In this guest blog, Andrew Moore, who has authored over 200 systematic reviewsIn systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research., 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.

For many years paracetamol has been the ‘go-to’ medicine for all sorts of acuteA health condition (or episodes of a health condition) that comes on quickly and is short-lived. and chronicA health condition marked by long duration, by frequent recurrence over a long time, and often by slowly progressing seriousness. For example, rheumatoid arthritis. 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 placeboAn intervention that appears to be the same as that which is being assessed but does not have the active component. For example, a placebo could be a tablet made of sugar, compared with a tablet containing a medicine.. 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 trialA trial in which the people taking part are randomly divided into groups. A group (the intervention group) is given the intervention being tested (for example a drug, surgery, or exercise) and compared with a group which does not receive the intervention (the control group). that described average pain intensity dropping steadily with paracetamol or placebo from over 6/10 points (severe pain) at the start of the trialClinical trials are research studies involving people who use healthcare services. They often compare a new or different treatment with the best treatment currently available. This is to test whether the new or different treatment is safe, effective and any better than what is currently used. No matter how promising a new treatment may appear during tests in a laboratory, it must go through clinical trials before its benefits and risks can really be known. 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 evidenceThe certainty (or quality) of evidence is the extent to which we can be confident that what the research tells us about a particular treatment effect is likely to be accurate. Concerns about factors such as bias can reduce the certainty of the evidence. Evidence may be of high certainty; moderate certainty; low certainty or very-low certainty. Cochrane has adopted the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) for assessing certainty (or quality) of evidence. Find out more here: https://training.cochrane.org/grade-approach 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-analysisThe use of statistical techniques in a systematic review to combine the results of included studies. Sometimes misused as a synonym for systematic reviews, where the review includes a meta-analysis. . For chronic neuropathic pain an ongoing Cochrane reviewCochrane Reviews are systematic reviews. In systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research. 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 safetyRefers to serious adverse effects, such as those that threaten life, require or prolong hospitalization, result in permanent disability, or cause birth defects. message may not be true either. Emerging evidence provides food for thought.

A systematic review of observational studies A study in which the researchers look at what happens over time to groups of people. They study changes or differences in one characteristic (e.g. whether or not people smoke) in relation to changes or differences in another characteristic (e.g. whether or not they get cancer). shows paracetamol is associated with increased mortality death , 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.

shows paracetamol is associated with increased , 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 An investigation of a healthcare problem. There are different types of studies used to answer research questions, for example randomised controlled trials or observational studies. of non-overdose paracetamol exposure resulted in twice the rate The speed or frequency of occurrence of an event, usually expressed with respect to time. For instance, a mortality rate might be the number of deaths per year, per 100,000 people. of acute liver failure leading to registration for transplantation than NSAIDs.

of non-overdose paracetamol exposure resulted in twice the of acute liver failure leading to registration for transplantation than NSAIDs. A large randomised Randomization is the process of randomly dividing into groups the people taking part in a trial. One group (the intervention group) will be given the intervention being tested (for example a drug, surgery, or exercise) and compared with a group which does not receive the intervention (the control group). 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.

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 A harmful or abnormal outcome, for example death or vomiting, that occurs during or after the use of a drug or other intervention (e.g. surgery or exercise) but has not necessarily been caused by that intervention. 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:

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. 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. 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. Much evidence on efficacy The extent to which an intervention (for example a drug, surgery, or exercise), produces a beneficial result under ideal conditions. is misleading. For opioids particularly, where withdrawal rates can be as high as 60% over 12 weeks, inappropriate handling of data Data is the information collected through research. 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. 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.

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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.