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.

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.

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.