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Ibuprofen: a journey from prescription to over-the-counter use


Nicholas Moore
J R Soc Med 2007;100(Suppl. 48):26

SUMMARY

NSAIDS: MECHANISM OF ACTION

Ibuprofen was the rst non-aspirin non-steroidal antiinammatory drug (NSAID) to be approved for over-thecounter (OTC) use and is widely considered to be the best tolerated drug of its class. Low-dose, OTC ibuprofen has been used for pain relief for over 30 years without any obvious major health issues. However, there is no clear differentiation between the OTC and prescription doses of ibuprofen, and their respective effects. Adverse reactions to ibuprofen appear to be dose and duration dependent, and this may be the reason for the observed tolerability of the drug at OTC doses. OTC ibuprofen is at least as effective as aspirin and more effective than paracetamol. The tolerability concerns associated with higher dose NSAIDs currently do not apply to low-dose, short-term use of ibuprofen for common pain. Ibuprofen is associated with the least risk of GI complications compared with other NSAIDs and is considered relatively benign in overdose. This review will aim to distinguish the safety of OTC or non-prescription use of ibuprofen from its prescription use.

INTRODUCTION

NSAIDs act on the COX system by blocking the COX receptors. All NSAIDs differ widely in their pharmacological proles; there are nine heterogeneous chemical classes of NSAIDs. Even within an individual class such as the propionic acid derivatives, the potency of COX inhibition varies, which has a direct effect on the safety prole of individual NSAIDs.1 Yet it is commonly and mistakenly thought that all NSAIDs pose a comparable risk to the GI tract.1 The safety prole of the NSAIDs is in fact related to the duration and intensity of COX (particularly COX-1) inhibition, i.e. pharmacological potency, and to pharmacokinetic parameters such as elimination half-life or tissue distribution, and therefore to dose and duration of treatment. NSAIDs generally require a higher dose to achieve maximum anti-inammatory action than to achieve analgesic action.2 For example, 200 to 600 mg of ibuprofen four times per day or 800 mg three times per day may be required for an analgesic effect, but 2400 to 3200 mg per day may be needed for an anti-inammatory effect.3 A meta-analysis determined that recommended and higherthan-recommended single doses of NSAIDs produced comparable changes in pain scores, indicating a ceiling dose effect for analgesia.4
IBUPROFENAN OVERVIEW

There has been some concern among the regulatory authorities about the cardiovascular safety of selective cyclooxygenase (COX) 2 inhibitors, which resulted in the withdrawal of rofecoxib. Since then, the safety of nonselective non-steroidal anti-inammatory drugs (NSAIDs), such as ibuprofen, has been re-examined in relation to cardiovascular and gastrointestinal (GI) tolerability and skin reactions. The availability and widespread use of over-the-counter (OTC) ibuprofen has raised concerns that need to be addressed. This paper provides a comprehensive overview of OTC and prescription doses of ibuprofen, their key safety considerations, and efcacy and safety compared with other common OTC analgesics.
Professeur de Pharmacologie Clinique, Chef de Service, Departement de Pharmacologie, CHU de Bordeaux - Universite Victor Segalen - INSERM U657 Case 36, 33076 Bordeaux Cedex, France

Email: nicholas.moore@pharmaco.u-bordeaux2.fr

Ibuprofen, a propionic acid derivative, was rst synthesized in December 1961. In 1969, Boots launched ibuprofen in the UK as a treatment for rheumatoid arthritis under the brand name Brufen. Ibuprofens safety record remained good and in 1983 it became one of the rst prescriptiononly drugs, and the rst prescription NSAID, to be approved for OTC use as an analgesic/antipyretic, under the brand name Nurofen in the UK, followed in 1984 by Advil in the USA. Ibuprofen is approved for OTC use at a single dose of 200 mg, up to a maximum of 1200 mg per day. The recommended prescription dose is 1200 to 3600 mg per day. Ibuprofen is a well accepted treatment for postoperative pain, arthritis, injuries and the aches and pains of febrile illnesses,5 and is the best tolerated NSAID at low doses.6 However, even at prescribed and presumably equipotent

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doses, ibuprofen seems to be associated with a lower risk of GI complications compared with most other NSAIDs.1,7,8
EFFICACY AND SAFETY PROFILE OF OTC IBUPROFEN

Ibuprofen has been studied in numerous clinical analgesic trials that have encompassed a wide variety of pain conditions in order to evaluate the OTC dosage regimen and its safety prole. Although ibuprofen is generally prescribed in relatively low doses, it is perceived by patients as being as effective as other NSAIDs used, even after allowing for the severity of their pre-treatment condition.9 There is a clear relationship between single doses of ibuprofen, over the range 50 400 mg, and the peak analgesic effect and the duration of analgesia. Ibuprofen 400 mg has been shown to be as effective as aspirin 600 or 900 mg/day in models of moderate pain and superior to aspirin or paracetamol in more sensitive models such as dental pain. The duration of action of ibuprofen 400 mg is at least 6 hours, compared with 46 hours for ibuprofen 200 mg or paracetamol. In patients undergoing oral surgery, ibuprofen 200 mg is comparable with naproxen 220 mg, and ibuprofen 400 mg is comparable with ketoprofen 25 mg.10 Low-dose ibuprofen is as effective as aspirin and more effective than paracetamol,11 and the incidence of GI adverse events associated with ibuprofen has been shown to be similar to that of paracetamol.12,13 Indeed, in a study by Moore et al. (1999), ibuprofen was shown to have a better adverse effects prole than other OTC analgesics. The PAIN (Paracetamol, Aspirin, Ibuprofen New tolerability) study was a blinded, randomized comparison of the tolerability of OTC analgesics in the treatment of common types of acute pain encountered in the community.14 A total of 8677 adults were randomized to treatment with ibuprofen 1200 mg/day, paracetamol 3 g/day or aspirin 3 g/day for 17 days. The most common indications for treatment were musculoskeletal conditions (3133%), colds or u (1920%), backache (1517%), sore throat (1112%) and headache (1011%). Rates of signicant adverse events were: aspirin 18.7%, ibuprofen 13.7% and paracetamol 14.5%. Ibuprofen was statistically equivalent to paracetamol, and both were signicantly better tolerated than aspirin (P50.001). Total GI events (including dyspepsia) and abdominal pain were less frequent with ibuprofen (4 and 2.8%, respectively) than with paracetamol (5.3 and 3.9%, respectively) or aspirin (7.1 and 6.8%, respectively; all P50.035). There were six reported events of non-serious GI bleeding, four with paracetamol and two with aspirin, and one event of peptic ulcer with aspirin. There were no cases of cardiovascular events. The risk factors for signicant adverse events, in addition to the

analgesic, were female gender (multivariate odds ratio [OR] 1.26; 95% condence interval [CI] 1.121.43); indicationfor example, compared to indication for osteoarticular pain, indication for menstrual pain(OR 0.38, 95% CI 0.220.71); concomitant contraindicated medicines (OR 2.16; 95% CI 1.62.93); number of concomitant medications greater than three (OR 2.72; 95% CI 2.09 3.53); and previous GI history (OR 1.35; 95% CI 1.04 1.76). The representativeness of patients in the PAIN study has been questioned on theoretical bases.15,16 Many studies show that these patients are not different from users of ibuprofen or other OTC NSAIDs1726 and that the main results of the PAIN study, that of equivalent tolerability or risk of ibuprofen and paracetamol, were conrmed by two other studies; the rst a study in 84,000 paediatric patients,27 the second a large epidemiological study of GI bleeding in high-risk patients using OTC analgesics for a prolonged duration.13 In a prospective trial of 1257 healthy volunteers taking the maximum permitted OTC dose of ibuprofen (1200 mg/ day for 10 days) there was no signicant difference in the incident of adverse GI events (placebo 16% versus ibuprofen 19%; P=0.187).1 The PAIN study28 compared the proportion of GI adverse events in those patients assigned to paracetamol, aspirin or ibuprofen. The analysis showed that the GI tolerability of ibuprofen, at OTC doses of up to 1200 mg daily for up to 7 days, was at least as good as that of paracetamol and signicantly better than aspirin. Nephrotoxicity associated with ibuprofen is also doseand duration-related, and generally reversible.29 Renal failure is more likely in elderly patients on diuretics, although studies have shown the lack of effect on renal function of OTC doses of ibuprofen.30 A case-control study by Grifn et al. in elderly patients showed a clear doseresponse for the risk of renal failure with ibuprofen.31 At doses 41200 mg/day (the recommended OTC dose), there was no increased risk of renal failure (OR 0.94; 95% CI 0.581.51). In summary, ibuprofen at low doses is at least as effective as aspirin and more effective than paracetamol. It is at least as well tolerated as paracetamol and signicantly better tolerated than aspirin. In terms of non-serious GI side effects such as dyspepsia, ibuprofen at low doses is signicantly better tolerated than either aspirin or paracetamol.
EFFICACY AND SAFETY PROFILE OF PRESCRIPTION IBUPROFEN

Typically, prescription ibuprofen is used for chronic conditions such as arthritis, which require longer-term management and regular medical attention. This is discussed further later in this supplement.

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As mentioned earlier, ibuprofen has been consistently associated with the lowest risk of GI complications of any NSAID at prescribed doses.1,7,8,31,32 It has also been associated with a lower risk of serious peptic ulcers compared with treatment with most other NSAIDs, especially at the lower end of the prescription dose range.7 A systematic review of GI toxicity with NSAID treatment8 included 36 case control studies and eight controlled cohort studies. The case control studies involved 19,648 exposed patients and 105,373 controls, and the cohort studies involved approximately 400,000 exposed patients and 1 million non-exposed controls. The analysis found that, compared with non-use of NSAIDs, the adjusted relative risk (95% CI) for serious peptic ulcer complications for ibuprofen at a dened dose of 51500 to 42400 mg/ day was 2.22 (95% CI 1.72.29), and ranged from 3.13 for aspirin (95% CI 2.44.1) to 8.7 for piroxicam (95% CI 6.210.4). Ibuprofen was associated with a lower risk of serious GI complications than other NSAIDs. However, this advantage was lost at doses 41800 mg/day. This analysis of the prescription use of NSAIDs conrms that the risk of GI complications with ibuprofen is dose-dependent. Renal adverse events associated with NSAIDs are uncommon at prescribed doses but if they do occur, they may be severe. Short half-life NSAIDs, such as ibuprofen, are associated with a lower risk of renal effects than NSAIDs with a longer half-life.33 Ibuprofen at prescription doses (41200 mg/day) and for a longer duration of use, is not commonly associated with adverse renal effects in controlled clinical trials in patients without underlying renal disease3437though in the elderly there is an increasing risk of renal failure with increasing daily doses of ibuprofen,31 even if the risk seems less than other NSAIDs
PRESCRIPTION VERSUS OTC USE OF IBUPROFEN

The effects of ibuprofen are dose- and duration-dependent. OTC ibuprofen is indicated for a maximum daily dose of 1200 mg taken for a maximum of 710 days, for the treatment of self-limiting conditions such as headache, fever, backache, dental pain and dysmenorrhoea. Experience shows that mean use will be 20 tablets (200 mg each) over 5 days.14 In contrast, prescription ibuprofen is used for chronic conditions such as rheumatoid arthritis (including juvenile rheumatoid arthritis or Stills disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies, which require longer term management at a higher dosage with regular medical attention. The mean use in these conditions is around 90100 days/year in osteoarthritis, and almost full time in rheumatoid arthritis.20,38,39 In contrast to the prescription-user population, the demographic prole of the OTC patient

comprises a higher proportion of younger and healthier individuals who use OTC analgesics intermittently.1 A meta-analysis by Henry et al.7 explored the effects of dose on GI risk. The relative risk of GI bleeding for low dose ibuprofen (41200, 1500 or 2400 mg/kg) was 1.6 (95% CI 0.83.2) and for high dose ibuprofen (51200, 1500 or 2400 mg/kg) was 4.2 (95% CI 1.89.8).7 There is a dose-response curve in the occurrence rate and severity of adverse reactions, and it is very important when assessing reaction rates to make sure that these apply to the situation under study (i.e. short-term use of less than 1200 mg/ day).40 In this regard, the Celecoxib Long-term Arthritis Safety Study (CLASS) study41 results are irrelevant to shortterm OTC use of ibuprofen at lower doses for common pain. The CLASS study was a three-arm trial comparing celecoxib 800 mg/day with ibuprofen 2400 mg/day or diclofenac 150 mg/day in patients with osteoarthritis or rheumatoid arthritis. Clinically relevant upper GI ulcer complications and symptomatic ulcers during the rst six months of treatment were described as the two main outcome measures. It was concluded that, compared with the traditional NSAIDs at standard dosages, celecoxib was associated with a lower incidence of symptomatic ulcers and ulcer complications combined; however, 2400 mg/day ibuprofen is well over the OTC standard dose. Other adverse effects of ibuprofen have also been shown to be dose dependent.8,31 The risk of GI bleeding is very low with OTC ibuprofen,42 which may be due to the low dose used and its short half-life (12 h).43 The short half-life allows ibuprofen to bind to COX-1 for shorter time and, therefore be the reason it is associated with the lowest GI toxicity relative to other NSAIDs.7,8 Lanza44 reviewed a series of studies in which the effect of ibuprofen on the gastric mucosa was assessed in 187 young, healthy adult volunteers. At a dose of 1200 mg/day, ibuprofen produced minimal damage to the gastric mucosa, of the same order as placebo. Little or no damage was observed when 1600 mg was taken daily for three days or when 2400 mg was taken for one day. However, the degree of damage increased when 2400 mg/day was taken on a regular basis, further conrming the association of GI damage to dosage and chronic use of ibuprofen. The low risk of ulcer complications for prescribed ibuprofen, compared with other NSAIDs with a similar efcacy and level of relief,9 results in a lower risk of mortality, morbidity and health-care costs. However, the risk of long-term use of OTC ibuprofen or other NSAIDs cannot be eliminated. The impact of this potential misuse (if prolonged use is not on medical advice) is difcult to assess; as the risk of high-dose prescription ibuprofen is not really major, a marginal misuse23,24,26 would at worst cause a minor risk increase in the

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populationespecially since the typical user of OTC ibuprofen is generally younger, healthier and at lower risk of vascular or other disease compared with users of prescription ibuprofen or other NSAIDs. Patients on prescription ibuprofen for chronic treatment tend to be older and are followed-up by clinicians, who monitor overall efcacy and potential adverse events.
OVERDOSE

In summary, prescription ibuprofen is used for chronic conditions that require long-term management and regular medical attention such as arthritis and chronic lower back pain. In contrast, OTC ibuprofen is used for self-limiting conditions with a maximum of 10 days use. The lower risk of GI adverse effects, in particular ulcer complications is likely to result in reduced cost, morbidity and mortality compared with other NSAIDs without compromising efcacy and level of relief.9
Competing interests NM has advised many pharmaceutical companies, especially in the eld of NSAIDs and the use of low-dose NSAIDs for OTC analgesia; including ketoprofen, ibuprofen, urbiprofen, naproxen and diclofenac. His University department has also been commissioned to perform clinical trials and epidemiological studies on the subject and on many others. Funding NM has not received any nancial payment for the present paper, which was prepared for an event sponsored by Reckitt-Benckiser. REFERENCES

Although ibuprofen is well tolerated when used at low doses, increasing the dose of any NSAID is associated with an increased risk of a toxic event. Ibuprofen is usually a benign drug in overdose,45 even though severe toxic effects have been reported. In cases of ibuprofen overdose reported consecutively to the Rocky Mountain Poison and Drug Center, a toxic reaction developed in 7 of 45 patients (16%).46 In overdose too, the renal effects of ibuprofen are doserelated, with clinical effects more likely at doses 4400 mg/ kg of ibuprofen. Lower doses can produce changes that are often clinically unimportant. Where renal failure has been reported, there has usually been a massive overdose of ibuprofen with metabolic acidosis, oliguric renal failure or additional factors (e.g. infection, dehydration, binge drinking or pre-existing renal disease).47,48 Symptoms of overdose are managed with supportive care where appropriate. In summary, ibuprofen does not usually cause major complications in overdose situations and also has a wide margin of safety. Although it is not possible to dene a potentially fatal dose of ibuprofen, it is much less toxic in acute overdose than either aspirin48 or paracetamol.49 Severe poisoning and death due to ibuprofen overdose are rare.50 Therefore, the consequences of ibuprofen overdose to patients and the healthcare system would be minimal, even with increased use of ibuprofen by the public.
CONCLUSION

Ibuprofen has a clinical heritage of 45 years and its safety prole has been studied extensively. Ibuprofen is widely regarded as being well tolerated compared with other traditional NSAIDs. There is a dose-related risk for GI and renal adverse events with its use, so that when it is used at OTC dosages, for short-term pain relief at a maximum daily dose of 1200 mg, its tolerability prole is clearly better than that associated with its use at higher prescribed doses. Serious GI adverse events associated with ibuprofen occur rarely and are predominantly associated with high doses prescribed for the long-term treatment of chronic disorders such as arthritis. With short-term use, its safety prole is at least comparable to other OTC treatments.14

1 Doyle G, Furey S, Berlin R, et al. GI safety and tolerance of ibuprofen at maximum over-the-counter dose. Aliment Pharmacol Ther 1999;13:897906 2 Mehlisch D. The efcacy of combination analgesic therapy in relieving dental pain. JADA 2002;133:86171 3 Ganzberg S. Analgesics: opioids and nonopioids. In: Ciancio SC (ed). ADA Guide to Dental Therapeutics. Chicago: ADA Publishing, 1998:80 107 4 Eisenberg E, Berkey CS, Carr DB, et al. Efcacy and safety of nonsteroidal antiinammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994;12:275665 5 Black P, Mitchell MD, Desjardins P, et al. A randomized, doubleblind, placebo-controlled comparison of the analgesic efcacy, onset of action, and tolerability of ibuprofen arginate and ibuprofen in postoperative dental pain. Clin Ther 2002;24:107289 6 Sachs C. Oral analgesics for acute nonspecic pain. Am Fam Physician 2005;71:9138 7 Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of GI complications with individual non-steroidal anti-inammatory drugs: results of collaborative met-analysis. BMJ 1996;312:15636 8 Henry D, McGettigan P. Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs. IJCP 2003;135(suppl):439 9 Hawkey CJ, Cullen DJ, Pearson G, et al. Ibuprofen versus other nonsteroidal anti-inammatory drugs: use in general practice and patient perception. Aliment Pharmacol Ther 2000;14:18791 10 Beaver WT. Review of the analgesic efcacy of ibuprofen. IJCP 2003;135(suppl):137 11 Ecker-Schlipf B. Ibuprofen is more effective and safer than paracetamol. Med Monatsschr Pharm 2006;29:43 12 Rainsford KD, Roberts SC, Brown S. Ibuprofen and paracetamol: relative safety in non-prescription dosages. J Pharm Pharmacol 1997;49:34576 13 Fries J, Bruce B. Rates of serious GI events from low dose use of acetylsalicylic acid, acetaminophen and ibuprofen in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol 2003;30:222633

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14 Moore N, van Ganse E, Le Parc JM, et al. The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A largescale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 1999;18:8998 15 Peterson GM. Risk factors... but only after excluding high-risk subjects. Pharmacoepidemiol Drug Saf 2004;13:253; author reply 2556 16 Peterson GM. Selecting nonprescription analgesics. Am J Ther 2005;12:6779 17 Depont F, Fourrier A, Merliere Y, et al. Channelling of COX-2 inhibitors to patients at higher gastrointestinal risk but not at lower cardiovascular risk: the Cox2 inhibitors and tNSAIDs description of users (CADEUS) study. Pharmacoepidemiol Drug Saf 2007;16:891900 18 Hasford J, Moore N, Hoye K. Safety and usage pattern of low-dose diclofenac when used as an over-the-counter medication: results of an observational cohort study in a community-based pharmacy setting. Int J Clin Pharmacol Ther 2004;42:41522 19 Layton D, Sinclair H, Bond C, Hannaford P, Shakir S. Pharmacovigilance of over-the-counter products based in community pharmacy: methodological issues from pilot work conducted in Hampshire and Grampian, UK. Pharmacoepidemiol Drug Saf 2002;11:50313 20 Moore N, Verschuren X, Montout C, Callens J, Kong SX, Begaud B. Excess costs related to non-steroidal anti-inammatory drug utilization in general practice. Therapie 2000;55:1336 21 Moore N. Place of OTC analgesics and NSAIDs in osteoarthritis. Inammopharmacology 2003;11:35562 22 Moore N, Charlesworth A, VanGanse E, Jones JK. Solving Mr Petersons doubts. Pharmacoepidemiol Drug Saf 2004;13:2556 23 Paulose-Ram R, Hirsch R, Dillon C, Losonczy K, Cooper M, Ostchega Y. Prescription and non-prescription analgesic use among the US adult population: results from the third National Health and Nutrition Examination Survey (NHANES III). Pharmacoepidemiol Drug Saf 2003;12:31526 24 Porteous T, Bond C, Hannaford P, Sinclair H. How and why are nonprescription analgesics used in Scotland? Fam Pract 2005;22:7885 25 Sinclair H, Bond C, Hannaford P. Over-the-counter Ibuprofen: how and why is it used? Int J Pharm Practice 2000;8:1217 26 Turunen JH, Mantyselka PT, Kumpusalo EA, Ahonen RS. Frequent analgesic use at population level: prevalence and patterns of use. Pain 2005;115:37481 27 Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial. JAMA 1995;273:92933 28 Rampal P, Moore N, van Ganse E, et al. Gastrointestinal tolerability of ibuprofen compared with paracetamol and aspirin at over-the-counter doses. J Int Med Res 2002;30:3018 29 Murray MD, Brater DC. Renal effects of ibuprofen. Rainsford KD (ed). Ibuprofen. A Critical Bibliographic Review. London: Taylor and Francis, Inc, 1999:45995 30 Furey SA, Vargas R, McMahon FG. Renovascular effects of nonprescription ibuprofen in elderly hypertensive patients with mild renal impairment. Pharmacotherapy 1993;13:1438 31 Grifn MR, Yared A, Ray WA. Nonsteroidal anti-inammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 2000;151:48896

32 Garcia-Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal antiinammatory drugs. Lancet 1994;343:76972 33 Sturmer T, Erb A, Keller F, Gurner KP, Brenner H. Determinants of impaired renal function with use of nonsteroidal anti-inammatory drugs: the importance of half-life and other medications. Am J Med 2001;111:517 34 Bonney SL, Northington RS, Hedrich DA, Walker BR. Renal safety of two analgesics used over-the-counter: ibuprofen and aspirin. Clin Pharmacol Ther 1986;40:3737 35 Bradley JD, Brandt KD Katz BP, Kalasinski LA, Ryan SI. Comparison of an antiinammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991;325:8791 36 Cummings DM, Amadio P, Nettler S, Freedman M. Ofce-based evaluation of renal function in elderly patients receiving non-steroidal anti-inammatory drugs. J Am Board Fam Pract 1988;1:7780 37 Fox DA, Jick H. Non-steroidal anti-inammatory drugs and renal disease. JAMA 1984;251:12991300 38 Moore N. Forty years of ibuprofen use. Int J Clin Pract 2003;135(suppl):28-31. 39 Moore N, Diris H, Martin K, et al. NSAID use proles derived from reimbursement data in France. Therapie 2004;59:5416 40 Moore N. Diclofenac potassium 12.5 mg tablets for mild to moderate pain and fever: a review of its pharmacology, clinical efcacy and safety. Clin Drug Investig 2007;27:16395 41 Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:124755 42 Perez-Gutthann S, Garcia-Rodriguez LA, Duque-Oliart A, VarasLorenzo C. Low-dose diclofenac, naproxen, and ibuprofen cohort study. Pharmacotherapy 1999;19:8549 43 Henry D. Variability in risk of major upper gastrointestinal complications with individual NSAIDs. Importance of drug dose and half-life: results of meta analysis. In: Rainsford KD (ed). Side Effects of Anti-Inammatory Drugs IV. Dordrecht: Kluwer Academic Publishers BV, 1997:327 44 Lanza FL. Endoscopic studies of gastric and duodenal injury after the use of ibuprofen, aspirin and other non-steroidal anti-inammatory agents. Am J Med 1984;2:1924 45 Barry WS, Meinzinger MM, Howse CR: lbuprofen overdose and exposure in utero: results from a postmarketing voluntary reporting system. Am J Med 1984;77:359 46 Hall AH, Smolinske SC, Kulig KW, Rumack BH: Ibuprofen overdosea prospective study. West J Med 1988;148:6536 47 Volans JN, Fitzpatrick R. Human toxicity of ibuprofen. In: Rainsford KD (ed). Ibuprofen. A Critical Bibliographic Review. London: Taylor and Francis, Inc., 1999:53960 48 Volans G, Monaghan J, Colbridge M. Ibuprofen overdose. Int J Clin Pract 2003;135(suppl):5460 49 Perry SJ, Streete PJ, Volans GN. Ibuprofen overdose: the rst two years of over-the-counter sales. Hum Toxicol 1987;6:1738 50 Wood DM, Monaghan J, Streete P, Jones AL, Dargan PI. Fatality after deliberate ingestion of sustained-release ibuprofen: a case report. Critical Care 2006;10:R44