How the discovery of ibuprofen helped pave the way for other NSAIDs

In our latest article on landmark drugs, Jenny Bryan looks at howibuprofen’s status as an anti-inflammatory drug has never beensuperseded

by Jenny Bryan

In our latest article on landmark drugs, Jenny Bryan looks at how ibuprofen’s status as an anti-inflammatory drug has never been superseded

 

Looking at the rows of branded and generic packs that now sit prominently on the shelves of every pharmacy, it is hard to believe that some of the first rheumatologists who tested ibuprofen raised doubts about its future as a treatment for rheumatoid  arthritis (RA) and osteoarthritis.

Short-term placebo-controlled studies of ibuprofen in doses of 600–900mg per day failed to demonstrate clinically significant improvement, the only positive finding being that ibuprofen had a placebo-like side effect profile.1

Fortunately, other studies showed that the drug compared favourably with aspirin2 — the gold standard treatment of the time — and the safety of ibuprofen proved a major strength.

So a research programme at the Boots Pure Drug Company Ltd that went back to the early 1950s was not in vain. The drug was duly marketed as Brufen in the UK in 1969 for the treatment of RA, in doses of 600mg–800mg per day.

In the same year, Ian Griffiths qualified as a doctor and remembers well the need for new anti-inflammatory drugs without the gastrointestinal side effects of aspirin and indometacin, and the additional blood dyscrasias associated with the other option, phenylbutazone.

“By the time that ibuprofen arrived, the pendulum had swung very much towards safety, and that was probably why ibuprofen was introduced at subtherapeutic doses. It was only later, when people could see how safe it was, that they started to use higher doses of ibuprofen and achieved the anti-inflammatory effects that we now take for granted,” explains Dr Griffiths, recently retired consultant rheumatologist at the Freeman Hospital, Newcastle upon Tyne.

A tortuous journey

Without the option of computer modelling and other modern techniques for identifying promising drug structures, the Boots researchers who developed ibuprofen initially looked for a “super aspirin” among the salicylates and phthalates.3

But, when these proved more toxic than aspirin, the team turned to the phenoxyalkanoic acids, which Boots had been investigating as herbicides.

Over 600 were screened before two promising candidates emerged in 1958 that were up to 10 times more potent than aspirin.3

However, even these proved not to have the necessary combination of analgesic, antipyretic and anti-inflammatory activity that researchers were looking for, and Boots moved on to a fourth group of compounds — the phenylalkanoic acids, which included the propionic acids.

Thinking that the propionic acids were likely to be too toxic, the research group first checked out the less potent phenylacetic acids only to find their initial compounds caused skin rashes, and their subsequent choice, ibufenac, which was briefly marketed in the UK in the mid 1960s, caused liver toxicity.3

Finally, it was the propionic acid derivative, ibuprofen, which proved to have the all-important combination of efficacy and safety that had been eluding Boots for nearly 15 years.

The “me too” years

With ibuprofen rapidly cornering a healthy share of the arthritis market, other major pharmaceutical companies developed their own non-steroidal anti-inflammatory drugs.

There were more propionic acid derivatives, including naproxen and ketoprofen, and plenty of unrelated drugs with similar anti-inflammatory properties, including diclofenac, mefenamic acid and piroxicam. NSAIDs fulfilled the criteria for “me too” drugs like few other groups.

“The efficacy of ibuprofen and the other NSAIDs was always greater for RA and ankylosing spondilitis because of the inflammatory component. Their efficacy in osteoarthritis was more contentious, with some studies showing that they were better than paracetamol, and some not,” recalls Dr Griffiths.

He explains that, during the 1960s, ’70s and early ’80s, when the NSAIDS had their heyday, the options for modifying the disease process in patients with rheumatoid disease were far more limited than they are today.

It was not until gold and penicillamine were superseded by methotrexate and, more recently, the biological therapies, that disease modifying treatments became a standard part of RA management.

From POM to P and OTC

During the 1970s and ’80s, ibuprofen continued to blaze the trail for other NSAIDs, expanding its indications to include migraine, dental pain and period pain and, in 1983, gained the ultimate accolade for safety, when its licence was extended to over-the-counter use, for which it was rebranded as Nurofen.

Development of topical formulations of ibuprofen for aches and sprains further reduced any lingering concerns about GI problems, and proved popular with patients.

Competition

Ibuprofen and the “me too” NSAIDs exert their anti-inflammatory action by blocking the cyclo-oxygenase (COX) enzymes 1 and 2, which are involved in prostaglandin synthesis. COX-2 is responsible for mediating synthesis of the inflammatory prostaglandins involved in RA.

But COX-1 has the potentially beneficial effect of promoting the synthesis of prostaglandins with protective effects on the lining of the stomach. So pharmaceutical research of the 1980s and ’90s started to focus on novel NSAIDs that could block COX-2, while leaving COX-1 unaffected.

The first COX-2 inhibitor, rofecoxib, was launched in 1999 and, as expected, was associated with a lower risk of GI problems than traditional NSAIDS. However, as few will be unaware, rofecoxib was withdrawn in 2004 after it emerged that the drug was associated with an increased risk of heart attacks and strokes.

Subsequent research has suggested that the effect is not unique to rofecoxib, but is true of other COX-2 inhibitors4 and some non-selective NSAIDS, such as ibuprofen and diclofenac,5,6 especially when they are used in high doses.6

There is also some evidence that naproxen is associated with a lower risk,4,6 although this has not been shown in all studies.5 The absolute vascular risk of NSAIDS appears to be small and has been estimated at  three to five per 1,000 patients per year for COX-2 inhibitors, depending on the level of compliance with treatment.6

Dr Griffiths explains that the vascular risk of non-selective NSAIDs probably went unrecognised for so many years because early studies often compared one NSAID with another, and OTC use of ibuprofen tended to involve short courses of treatment with low doses.

“Although the risk is undoubtedly small, it has helped to change the way we prescribe NSAIDs. At one time, people had repeat scripts for many years, but osteoarthritis patients are now encouraged to use paracetamol or NSAIDs for short periods just to relieve symptoms.

“Those with rheumatoid disease probably do need to take them for longer, but the growing use of methotrexate and biological therapies means that their disease is better controlled so they also have less need for NSAIDs,” he says.

In the 40 years that ibuprofen has been relieving pain and inflammation, the management of arthritis has come a long way and, as Dr Griffiths concludes, ibuprofen’s legacy is its longevity.

“It appeared at the dawn of a new age of safer anti-inflammatory drugs, especially in relation to the gut. The fact that it is still so widely used is evidence that patients find it to be very effective in relieving their symptoms and so it has never really been superseded.

“Naproxen has had a bit of a renaissance because of its possible lack of vascular effects, but ibuprofen is still right there in the mix.”

 

References

1. Boardman PL, Nuki G, Dudley Hart F. Ibuprofen in the treatment of rheumatoid arthritis and osteoarthritis. Annals of the Rheumatic Diseases 1967;26:560–1.

2. Chalmers TM. Clinical experience with ibuprofen in the treatment of rheumatoid arthritis. Annals of the Rheumatic Diseases 1969;28:513–7.

3. Rainsford KD. Ibuprofen: a critical bibliographic review. CRC Press; 1999.

4. Solomon DH, Avorn J, Stürmer T, Glynn RJ, Mogun H, Schneeweiss S. Cardiovascular outcomes in new users of coxibs and non-steroidal anti-inflammatory drugs: high-risk subgroups and time course of risk. Arthritis and Rheumatism 2006;54:1378–89.

5. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330:1366.

6. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302–8.

Citation: The Salvadore URI: 10670317

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  • The fact that ibuprofen is still so widely used is evidence that patients find it to be effective in relieving their symptoms and so it has never really been superseded (Martyn F. Chillmaid/Science Photo Library)

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