EDITORIAL Fifty years of : advancing pain and fever management

Overview ing removal of third molars, ibuprofen has been quantified to have a Number Needed to Treat (NNT; It is now 50 years since the first discovery by Dr an empirical method), which is dose-related and (now Professor) Stewart Adams (of the Pure ranges from about 1–3. A few more potent and Drug Company, , UK) of the pharmaco- longer half-life NSAIDs (e.g. ) may have logical effects of the non-steroidal anti-inflammatory smaller values for NNT of about 1–2, but for the drug (NSAID), ibuprofen, in a guinea pig model of majority of NSAIDs, ibuprofen is in the more potent skin inflammation. It is now over 40 years since this group and is more active than paracetamol. In other drug was introduced into clinical use at doses of pain models (sore throat, migraine and headache), 1800–2400 mg ⁄ d for the treatment of arthritic pain ibuprofen is relatively potent and effective at OTC and inflammation. Subsequently, the acceptance of doses, is comparable with other NSAIDs and possibly its relatively favourable safety profile led to approval more effective than paracetamol. by the UK authorities in 1983 and the US FDA in Spontaneous reports of adverse events and adverse Outline of the 1984 of low-dose ibuprofen (< 1200 mg ⁄ d) for non- drug reactions (ADRs) in long-term coxib compara- prescription over-the-counter (OTC) sale direct to tor mega-trials, as well as in epidemiological studies, historical the public. show that the risks of GI, hepato-renal and other development Historically, the development of ibuprofen by Dr rarer ADRs with ibuprofen is relatively low compared of ibuprofen Adams at Boots was based on the need to have a with other NSAIDs and coxibs. A limited risk of car- safer form of (a ‘super aspirin’), without the diovascular (CV) events has been reported in some, and its current gastro-intestinal (GI) effects of aspirin, and without but not all, studies but the risks are, in general, lower status the serious adverse effects of and than with some coxibs and . The possibility ; these being the principal anti-inflam- that ibuprofen may interfere with the anti-platelet matory agents available at the time. With particular effects of aspirin, although arguably of low grade or attention to the pharmacokinetics, GI effects and significance, has given rise to caution for its use in liver toxicity, ibuprofen was selected after an exten- patients who are at risk for CV conditions and take sive programme of drug screening. aspirin for preventing these conditions. Ibuprofen is now widely used in many countries, Ibuprofen has unique pharmacokinetics and fea- often as a first-line treatment for the relief of symp- tures, such as low plasma elimination half-life and toms of pain, inflammation and fever. The OTC for- lack of systemic accumulation, that account for the mulations are available in over 80 countries, with the relatively low overall toxicity of the drug in humans. prescription dosage being available in many other Ibuprofen also has a broad spectrum of action on countries. different inflammatory pathways, as well as inhibiting A large number of mega-trials in recent years have pathways of prostaglandin metabolism. This may not focussed on the clinical uses, safety and pharmaco- only be of considerable significance for the actions of logical properties of ibuprofen given at prescription ibuprofen in relation to controlling multiple path- level doses (< 2400 mg ⁄ d) compared with newer ways of inflammation, but also in relation to its rela- NSAIDs (including cyclo-oxygenase-2 selective inhib- tively low toxicity. itors [coxibs]). In many of these studies, ibuprofen Use of ibuprofen in paediatric populations has was used as the reference drug in view of its estab- shown that it has relatively few safety concerns, espe- lished safety and efficacy profile. These studies have cially in comparison with paracetamol, and is as shown that ibuprofen has comparable safety and effi- effective as a treatment of acute pain. In addition, it cacy with that of newer drugs in long-term usage is probably more effective than paracetamol as an (6 months or more). . At OTC doses (< 1200 mg ⁄ d) in adults, An immense number of investigations have also ibuprofen has a comparable safety profile with that been performed on the pharmacological and thera- of paracetamol. peutic activities of ibuprofen. Modern models of The anti-inflammatory activity of ibuprofen is assessing acute pain have been employed to show the linked to its analgesic effects. The analgesic activity quantitative effects of ibuprofen in comparison with at OTC doses or higher is related to reduction in the other NSAIDs and analgesics. In dental pain, follow- ex vivo production in blood of cyclo-oxygenase

ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 1–2 1 2 Editorials

(COX)-1 and COX-2 derived prostanoids. Moreover, nations of ibuprofen with anti-acid secretory com- both enantiomers of ibuprofen have been found to pounds are also being explored at present and might individually contribute to the broad basis of the be of benefit in reducing gastric irritation, although analgesic action of the drug. S(+)-ibuprofen inhibits this would represent a more expensive alternative both COX-1 and COX-2. The R()) isomer has little with the additional consideration of adverse reactions direct effect on both COX activities, except after from the anti-acid secretory agents (e.g. esomepraz- absorption when about 40–60% is metabolically con- ole, famotidine). verted to the actively inhibitory S(+) form. COX-1 Exciting observations have been reported over the inhibition by S(+)-ibuprofen in the stomach is years that ibuprofen might reduce the development masked by the R()) enantiomer, which can compete of some cancers, Alzheimer’s and Parkinson’s dis- with the S(+) enantiomer at the active site of the eases, as well as other neurodegenerative disorders. COX-1 enzyme. This along with unique physico- The widespread long-term use of ibuprofen by the chemical properties of ibuprofen combined with its public may lead to what could be described as ‘col- short plasma half-life may account for the apparent lateral benefits’ in reducing the incidence of these low incidence of GI ulcers and bleeding, particularly diseases in addition to the self or prescribed applica- at low OTC doses. The R()) enantiomer affects the tions for relief of pain and other inflammatory production of leucocyte-derived proteases and leuko- symptoms. It is remarkable that following the simple trienes and this may contribute to the spectrum of discovery of the anti-inflammatory effects of ibupro- anti-inflammatory activity of ibuprofen. fen half a century ago, remarkable therapeutic bene- Patients taking ibuprofen at OTC doses are at a fits have accrued over the years and more will relatively low risk of developing renal and associated doubtless develop in the future. CV events, although interactions with diuretics and antihypertensive agents can influence the develop- Disclosures ment of these adverse reactions. Serious adverse reac- tions are rare and most minor reactions are The author is a consultant and expert witness on the reversible upon cessation of the drug. OTC ibupro- safety of ibuprofen to Reckitt Benckiser and has also fen does not represent a risk for developing liver consulted on NSAIDs for other pharmaceutical com- injury, in contrast to the irreversible liver damage panies. The author does not hold any shares, stocks observed with paracetamol and the occasional liver or options, or any other financial instruments in any reactions caused by aspirin. pharmaceutical company. Thus, over the years, ibuprofen has withstood K. D. Rainsford PhD, FRCPath, FRCPEdin, FSB, FRSC, competition from newer NSAIDs and paracetamol CChem, CSci, FIBMS, Dr(hc), Emeritus Professor and commands a place in the mainstay of therapy Biomedical Research Centre, for pain and inflammation. The future for ibuprofen Sheffield Hallam University, may be in the development of new formulations and Sheffield, S11 WB, UK novel applications to meet specific needs for patients Tel.: + 44 114 225 3006 Fax: + 44 114 225 2020 with complex chronic diseases. For example, combi- Email: [email protected] nation with lecithin-type phospholipids may reduce the gastric reactions from OTC ibuprofen in the doi: 10.1111/ijcp.12050 stomach of elderly and other at-risk patients. Combi-

ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 1–2