Paracetamol: widely used and largely ineffective

In this guest blog, Andrew Moore, who has authored over 200 systematic reviews, many on pain, lifts the lid on paracetamol. Effective and safe? We are challenged to think again…

People with pain have some very simple demands. They want the pain gone, and they want it gone now. A successful result is one where the pain is reduced by half or more, or where they have no or only mild pain. That result delivers not just on pain, but also improves sleep, depression, quality of life, work, and the ability to get on with life.

Young woman taking paracetamol in bathroom

Paracetamol – the ‘go-to’ painkiller but largely ineffective

For many years paracetamol has been the ‘go-to’ medicine for all sorts of acute and chronic pain conditions. NICE recommends it for back pain and osteoarthritis, and paracetamol or paracetamol/opioid combinations are among the most common medicines for treating neuropathic pain, including back pain with a neuropathic component. Primary care in England spent £87 million on paracetamol in 2015, much for chronic pain conditions – and that does not include equally large amounts for fixed-dose combinations of paracetamol and opioids.

So how does paracetamol stack up against what people with acute back pain want? A Cochrane review is unequivocal – it doesn’t work. Not immediately, not later. At no stage between one and 12 weeks is 4,000 mg daily any better than a placebo. Nor does the review find any evidence that it works in chronic back pain either. The results were heavily dependent on one impeccable, large, randomised trial that described average pain intensity dropping steadily with paracetamol or placebo from over 6/10 points (severe pain) at the start of the trial to 3.7 at week 1 (moderate pain), 2.6 by week 2 (mild pain), and then 1.2 by week 12 (mild pain).

It is really difficult when an almost ubiquitous practice (using paracetamol) meets a distinctly inconvenient truth (it doesn’t work). The high quality of the evidence cannot be challenged, so let’s have a quick look for evidence showing that paracetamol is effective in other chronic pain conditions. That’s where the trouble starts – in osteoarthritis, our most recent best evidence indicates a barely significant and tiny benefit of around 3/100 mm over placebo, and a ranking barely above placebo in a network meta-analysis. For chronic neuropathic pain an ongoing Cochrane review reveals a complete lack of any evidence for paracetamol at all. Paracetamol is without effect in cancer pain, and it is the poor relation in acute postoperative pain and migraine.

How safe is paracetamol?

That makes it time to start using our brains. We have probably given up thinking about paracetamol because it is over 50 years old, and we have it drummed into us that ‘at least it is safe’. Well the safety message may not be true either. Emerging evidence provides food for thought.

  • A systematic review of observational studies shows paracetamol is associated with increased mortality, cardiovascular adverse events (fatal or non-fatal myocardial infarction, stroke, or fatal coronary heart disease), gastrointestinal adverse events (ulcers and complications such as upper gastrointestinal haemorrhage), and renal impairment.
  • A national case-population study of non-overdose paracetamol exposure resulted in twice the rate of acute liver failure leading to registration for transplantation than NSAIDs.
  • A large randomised trial in chronic pain showed that patients taking paracetamol were four times more likely to have abnormal results on liver function tests than those taking placebo.
  • A large randomised study in arthritis showed similar adverse event rates for paracetamol and ibuprofen over three months.

The bottom line is that paracetamol doesn’t effectively relieve pain but has demonstrable rare but serious adverse events. If it were just a few tablets, then maybe we could ignore it, but it isn’t. Paracetamol consumption is measured not in kilograms, not even tons, but thousands of tons a year. Both public health and ethical questions are being ignored.

Where do we go from here?

It makes best sense to go to the fundamentals of what the evidence in pain tells us. We know:

  1. People in pain tend to have either a very good response to medication/treatment (more than 50% pain reduction) or little or none. Responses are not Gaussian, but U-shaped or all-or-nothing.
  2. When people have good pain relief they tend to have benefit in a range of accompanying symptoms. Their quality of life goes back to normal and they can work or look after themselves and family.
  3. Not many are so lucky with any single drug – success rates for chronic pain are well below 50%, typically 10% for chronic low back pain or fibromyalgia to 30% for osteoarthritis or painful diabetic neuropathy.
  4. Much evidence on efficacy is misleading. For opioids particularly, where withdrawal rates can be as high as 60% over 12 weeks, inappropriate handling of data from withdrawals indicates the drugs work when they probably do not. That is true for all opioids apart from tramadol and probably tapentadol. And spending on opioids dwarfs that of paracetamol.
  5. There is virtually no reliable evidence for any of the non-drug therapies.

Back to low back pain

There are no easy answers. We have very limited evidence on back pain. That makes it even more important that when solid evidence comes along – even if it is a solid negative as with paracetamol – we take it on the chin and move on. Too much in the past have we been like the ‘wise’ monkeys – unwilling to see, unwilling to hear, and unwilling to speak about obvious issues right under our noses. Time to look, listen, and open up a new conversation.

Other posts

How well do over-the-counter painkillers work?

Topical NSAIDs: good relief for acute musculoskeletal pain

Traditional opioids for chronic non-cancer pain: untidy, unsatisfactory, and probably unsuitable

Andrew Moore reports grants and personal fees from RB, grants and personal fees from Gruenenthal, personal fees from Menarini, grants and personal fees from Novartis, personal fees from Futura, personal fees from Omega,  outside the submitted work.

References can be found here.

Related Post


Andrew Moore

About Andrew Moore

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Andrew Moore was the founding editor of Bandolier, an evidence-based journal, in 1994. He has spent 40 years in biomedical research, with over 500 scientific and clinical publications, with contributions to writing systematic reviews and meta-analyses, as well as to methodological improvement. Andrew has written over 200 systematic reviews, many in pain, including around 100 Cochrane reviews. He is the author of a number of books on evidence based medicine and pain.

19 Comments on this post

  1. Thank you for this informative article on paracetamol. In your final paragraph you mention the lack of evidence of what works for low back pain. Are you aware of the ATEAM trial with the results published in the BMJ in 2008? This trial showed that Alexander Technique lessons offered a significant long-term benefit for sufferers of non-specific recurrent chronic low back pain. http://www.bmj.com/content/337/bmj.a884

    Brita Forsstrom / Reply
    • Andrew Moore

      Thank you Brita. That trial did not publish pain scores – days of pain – so uncertain as to how many patients had the high levels of pain relief we use for drug assessment (typically now at least 50% reduction in pain intensity over baseline) so hard to compare. But the QoL benefits were impressive.

      Andrew Moore / (in reply to Brita Forsstrom) Reply
  2. Hi

    Has any of these findings been published as a peer reviewed journal article and if so where would I best find it.

    Thanks

    Caillan kelly / Reply
    • Sarah Chapman

      Hi Caillan, yes indeed. If you go to the end of the blog and click the ‘references’ link it will take you to those used by Andrew Moore in this blog.

      Sarah Chapman / (in reply to Caillan kelly) Reply
  3. “The Truth that dare not speak its name” ( Its in all the guidelines but the patients say it doesn’t work)

    I’m a GP, Locum, Ex-Principal/ Partner with 25+yrs in UK Primary Care. I’ve prescribed a lot of paracetamol over the years. That was what we were taught, later that became incorporated into guidance. Guidance became incorporated into KIPs – Prescribing Performance Indicators aimed at reducing NSAIDs ( primarily Diclofenac). Prescribing of paracetamol increased (as presumably did incentives). Consultation rates increased ( returning patients due to lack of efficacy and overriding message from patients paracetamol doesn’t work, Diclofenac does) The result of that consultation was probably a prescription for Ibuprofen, with a further follow -up with the patient reporting some effect, but not as good as diclofenac, Choice then was either to prescribe diclofenac, after discussion on cardiac, renal and GI side effects,and presumed “informed” decision, with or without a PPI, and accept negative performance implications on prescribing quality. Mentally rationalise and accept this uncomfortable position by considering this as a patient anecdote,and trust the level of similar anecdotes does not reach say 20% of denominator to impact quality target.

    This was a regularly repeating anecdote played out over many consultations. Like most anecdotal evidence we are taught not to pay much heed to it ( unless its an ADR,type anecdote in which case, record all details and file yellow card report promptly). It has always surprised me why we have such different views to patient reported anecdotes depending on whether they are positive or adverse events. Countless hours were spent auditing prescribing data aimed at reviewing repeat prescriptions for NSAIDS and replacing them with paracetamol. This could generate three appointments ( or more time consuming home visits) per patient, two of which could be considered unnecessary, two unnecessary unused prescriptions for paracetamol and ibuprofen. Your blog has confirmed what patients had been telling us ( and what most GPs who listened to their patients actually knew, “the truth that dare not speak its name”).

    To risk committing another cardinal sin and quote from Wikipedia, Paracetamol’s use as an anti-pyretic in children is said to be less effective than ibuprofen, and it quotes WHO guidance that it should only be given to a child when a fever is over 38.5 degrees C. Yet paracetamol syrup “Calpol” remains the most prescribed, and over the counter medication for children.

    Few regular clinicians know a much about glutathione, yet it is one of the most discussed molecules in the field of functional and integrative medicine where many practitioners see this as the key intra-cellular anti-oxidant, responsibe for protecting the cell and the mitochondria from oxidative stress and damage from free radicals. Levels of glutathione decrease as we age, and there are practitioners that advocate that the level of glutathione is predictive of morbidity and mortality. Most paracetamol is eliminated by glucuronidation in the liver but a small fraction is oxidised (5%) by CYP450 enzymes to the highly reactive NAPQI metabolite which is hepatotoxic and exhibits mitochondrial toxicity. This metabolite is reduced by Gluathione,and excreted in the urine. This reaction is what forms the basis of the iv N-Acetyl-Cysteine ( NAC) rescue given in A&E for paracetamol overdose. The depletion of glutathione is reversed by giving NAC.

    By prescribing paracetamol as an ineffective pain treatment we seem to be turning a blind eye to the small, but constant and repeated amount of harm we are causing both by producing a toxic metabolite and by reducing the body’s natural defence against oxidative stress, Glutathione. The otherwise unexplained increase in cardiovascular and all cause mortality seen with paracetamol may possibly be explained by this mechanism.

    “Primum non nocere”. First do no harm, the guiding principle of bioethics, does not seem to have been applied to one of the most commonly prescribed prescription medicines. You are absolutely correct when you say public health and ethical messages are being ignored. This may well be explained by the ‘at least it’s safe’ message that you rightly describe as being drummed into us. If anything is to change we need to hear the message and try to act on it. We have ignored the patient message telling us it is ineffective, conveniently dismissing this as anecdotes, until finally and uncomfortably being presented with the same message draped in evidence that we have placed at the top of the hierarchy of credibility.

    There may be lots of reasons why we may not want to hear this message. Doctors state they feel they are under immense pressure to prescribe, and it is even more difficult when the presenting problem is pain. We don’t have any completely safe and effective remedies for pain. The rug has been pulled from under all of them. Each case is a delicate individual balancing act between pain relief and causing harm. This sobering message has not reached the public consciousness, with most patients believing that ‘in this day and age’ there must be a safe solution, and if one doctor can not provide it, there must be one that can. The temptation to keep prescribing something different is very strong, and fuelled by the patient’s consumer driven belief that medicine must have an answer. Admitting inability to know how to help, rather than prescribing something unlikely to help, but likely to harm, is harshly judged by patients and their relatives ( any doctor who has tried it will have ample anecdotal evidence to support that, sometimes subsequently logged officially in the files of the patients complaints department)

    Patients may be right, there may be effective, and less harmful remedies for certain types of pain. Some foods and supplements, such as turmeric are potential candidates but as foods they are never going to produce the level of evidence we set as the standard we accept, which is an effective barrier to even a discussion about the use of these agents.. ‘In this day and age’ to produce the evidence required for formal acceptance as a medication for treatment, funding needs to be found to support an RCT and where no sponsor can be found, there is not likely to me much evidence. Unless public funded or charitable bodies sponsor research that produces evidence for nutritional, herbal or traditional remedies, the lack of potential profit will ensure a lack of commercial interest and hence a lack of suitable evidence. ‘Lack of evidence’, so often quoted as an ‘end of topic discussion’ phrase by experts is another way of saying lack of apparent commercial interest in this subject.

    As a locum doctor, working in other doctors practices filling in for colleagues and reviewing their patients and their medications I often become aware of ‘quirks’ in prescribing. Sometimes a discussion with a permanent colleague reveals a long tale that explains these quirks and the extraordinary lengths colleagues have gone to, to work with their patients to find solutions to their problems. Sometimes the explanation is less clear and some changes need to be broached. Time ultimately limits any intervention, and balancing this with the needs of other patients in the waiting room means it is only possible to do so much but listening to the patient and working from the principle ‘first do no harm’ brings a focus to every individual and complicated situation.

    Increasingly as knowledge advances we are seeing 180 degree shifts in our practice. This inevitably causes uncertainty and discomfort for doctors and patients. The low fat diet for weight reduction being a current example where knowledge and practice are not yet aligned. The message that we were taught about paracetamol ‘at least it is safe’ is facing a 180 degree shift. Not only are we having to face this uncomfortable truth but the search for a replacement is also fraught with problems and there is no let up in the patient expectation of a safe solution.

    Chris Jenkins / Reply
  4. […] Suffering from back pain, headache, fever or cold? The pill of choice is usually paracetamol. The drug was introduced into the market in 1956, and GPs issue a staggering 22.9m prescriptions for paracetamol every year. So it’s disconcerting to read that it’s largely ineffective, according to a blog on Evidently Cochrane. […]

  5. We also analysed a lot of studies. And our analyses say that paracetamol works well for fever.. http://www.tas-ev.org
    Read it if you want..

    Helene Schönewolf / Reply
  6. The large GERAC studies seemed to indicate that accupuncture as well as pseudo-accupuncture work for chronic lower back pain. What’s your opinion on these treatments?

    Ulrich Berger / Reply
  7. […] Available at http://www.evidentlycochrane.net/paracetamol-widely-used-ineffective/ […]

  8. […] Evidently Cochrane: Paracetamol: widely used and largely ineffective […]

  9. […] 1、NICE publishes updated advice on treating low back pain 2、Paracetamol: Widely used and largely ineffective 3、Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and […]

  10. I use paracetamol for hip pain, degeneration, and have done for the last six weeks. Generally 2 tablets twice per and along with ibuprofen.
    I find it effective!

    How long can I continue this medication without causing damage to liver or kidney?

    Thank you

    Gordon McCready

    Gordon McCready / Reply
    • Sarah Chapman

      Good to hear you have found effective pain relief! We can’t comment on individual clinical matters but your GP or pharmacist would no doubt be happy to discuss this with you.
      Sarah Chapman (Editor)

      Sarah Chapman / (in reply to Gordon McCready) Reply
  11. b.sutton26@icloud.com. 90 year old requiring surgery for replacement knee taking Paracetemol occasional codene to relieve pain for osteoarthritis living alone suffering high level of pain, after care problem putting off operation. What should I do?

    Harold Sutton / Reply
    • Sarah Chapman

      I’m afraid we can’t offer advice on individual cases, but I hope discussing this with your GP or pharmacist will help.
      Sarah (Editor)

      Sarah Chapman / (in reply to Harold Sutton) Reply
  12. I have never even thought of paracetamol for anything other than a headache or a fever. The only over the counter pain reliever that helps me with chronic (not acute) pain is ibuprofen. At age 62 I probably would not be able to play golf without it. I understand there are risks. The decision is based on being able to do something I love with regularity.

    Nick / Reply
  13. So, if paracetamol doesn’t work for osteoarthritis, what do you suggest? That’s half a story!

    Glenys / Reply

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