Fifty years of ibuprofen: advancing pain and fever management

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