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A brief history of ibuprofen

pharmaceutical-journal.com /news-and-analysis/infographics/a-brief-history-of-ibuprofen/20203273.article

The Pharmaceutical Journal 27 JUL 2017 By Dawn


Connelly

This timeline traces the history of popular anti-inflammatory drug ibuprofen, from its invention in the 1960s to its
association with cardiac side effects.

View the full infographic here


1953

Pharmacist and pharmacologist Stewart Adams (pictured) and chemist John Nicholson, employed at Boots
Pure Drug Company Ltd, begin work to identify an analogue of aspirin that might be suitable for long-term use
for rheumatoid arthritis

Source: Boots UK

1961

After screening more than 600 candidates, Adams and Nicholson file a patent for the compound 2-(4-
isobutylphenyl) propionic acid, later to be called ibuprofen; it is granted the following year

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1966

Clinical trials of ibuprofen take place in Edinburgh in six patients with rheumatoid arthritis

1969

Ibuprofen is launched in the UK for treatment of rheumatic diseases and marketed as prescription medicine
Brufen at a dose of 600800mg per day
Ibuprofen compares favourably with gold standard treatment for rheumatoid arthritis, aspirin, but with a better
gastrointestinal side-effect profile[1]

Early 1970s

Brufen tablets are granted a product licence of right by the Medicines and Healthcare products Regulatory
Agency (MHRA) following the introduction of a licensing system in 1971

Source: Museum of the Royal Pharmaceutical Society

1979

Additional indications for ibuprofen are added to the datasheet in the UK, including non-articular rheumatic
conditions, periarticular conditions and soft tissue injuries

1981

Mild to moderate pain is added as an indication for ibuprofen in the UK

1983

Ibuprofen is approved as an over-the-counter (OTC) medicine in the UK at a maximum daily dose of 1,200mg
and launched as Nurofen
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1985

Boots worldwide patent for ibuprofen expires and generic products are launched
Boots receives the Queens Award for Technological Achievement for discovering ibuprofen, and by this time
more than 100 million people in 120 countries have received ibuprofen

1995

A randomised, double-blind, placebo-controlled trial reveals that high doses of ibuprofen (mean dose
25mg/kg) slow lung disease in patients with cystic fibrosis by inhibiting release of lysosomal enzymes and the
migration, adherence, swelling and aggregation of neutrophils[2]

Source: Shutterstock.com

1996

Ibuprofen is switched to general sale list (GSL) status, meaning it can be sold in general retail outlets without
the supervision of a pharmacist

2005

An observational study involving 114,000 women suggests that long-term (>5 years) daily use of ibuprofen is
associated with a 51% higher risk of breast cancer[3]. Information on dose was not collected

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Source: Shutterstock.com

An epidemiological study suggests that regular use of ibuprofen lowers the risk of Parkinsons disease
(PD)[4]. A Cochrane review in 2011 also shows that ibuprofen may reduce the risk of PD but says many
questions remain before its potential use[5]

2006

Following a review of new thrombotic cardiovascular safety data, the European Medicines Agency (EMA)
concludes that non-selective non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with a small
increase in the absolute risk for thrombotic events, especially when used at high doses (>2,400mg for
ibuprofen) for long-term treatment. However, the overall benefitrisk balance remains favourable

2008

An observational study suggests that use of ibuprofen for more than 5 years is associated with a 44%
reduction in risk of developing Alzheimers disease[6]

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Source: Shutterstock.com

2014

A systematic review finds that fast-acting formulations of ibuprofen demonstrate more rapid absorption, faster
initial pain reduction, good overall analgesia in more patients at the same dose, and probably longer-lasting
analgesia, but with no higher rate of patients reporting adverse events[7]
The MHRA asks the EMA (pictured) to review the safety of ibuprofen. The following year, the EMA confirms
that high doses (>2,400mg per day) of ibuprofen carry a small increased risk of cardiovascular diseases, such
as heart attack and stroke. No increase is seen at OTC doses (up to 1,200mg)

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Source: Shutterstock.com

2016

The advertising watchdog bans a UK TV advertisement for Nurofen because it falsely claims that the product
can specifically target joint and back pain. Nurofen products marketed for specific types of pain were removed
from sale in Australia in 2015 because they misled consumers
In laboratory and animal studies, researchers at Imperial College London find that ibuprofen arginine (not
licensed in the UK but available elsewhere) could protect from adverse cardiovascular effects by preserving
the nitric oxide pathway, as well as being released into the bloodstream more quickly than standard
ibuprofen[8]
Current use of ibuprofen or other NSAIDs is linked to a 19% increased risk of hospital admission for heart
failure, an observational study of more than 8 million NSAID users in four countries, finds[9]. The authors say
that although the study focused only on prescription NSAIDs, the findings might apply to NSAIDs obtained
over the counter as well
Based on prescription data, ibuprofen is linked to a 31% increase in risk of out-of-hospital cardiac arrest in an
observational study of nearly 30,000 patients. No information on OTC use was available[10]

2017

An observational study suggests that taking ibuprofen (and other NSAIDs) during a cold or flu infection
increases risk of heart attack by 3.3 times for high dose and 3 times for low-dose preparations[11]
A systematic review finds that ibuprofen and other NSAIDs do not provide clinically important effects for back
pain over placebo[12]

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Source: Shutterstock.com

Ibuprofen at doses >1,200mg daily, along with other NSAIDs, increases risk of myocardial infarction,
especially within the first month, according to an analysis of data from nearly 450,000 patients[13]

References:
Sources: Medicines and Healthcare products Regulatory Agency (MHRA); European Medicines Agency (EMA).

Editorial advisers: Roger Knaggs, associate professor in clinical pharmacy practice, University of Nottingham;
Emily Rose-Parfitt, rheumatology specialist pharmacist, North Bristol NHS Trust.
[1] Chalmers TM. Clinical experience with ibuprofen in the treatment of rheumatoid arthritis. Ann Rheum Dis
1969;28:513. PMCID: PMC1031238
[2] Konstan M, Byard P, Hoppel C et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med
1995;332:848854. doi: 10.1056/NEJM199503303321303
[3] Marshall SF, Bernstein L, Anton-Culver H et al. Nonsteroidal anti-inflammatory drug use and breast cancer risk by
stage and hormone receptor status. J Natl Cancer Inst 2005;97:805812. doi: 10.1093/jnci/dji140
[4] Chen H, Jacobs E, Schwarzschild M et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinsons
disease. Ann Neurol 2005;58:963967. doi: 10.1002/ana.20682
[5] Rees K, Stowe R, Patel S et al. Non-steroidal anti-inflammatory drugs as disease-modifying agents for
Parkinsons disease: evidence from observational studies. Cochrane Database Syst Rev 2011;Nov 9;
(11):CD008454. doi: 10.1002/14651858.CD008454.pub2
[6] Vlad SC, Miller DR, Kowall NW et al. Protective effects of NSAIDs on the development of Alzheimer disease.

Neurology 2008;70:16721677. doi: 10.1212/01.wnl.0000311269.57716.63

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[7] Moore RA, Derry S, Straube S et al. Faster, higher, stronger? Evidence for formulation and efficacy for ibuprofen

in acute pain. Pain 2014;155:1421. doi: 10.1016/j.pain.2013.08.013


[8] Kirkby NS, Tesfai A, Ahmetaj-Shala B et al. Ibuprofen arginate retains eNOS substrate activity and reverses

endothelial dysfunction: implications for the COX-2/ADMA axis. FASEB J 2016;30:41724179.


doi: 10.1096/fj.201600647R
[9] Arf A, Scotti L, Varas-Lorenzo C et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four
European countries: nested case-control study. BMJ 2016;354:i4857. doi: 10.1136/bmj.i4857
[10] Sondergaard K, Weeke P, Wissenberg M et al. Non-steroidal anti-inflammatory drug use is associated with
increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. Eur Heart J Cardiovasc
Pharmacother 2017;356:100107. doi: 10.1093/ehjcvp/pvw041
[11] Wen YC, Hsiao FY, Chan KA et al. Acute Respiratory Infection and Use of Nonsteroidal Anti-Inflammatory Drugs
on Risk of Acute Myocardial Infarction: A Nationwide Case-Crossover Study. J Infect Dis 2017;215:503509.
doi: 10.1093/infdis/jiw603
[12] Machado GC, Maher CG, Ferreira PH et al. Non-steroidal anti-inflammatory drugs for spinal pain: a systematic

review and meta-analysis. Ann Rheum Dis 2017;76:12691278. doi: 10.1136/annrheumdis-2016-210597


[13] Bally M, Dendukuri N, Rich B et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian
meta-analysis of individual patient data. BMJ 2017;357:j1909. doi: 10.1136/bmj.j1909

Citation: The Pharmaceutical Journal, PJ July 2017 online, online | DOI: 10.1211/PJ.2017.20203273

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