cause of the differences in blood pressure rather than the paracetamol itself.

“This randomised clinical trial avoids that issue in several ways.  First, the researchers asked all the participants to take paracetamol for two weeks and also, on another occasion, to take a placebo (an inactive tablet that looks just like the paracetamol) for two weeks, so that they could compare the changes in blood pressure over the two periods.  This means that each participant’s blood pressure changes on paracetamol are being compared with their own blood pressure changes on the inactive placebo, which takes account of most individual differences between the patients.  The comparison with placebo is used so that any effects on blood pressure of simply taking a pill (the so-called ‘placebo effect’) are taken account of – and the use of a placebo also ensures that neither the patients, nor the people treating them and measuring the effects, knew which treatment they were on at any time, so that their reactions would not affect blood pressure.

“Second, half of the participants took paracetamol for their first set of two weeks, the other half took the placebo, and they swapped over to the other treatment for their second set of two weeks, in what’s called a crossover trial.  The reason for using both orders of treatment is because which treatment came first could make a difference to the outcome.  Whether they took paracetamol or placebo first was determined at random, partly again so that neither the participants or the researchers knew which treatment they were on at any time, and partly so that both sets of participants (paracetamol first or placebo first) would broadly match in terms of their characteristics.  There was a two-week gap between the two weeks on the first treatment and the two weeks on the second treatment, to give time for any effect of the first treatment to wear off before the second period of treatment began.

“Third, because of the possibility that changes in blood pressure in the first treatment period might be different from changes in the second treatment period, regardless of the actual treatment, the researchers used a standard statistical procedure to allow for that.

“During the two treatment periods, the researchers measured the participants’ blood pressures on several occasions and in more than one way.  They generally found that, on average, the participants’ blood pressures increased more in the two weeks when they were taking paracetamol than in the two weeks when they were taking the placebo.  (In fact there was very little change in blood pressure when they were taking the placebo, on average.)  Overall, that provides clear evidence that, in people like these trial participants, taking paracetamol for two weeks, at the dosage that was used, increases blood pressure on average.

“The researchers point out some limitations of their findings, which are all the kind of limitations that are pretty inevitable in most randomised trials.  Any randomised trial can provide direct information only about people who are broadly like the trial participants, and clinical trials always have careful criteria on which people are eligible to take part and which are not. In this trial, all the patients already had high blood pressure (hypertension).  This means that the trial cannot directly give information on whether taking paracetamol in these doses would increase blood pressure in people who did not already have hypertension.  The researchers do point out that their main concern, in terms of regular treatment with paracetamol, is in its use for chronic pain, and that both chronic pain and hypertension become more likely in older people.  That is a reason why looking for an effect of paracetamol on blood pressure in people who already have hypertension is particularly important – but it remains the case that these results don’t tell us anything specific about what might happen in people who did not have high blood pressure to begin with.  (That’s despite the quotation from Professor Dear in the press release, which does not specify that the results apply to people with hypertension.)  Of course, even though this trial doesn’t tell us directly that paracetamol increases blood pressure in people that don’t have hypertension, it remains perfectly possible that it does in fact increase blood pressure in such people, when taken in similar doses and over extended periods as in this trial.  As a statistician, I can’t comment on how plausible that is in the light of other evidence.

“Other limitations are mentioned by the researchers, as follows.  The researchers’ main concern about blood pressure and paracetamol is about those who take it regularly, possibly for long periods, for chronic pain.  It’s not clear from this trial that the increase in blood pressure would continue for longer than the two week periods used in the trial, though the researchers give very plausible reasons that it probably would.  Also, the trial participants were not already taking the usual medications for chronic pain, and so it can’t be ruled out that things would be different in patients who did have chronic pain.  Finally, the participants all came from one area of the country and were all Caucasian, so again there’s no direct evidence that things would be the same in other places or ethnic groups.

“The main trial report calls the drug ‘acetaminophen’ rather than ‘paracetamol’.  That’s simply because the journal where it is published is American, and in America the usual term for the drug that is called paracetamol in the UK and many other countries is acetaminophen.”

Dr Richard Francis, Head of Research, Stroke Association, said:

“High blood pressure is the single biggest risk factor for stroke.  This new and robust study, adds to previous research and suggests regular paracetamol causes blood pressure to quickly increase in people who are already at risk of stroke and heart attacks.  It’s therefore important that doctors regularly review and weigh up the risks and benefits of prescribing paracetamol.  Patients in this study had pre-existing high blood pressure, so further studies in people with normal healthy blood pressure, over longer time periods are needed to confirm the risks and benefits of using paracetamol more widely.

“Getting your blood pressure checked regularly is vital to reduce your risk of a stroke.  You can get your blood pressure checked at your local pharmacy, at an NHS Health Check appointment, at your GP surgery and at home.  If caught early, high blood pressure can be monitored and treated, reducing your risk of a life-changing stroke.”

Dr Dipender Gill, NIHR Clinical Lecturer in Clinical Pharmacology and Therapeutics, St George’s, University of London, said:

“This a high-quality randomised controlled trial providing robust evidence that use of paracetamol over two weeks causes a small but meaningful increase in blood pressure in a white Scottish population with pre-existing hypertension.  The study was carefully designed to mitigate potential sources of bias or confounding.  Its findings highlight the importance of only taking paracetamol in cases where it is likely to offer meaningful benefit.

“However, many unknowns remain.  Firstly, it is not clear whether the observed increase in blood pressure would be sustained with longer term use of paracetamol.  Secondly, it is not known for certain whether any increase in blood pressure attributable to paracetamol use would lead to an increased risk of cardiovascular disease.  Thirdly, these findings may not apply to a population taking paracetamol for pain symptoms, particularly as pain itself often increases blood pressure, and paracetamol can reduce pain symptoms.  Fourthly, this study was performed in white Scottish patients with hypertension and it is not known whether the findings will also apply to other populations groups.

“Further work is now required to more clearly establish the potential harms that may result from injudicious use of paracetamol.”

‘Regular acetaminophen use and blood pressure in people with hypertension: The PATH-BP Trial’ by Iain M. MacIntyre et al. was published in Circulation at 19:00 UK time on Monday 7 February 2022.

Declared interests

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”

Dr Richard Francis: “No COIs to declare.”

Dr Dipender Gill: “I am an NIHR Clinical Lecturer in Clinical Pharmacology and Therapeutics, based at St George’s, University of London. I am employed part-time by Novo Nordisk, for activities unrelated to the topic of the current study.”