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Science
Adrian

Everyday Painkillers: What are NSAIDs?

Your Everyday Painkillers

Aspirin, paracetamol, ibuprofen and diclofenac: despite the different packaging and multiple combinations, almost all our over-the-counter painkillers involve one of these four drugs. They have been around a long time. Aspirin and paracetamol were discovered in the 19th century while ibuprofen and diclofenac were discovered in the 1960s. Diclofenac – brand names “Voltaren” or “Voltarol” – and Ibuprofen – “Nurofen” or “Ibuleve” – are both available in topical form for the alleviation of pain.

Collectively these are known as non-steroidal anti-inflammatory drugs, or NSAIDs, and they have almost identical modes of action: they inhibit the action of the enzyme cyclooxygenase, which would otherwise promote inflammation when a pain signal is triggered. Noteworthy then: none of these actually prevent the pain; they act only after-the-fact and only on the inflammation.

COX-1 and COX-2 Side Effects

Cyclooxygenase is a molecule which comes in two isoforms, that is to say mirror-images of each other: COX-1 and COX-2. Each of these NSAIDs acts on these isoforms in different proportions. Aspirin and paracetamol act more on COX-1 while ibuprofen and diclofenac act more on COX-2. As a side effect to some extent they all impair healing and delay recovery and they vary in efficacy depending on the location and type of inflammation. The greatest contrast between them is not in their efficacy but in their other side effects.

COX-1 inhibitors affect the alimentary system (the digestive tract). Paracetamol is heavily implicated in liver damage while aspirin can cause ulcers and bleeding in the stomach. Aspirin does however prevent blood clots so small doses are a preventative for heart attacks, which is ironic because the COX-2 inhibitors instead cause blood clots and heart attacks. 

The discovery of this side effect came only after thirty years of widespread use; in 2005 the FDA flagged an increased heart attack risk with ibuprofen and diclofenac. The conduct of the drug companies in the circumstances of this discovery came in for withering criticism in Ben Goldacre’s “Bad Pharma”.

In 2013 definitive research established that any use of diclofenac increased the risk of a heart attack by a third and as a consequence oral diclofenac became prescription-only in 2015, some forty years after it was introduced to the general public as a non-prescription solution to pain. In 2018 diclofenac became implicated in both heart attacks and stomach bleeding with the recommendation that it only be prescribed only as a last resort. You may have noticed increased promotion of Voltarol gel – this is why. Novartis are determined not to abandon such a valuable brand.

Disappointing Efficacy for NSAIDs

The increased awareness of side effects can sometimes be compensated by an increasing appreciation of pain-killing efficacy but for diclofenac the reverse is true. For the “gold standard” of medical research one usually turns to a Cochrane Report, which exhaustively reviews all of research to reach a state-of-the-art conclusion. It is the so-called “gold standard” of medical research and in 2017 it published two reviews of topical analgesics.

The broader “Topical analgesics for acute and chronic pain in adults” covered 206 studies and 30,700 patients. The conclusions were:

There is good evidence that some formulations of topical diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains…In chronic musculoskeletal conditions with assessments over 6 to 12 weeks, topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis.

Cochrane Database Syst Rev. 2017 May 12;5:CD008609. doi: 10.1002/14651858.CD008609.pub2

The efficacy for acute (high-inflammation) pain was good, so applying Voltarol gel will damp down a swollen ankle but the efficacy for chronic (low-inflammation) pain is limited.

Drilling deeper into NSAIDs in their companion review “Topical NSAIDs for chronic musculoskeletal pain in adults”, which covered 39 studies and 10,361 patients, the authors put numbers on their efficacy:

Topical diclofenac and topical ketoprofen can provide good levels of pain relief in osteoarthritis, but only for about 10% more people than get this result with topical placebo. There is no evidence for other chronic painful conditions.

Cochrane Database Syst Rev. 2016 Apr 22;4:CD007400. doi: 10.1002/14651858.CD007400.pub3

They also poured cold water on any other forms of topical treatment:

There is no good evidence to support any other topical painkiller in any other painful condition.

Cochrane Database Syst Rev. 2016 Apr 22;4:CD007400. doi: 10.1002/14651858.CD007400.pub3

Chronic Pain Needs a New Approach

For over a century NSAIDs have been the only form of painkiller available without prescription but we do seem to have reached the end of the road for this approach. There is an increasing awareness of side-effects and their unsuitability for long-term usage which for long-term chronic pain sufferers is a serious problem, now amplified by the realisation of their very limited efficacy.

It is no surprise therefore that in the past decade opioids, lacking any warning of addiction, have become the treatment of choice for many sufferers. They most certainly work – they quite simply block pain signals reaching the brain – but at a terrible cost to the individual and society as a whole. Another way has to be found.

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