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The Study: , Aspirin and New Tolerability Study

Article in Clinical Investigation · August 1999 DOI: 10.2165/00044011-199918020-00001

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Nicholas D Moore Jean-Marie Leparc Université de Bordeaux Assistance Publique – Hôpitaux de Paris

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The PAIN Study: Paracetamol, Aspirin and Ibuprofen New Tolerability Study A Large-Scale, Randomised Comparing the Tolerability of Aspirin, Ibuprofen and Paracetamol for Short-Term Analgesia

Nicholas Moore,1 Eric Van Ganse,2 Jean-Marie Le Parc,3 Richard Wall,4 Hélène Schneid,5 Mahdi Farhan,4 François Verrière 5 and François Pelen 5 1 Department of , Université Victor Segalen, Hôpital Pellegrin, Bordeaux, France 2 Department, University of Lyon, Lyon, France 3 Service de Rhumatologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France 4 Boots Healthcare International, Nottingham, England 5 Boots Healthcare, Courbevoie, France

Abstract Objective: This study aimed to compare directly aspirin (acetylsalicylic ), ibuprofen and paracetamol (acetaminophen), first-line which are generally well tolerated, from a safety perspective in general practice. Methods: This was a blinded, multicentre study in general practice of up to 7 days of aspirin, paracetamol (both up to 3g daily) or ibuprofen (up to 1.2g daily), administered for common painful conditions, using patient-generated data with assistance. The main outcome was the rate of significant adverse events (serious, severe or moderate events, events resulting in treatment discontinuation or a physician visit). Statistical analysis tested for equivalence between ibuprofen and paracetamol, and for difference with aspirin. Results: 1108 general practitioners included 8677 adults (2900 aspirin, 2886 ibuprofen, 2888 paracetamol; three patients had no code label number). 8633 (99.5%) were evaluable, of whom 8233 (95%) adhered to the study protocol. The main indications were musculoskeletal or back pain (48%), sore throat, the com- mon cold and flu (31%). Rates of significant adverse events were: aspirin 18.7%, ibuprofen 13.7%, and paracetamol 14.5%. Ibuprofen was statistically equivalent to paracetamol. Both were significantly better tolerated than aspirin (p < 0.001). Total gastrointestinal events (including dyspepsia) and were less frequent with ibuprofen (4 and 2.8%, respectively) than with paracetamol (5.3 and 3.9%) or aspirin (7.1 and 6.8%) [all p < 0.035]. There were six cases of non-serious gastrointestinal bleeding, four with paracetamol and two with aspirin, and one case of peptic ulcer with aspirin. Conclusion: The overall tolerability of ibuprofen in this large-scale study was equivalent to that of paracetamol and better than that of aspirin. These findings could lead to a reassessment of the use of first-line analgesics for the short-term management of painful conditions in general practice, recommending ibuprofen first, because of the poor tolerability of aspirin and the potential risks of para- cetamol overdose. 90 Moore et al.

Aspirin (acetylsalicylic acid), ibuprofen and (Hôpital Ambroise Paré, Boulogne-Billancourt, paracetamol (acetaminophen) are first-line anal- France). The study was conducted according to gesics, generally available over the counter (OTC). Good Clinical Practices and the Declaration of Paracetamol has a reputation for good tolerability, Helsinki (as revised in 1989). somewhat offset by severe hepatic in Non-inclusion criteria were mainly limited to suicidal or accidental overdose.[1-4] Acommon the contraindications for the from their concern with NSAIDs is gastro-toxicity, which is Summary of Product Characteristics (SPC), or to dose- and product-dependent. Case-control studies methodological or legal requirements (details of have shown an increased risk of gastrointestinal inclusion and non-inclusion criteria are available (GI) bleeding even with low-dose aspirin as used from the authors upon request). [5,6] in cardiovascular prevention, whereas at all Patients were given treatment for at least 1 and doses ibuprofen seems to carry a lower risk of at most 7 days, to be started within 24 hours of [7] gastro-toxicity than other NSAIDs. In some consultation unless the GP recommended other- studies at OTC doses this risk has been shown to be wise (e.g. for dysmenorrhoea). They were provided [8,9] similar to or less than placebo or paracetamol. with a diary on which to record adverse events and No study has addressed the relative tolerability their severity, taken (trial and concom- of aspirin, ibuprofen and paracetamol, as used in itant medication), and any comments. The diary daily practice to treat mild to moderate acute pain included specific instructions on the reporting of in adults. Because these drugs are widely used and events and their severity. Patients gave a global the disorders treated are not life-threatening, this opinion of the treatment at the end of the diary, question is a major issue. The present according to a 4-point scale. The diary and unused study was therefore designed to compare directly medication were to be returned to the prescriber at the tolerability of aspirin, ibuprofen and para- the end of treatment in a sealed envelope. cetamol in situations mimicking everyday use at Patients were not required to see their physician OTC doses and durations for various common again. called the patients on the day acute pain indications. This study relied mainly after the expected start of treatment to ensure that on patient data, which a previous study had shown to be feasible.[10] Basedonexistingdataonthe medication had been started, to record or qualify relative safety of aspirin, ibuprofen and para- any early adverse event, and to verify that the cetamol,[8,9,11] the basic premise tested in this study patients understood and would complete the diary. was that paracetamol and ibuprofen would have They called again 7 to 9 days after the start of treat- equivalent tolerability, and that ibuprofen would be ment to make sure the diary would be returned, better tolerated than aspirin. and/or to record any adverse event. Any second consultation and its reason were also recorded. Adverse events were identified and graded Patients and Methods from the patient diary, from the telephone calls, and The PAIN study (Paracetamol, Aspirin, from further GP visits. Classification and coding Ibuprofen New tolerability study) was a random- (COSTART) of events were checked by a Study ised, multicentre, blinded, parallel-group trial. Safety Committee before unblinding. Events that French general practitioners (GPs) were to include were identical to treatment indication were consid- patients aged 18 to 75 years requiring short-term ered as lack of treatment effect. Those not identifi- treatment of mild to moderate pain. able were coded as ‘unevaluable reaction’. Events All patients gave written informed consent to were graded as serious, severe, moderate or mild. participate in the study, which had been previously Serious events were those causing hospitalisation, approved by the Committee for the Protection of that were fatal or life-threatening, or that resulted Persons participating in Biomedical Research in sequelae. Severe events were those rendering

© Adis International Limited. All rights reserved. Clin Drug Invest 1999 Aug; 18 (2) PAIN Study of Aspirin, Ibuprofen and Paracetamol 91

daily activities impossible, moderate events were The study were all white round those interfering with daily activities, and mild unmarked tablets of approximately the same size. events were those without impact on daily acti- The physicians never saw the tablets, and patients vities. Severity grading was considered first from saw only their own treatment. The envelopes the patient diary, then from the physician consult- containing returned medication were retrieved ations or telephone contacts. If severity was not intact by the study monitors, to ensure physician indicated, it was classified by the Safety Commit- blinding throughout the study. tee as missing. Statistical Analysis Primary Outcome Measure The study analysis tested two primary hypo- The number of patients with at least one signi- theses, that of equivalence between ibuprofen and ficant adverse event, defined as an event that was paracetamol, and that of difference between serious, severe or moderate, resulted in a second ibuprofen and aspirin. The study was not powered physician consultation, led to cessation of treat- to assess the difference between paracetamol and ment, or was of missing intensity. aspirin, since this difference was deemed estab- lished from the literature and current practice. The Secondary Outcomes Measures and expected incidence rates for significant events, Other Variables from the literature, were 9% for both paracetamol [8,11] The following secondary outcomes measures and ibuprofen, and 12% for aspirin. and additional variables were also determined: Aspirin and ibuprofen were compared using a χ2 test to establish whether there was a difference • adverse events by COSTART body systems and between the groups, using the evaluable or inten- terms; tion-to-treat population (patients who took at least • the distribution of serious, severe, moderate and one dose of study medication). other categories of events; Ibuprofen and paracetamol were compared • the reasons for premature discontinuation; to establish equivalence, using the per-protocol • prognostic factors such as the indication and population (patients who followed the study in- duration of treatment, number of tablets taken, structions correctly). Ibuprofen would be consid- concomitant disorders and medication; ered equivalent to paracetamol if the incidence of significant adverse events was within 30 percent- • all adverse events (including mild adverse age points of the expected rate for paracetamol, i.e. events); if the upper limit of the confidence interval (CI) of • patients’ global opinion of treatment. the difference was less than 2.7% (30% of 9%). Study Medication Hence this test was constructed as a 1-sided test. The hypothesis that ibuprofen could be better Aspirin 500mg tablets, ibuprofen 200mg tablets tolerated than paracetamol was not tested. and paracetamol 500mg tablets were marketed To account for multiple testing, and achieve an drugs repackaged identically (Creapharm, Le overall 5% level of significance, both comparisons Haillan, France) and identified only by treatment were held to 3.5%, using Dunnett’s correction.[12] number. Each patient was issued 42 tablets. The For the equivalence comparison, the 1-sided dose prescribed was up to 6 tablets per day, as 96.5% upper confidence limit for the difference approved for analgesic use in France. was constructed. Patients were allocated randomised treatment Considering the expected incidence of sig- numbers through a central telephone service to nificant adverse events for aspirin, ibuprofen and ensure continuously balanced group distribution. paracetamol (12, 9 and 9%, respectively), 2583

© Adis International Limited. All rights reserved. Clin Drug Invest 1999 Aug; 18 (2) 92 Moore et al.

patients per group were sufficient to have 90% protocol deviations were allocation of treatment by power. Assuming a 10% dropout rate, the target the GP without using the central telephone service recruitment was 8610. (177 patients), and the use of prohibited medica- tions (215 patients). These were equally distributed Results among the treatment groups (fig. 1). The baseline characteristics of the treatment Study Population groups were similar, and factors probably affecting tolerability such as age, indication, concomitant One thousand one hundred and eight GPs medication or diseases were equally distributed included 8677 patients between September 1997 and March 1998: 2900 were randomised to aspirin, (table I). The most common indications were 2886 to ibuprofen, and 2888 to paracetamol musculoskeletal and back pain (48.3%) and symp- (three patients had no code label number). 8633 toms associated with sore throat, the common cold patients (99.5%) were evaluable (intention-to-treat and flu (31.5%). The mean treatment duration and population), of whom 8233 (95%) adhered to the the mean number of tablets taken per patient were study protocol (per-protocol population). The main not different between treatment groups (table I).

8677 patients were randomised into three groupsa

Aspirin (n = 2900) Ibuprofen (n = 2886) Paracetamol (n = 2888)

NEP = 10 NEP = 16 NEP = 14 Evaluable population Evaluable population Evaluable population (n = 2890) (n = 2869) (n = 2874)

DP: DP: DP: 1 Ineligibility criteria 2 Ineligibility criteria 6 Ineligibility criteria 74 Took forbidden medication 66 Took forbidden medication 75 Took forbidden medication 2 Took more than 0 Took more than 1 Took more than recommended daily dose recommended daily dose recommended daily dose 61 NCR 59 NCR 57 NCR

Per-protocol population Per-protocol population Per-protocol population (n = 2753) (n = 2743) (n = 2737)

a Three patients received unknown treatment and were excluded from the evaluable population.

Fig. 1. Disposition of the patients in the trial. NEP = non-evaluable population; DP = deviant population; NCR = non-central randomisation used.

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Table I. Baseline characteristics (evaluable population) Criteria Treatment group aspirin ibuprofen paracetamol (n = 2890) (n = 2869) (n = 2874) Mean (SD) baseline characteristics Age (y) 43.6 (14.7) 43.3 (14.7) 43.6 (14.8) Body mass index (kg/m2) 24.4 (4.4) 24.4 (4.4) 24.3 (4.2) Body temperature (°C) 37.5 (0.7) 37.4 (0.7) 37.4 (0.8) Gender (no. female, % female) 1672 (57.9) 1673 (58.3) 1664 (57.9)

Indication for treatment [no. (%)] Musculoskeletal condition 925 (32.0) 954 (33.3) 907 (31.6) Cold/flu 586 (20.3) 571 (19.9) 548 (19.1) Backache 461 (16.0) 431 (15.0) 476 (16.6) Sore throat 317 (11.0) 332 (11.6) 341 (11.9) 304 (10.5) 297 (10.4) 291 (10.1) Other 126 (4.4) 105 (3.7) 123 (4.3) 112 (3.9) 116 (4.0) 113 (3.9) Pain of menstrual 55 (1.9) 59 (2.1) 65 (2.3)

Concomitant disease [no. (%)]a 726 (25.1) 739 (25.8) 713 (24.8) Concomitant medication [no. (%)]a 1289 (44.6) 1303 (45.4) 1266 (44.1) Mean treatment duration (days) 5.4 (1.8) 5.6 (2.2) 5.5 (1.8) Mean no. of tablets per treatment 20.0 (9.8) 20.5 (9.8) 20.5 (9.8) All tests for differences between groups were nonsignificant. a Reported as ongoing during the study.

Treatment Discontinuation Committee as treatment related. These events were: gardening accident, pneumothorax, neck of The study was completed by 7456 patients, of right humerus fracture, cerebral neoplasm, renal whom 3771 used the drug to the end of prescrip- colic, and bronchitis. Three occurred in the aspirin tion, and 3685 stopped early because of cessation group and three in the ibuprofen group. There was of pain (aspirin 1235, ibuprofen 1246, paracetamol a suicide attempt with study medication by a friend 1204; differences not significant). 1177 patients of a patient randomised to paracetamol, with withdrew early from the study, 541 because of uneventful outcome. There was no difference adverse events [aspirin 7.6%, ibuprofen 5.1%, in serious event frequency between the treatment paracetamol 6.1% (table II)], and 576 because of groups. lack of treatment effect (aspirin 7.0%, ibuprofen 6.1%, paracetamol 6.9%). In addition, 55 patients withdrew for other reasons and five were lost to Primary Outcome follow-up. Significant adverse events were reported by Serious Adverse Events 18.7% of evaluable patients on aspirin, 13.7% on ibuprofen, and 14.5% on paracetamol (table II). There were six serious adverse events, none The 1-sided 96.5% confidence limit for the considered by the investigator or the Safety difference between paracetamol and ibuprofen

© Adis International Limited. All rights reserved. Clin Drug Invest 1999 Aug; 18 (2) 94 Moore et al.

Table II. Rates of significant adverse event categories (evaluable population)

Parameter Aspirin Ibuprofen Paracetamol p-Value IBU vs PARA (ASA) (IBU) (PARA) (ASA vs IBU) difference 96.5% (upper conf. limit) a No. of patients 2890 2869 2874

All significant events 539 392 416 <0.001 0.85 (primary analysis, ITT) (18.7%) (13.7%) (14.5%) Equivalence All significant events 509 367 378 <0.001 1.24 (per-protocol analysis) (18.5%) (13.4%) (13.8%) Equivalence Severe AE 138 100 92 0.014 1.15 (4.8%) (3.5%) (3.2%) Equivalence Moderate AE 353 245 294 <0.001 − 0.31 (12.2%) (8.5%) (10.2%) p < 0.02 AE leading to premature 221 145 175 <0.001 0.06 discontinuation (7.6%) (5.1%) (6.1%) Equivalence AE leading to extra GP visit 142 101 101 0.009 0.89 (4.9%) (3.5%) (3.5%) Equivalence a One-sided 96.5% confidence limit for difference between ibuprofen and paracetamol. Equivalence is concluded if upper limit of the confidence interval of the difference in the incidence was <2.7%. AE = adverse events; conf. = confidence; GP = general practitioner; ITT = intention-to-treat.

was below 2.7, thus fulfilling the requirements for Secondary Outcomes equivalence. Significantly fewer patients on ibuprofen or paracetamol had significant adverse Categories of Significant Adverse Events events than on aspirin. The of signifi- In each category, there were significantly more cant adverse event with aspirin was 1.36 (95% CI: patients in the aspirin than in the ibuprofen or para- 1.18 to 1.57) compared with ibuprofen and 1.29 cetamol groups. Equivalence between ibuprofen (95% CI: 1.12 to 1.48) compared with paracetamol. and paracetamol was confirmed for all categories Within the per-protocol population, 509 of 2753 of significant adverse event, except for moderate patients (18.5%) on aspirin had significant adverse events which significantly fewer patients experi- events, significantly more than the 367 of 2743 enced with ibuprofen than with paracetamol. (13.4%) with ibuprofen or the 378 of 2737 (13.8%) Adverse Events by Body System and Term with paracetamol. The 1-sided 96.5% confidence Adverse events by body system and specific ad- limit for the difference between ibuprofen and verse event term are listed in table III. Differences paracetamol was 1.24, which fell within the between ibuprofen and aspirin, and ibuprofen and defined equivalence range (table II). The relative paracetamol were tested at the 3.5% significance risk of significant adverse events with ibuprofen level. compared with paracetamol was 0.99 (95% CI: More patients reported significant events 0.85 to 1.16). concerning the body as a whole (which includes Overall for every 100 patients treated with abdominal pain) with aspirin (10.1%) than with aspirin, five more will have significant adverse ibuprofen (7.0%) [p < 0.001] or paracetamol events than if they had been treated with ibuprofen, (7.8%). More patients reported significant diges- or four more than if they had been treated with tive events with aspirin (7.1%) than with ibuprofen paracetamol. (4.0%) [p < 0.001] or paracetamol (5.3%), and

© Adis International Limited. All rights reserved. Clin Drug Invest 1999 Aug; 18 (2) PAIN Study of Aspirin, Ibuprofen and Paracetamol 95

more with paracetamol than ibuprofen (p = 0.025). All Adverse Events This was also true for dyspepsia (aspirin 3.1%, ibuprofen 1.4%, paracetamol 2.2%) and for Including adverse events of mild intensity, 748 abdominal pain (aspirin 6.8%, ibuprofen 2.8%, patients had adverse events on aspirin (25.9%), paracetamol 3.9%). More patients reported nausea 615 on paracetamol (21.4%) and 560 on ibuprofen (19.5%). The difference between aspirin and with aspirin (2.5%) than with either paracetamol ibuprofen was significant (p < 0.001). Ibuprofen or ibuprofen (1.5% each). There was no significant and paracetamol were equivalent (96.5% confi- difference in the other system organ classes, or dence limit for difference 0.04). individual adverse reaction terms. The analysis including mild adverse events did There were two rectal haemorrhages and two not change the conclusions concerning all GI haematemesis with paracetamol (0.14%), two events. Abdominal pain (aspirin 11.3%, ibuprofen rectal haemorrhages and one peptic ulcer with 6.1%, paracetamol 7.0%) and dyspepsia (aspirin aspirin (0.1%), and none with ibuprofen (upper 6.3%, ibuprofen 2.9%, paracetamol 4.1%) were limit of 95% CI: 0.1%). significantly more frequent with aspirin than with

Table III. Rates of most frequent significant adverse events by COSTART body system and terms (evaluable population) Aspirin Ibuprofen Paracetamol Ibuprofen vs Ibuprofen vs (%) (%) (%) aspirina paracetamola (p-value) (p-value) Systems Body as a whole 10.1 7.0 7.8 <0.001 0.25 Digestive 7.1 4.0 5.3 <0.001 0.025 Nervous system 2.0 1.9 1.9 0.88 0.99 Respiratory 1.0 0.6 0.6 0.15 0.99 Other special senses 0.9 0.5 0.6 0.09 0.60 Cardiovascular 0.7 0.4 0.6 0.13 0.28 Skin 0.7 0.8 0.6 0.43 0.21 Musculoskeletal 0.4 0.3 0.2 0.67 0.61 Urinary disorders 0.2 0.3 0.2 0.32 0.20 Metabolic-nutritional 0.1 0.1 0.1 0.99 0.42

Terms Abdominal pain 6.8 2.8 3.9 <0.001 0.024 Dyspepsia 3.1 1.4 2.2 <0.001 0.019 Nausea 2.5 1.5 1.5 0.01 0.91 Unevaluable reactionb 1.8 1.4 1.3 0.23 0.73 Headache 1.3 1.4 1.6 0.88 0.59 Diarrhoea 0.9 0.8 1.1 NT NT Asthenia 0.9 0.8 0.7 NT NT Somnolence 0.7 0.6 0.8 NT NT Pain 0.9 0.6 0.6 NT NT Vomiting 0.7 0.4 0.6 NT NT Dizziness 0.6 0.6 0.5 NT NT Back pain 0.4 0.5 0.7 NT NT Flatulence 0.3 0.4 0.4 NT NT a Significance level set at 0.035. Formal comparisons assessed only when overall rate >1.0%. p-Values quoted are 2-sided χ2 tests. No adjustments have been made for multiple comparisons. b Adverse event type not specified. COSTART = Coding Symbol Thesaurus for Adverse Reaction Terms (3rd ed.); NT = not tested.

© Adis International Limited. All rights reserved. Clin Drug Invest 1999 Aug; 18 (2) 96 Moore et al.

ibuprofen. Dyspepsia was more frequent with para- Patients in our study were selected according to cetamol than with ibuprofen (p = 0.012), and the the general contraindications of the drugs as total number of patients with digestive events was described in their SPC. Because at-risk patients also greater (p = 0.014). were excluded by the protocol (which was consis- tent with product labelling), there may have been Prognostic Factors less risk of GI events with the two NSAIDs than in real OTC use. The patient profiles were very much Rates of significant events by age, indication or as expected, including the indications for the drugs. gender were consistently statistically higher with The drugs were blinded, marketed formulations to aspirin. There was no evidence for a treatment by ensure maximum applicability of the results. subgroup for any of the parameters Choosing an aspirin rather than a buffered or (data not shown). soluble form probably did not increase the rate of [6] Effect of Treatment adverse events. Primary outcome results were those expected On global evaluation, 74.2% of patients on when designing the study, i.e. equivalence of signi- ibuprofen rated the treatment as excellent or good, ficant adverse event rates between ibuprofen and a significantly higher rating than for paracetamol paracetamol, and a lower rate than aspirin, except (69.2%) or aspirin (68.6%) [both p < 0.001]. that the observed rates of significant events were higher than expected (13.7, 14.5 and 18.7% vs 9, Discussion 9 and 12% for ibuprofen, paracetamol and aspirin, respectively). This could be related to patient- This blinded randomised parallel-group study in rather than physician-based recording of data, general practice showed that the tolerability of and/or to the evaluation options, which were de- low-dose, short-term ibuprofen and paracetamol was equivalent, both being better tolerated than as- signed to maximise event recognition and severity pirin. Overall, the adverse events were of the same attribution. nature for the three drugs, though those observed with The decreasing rates of events from aspirin to aspirin tended to be more severe and more frequent. paracetamol to ibuprofen were consistent over the Contrary to common belief, non-major GI entire range of events, whether they were signifi- events were not more frequent with ibuprofen than cant or nonsignificant, and for most organ systems with paracetamol. This had already been estab- or adverse reaction terms. If adverse event intensity lished for serious events in children receiving is a continuum from mild to severe, attribution of short-term treatment.[13] significance only to those rated at least moderate The study was designed to assess the safety of may be arbitrary, but wherever the line is drawn, these drugs as used commonly for analgesia, i.e. the same results would be obtained: ibuprofen is at short-term use at low doses. The primary source least as well (and possibly better) tolerated than of information for adverse events was the patient paracetamol, both being better tolerated than diary card. When only the data from the diary cards aspirinwhenusedonashort-termbasis. was considered, the results were the same as when These findings are consistent with the general physician data was also included (data not shown). pattern of aspirin, ibuprofen and paracetamol The study format and results were comparable to tolerability, whether from single-dose clinical trials, those of a previous noncomparative study with from anti-inflammatory dose trials or from retro- ,[10] in which the number of unevaluable spective case-control studies of GI bleeding. In or lost to follow-up patients was also less than 1%, endoscopic studies the mucosal damage observed and the rate of GI events (8.4%) was similar to that was similar for low-dose ibuprofen and paraceta- observed here with aspirin. mol or placebo, and lower than with aspirin.[14,15]

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In single-dose comparative studies at doses similar least ibuprofen was not used at less effective anal- to the unit doses studied here, the overall event rate gesic doses. Many studies show that the analgesic was 2.4% with ibuprofen, 3.2% for paracetamol, of ibuprofen at these doses is in fact and 2.1% for placebo.[9] In a review of studies greater than that of paracetamol,[17-20] and also mostly at anti-inflammatory doses, the overall greater than that of the paracetamol-[21] or frequency of adverse events was 22.0% with paracetamol- combinations,[22] ibuprofen, compared with 16.2% with placebo, which are less well tolerated than paracetamol 24.9% with paracetamol, and 30.5% with aspi- alone. In fact, the doses of aspirin and paracetamol rin;[8] approximately 60% of the adverse reactions used here are lower than those allowed in many were GI-related. These rates are higher than ob- other countries, so that in those countries one could served here, but the differences between treatments even expect higher event rates for paracetamol and are similar, as is the ratio of GI to non-GI events. aspirin. The frequency of GI bleeding with ibuprofen was Our findings therefore confirm the general [16] [8] 0.01% to 0.02%, compatible with the present conclusion[7] that low-dose ibuprofen could be the study. analgesic of first choice for the short-term manage- Case-control studies of GI bleeding, which ment of mild to moderate pain before resorting to consider the upper end of the severity spectrum, higher doses or other NSAIDs, especially aspirin. generally give ibuprofen as the safest of the This is particularly the case considering other NSAIDs, with an odds ratio (OR) for the associa- problems such as the occurrence of Reye’s syn- tion with GI bleeding between 1.0 (no difference drome in children receiving aspirin and the with non-users of NSAIDs, including paracetamol dangers of voluntary or inadvertent overdose with users) and 2.6.[7] both paracetamol[3] and aspirin[23] in adults and In all studies, aspirin had a higher OR for the the elderly. There are few if any instances where association with GI bleeds, even at the low doses aspirin could be used but not ibuprofen. used for cardiovascular prevention, with ORs Paracetamol has a reputation for good tolera- ranging from 2 to 4 with NSAID non-users or bility and digestive innocuity compared with ibuprofen as reference.[7] In our study, the relative risk for non-major GI events between aspirin and NSAIDs, offsetting its risk in overdose. Our study ibuprofen was 1.8 (95% CI 1.4 to 2.2). It may also shows that, within the constraints of the selected be emphasised that the good GI tolerability of patient population, i.e. a population with no ibuprofen did not come at the expense of renal, previous GI bleeding or major risk factors for pulmonary or allergic adverse events. GI bleeding, paracetamol is not better tolerated The digestive tolerability of NSAIDs is dose than ibuprofen, and could in fact be associated with dependent, so it might be argued that the good more GI events. tolerability of ibuprofen in our study was related There are few arguments against the use of to a low dose, or that the doses may not have been ibuprofen rather than paracetamol for the short- equipotent. The doses were the approved doses for term management of acute pain; at analgesic doses OTC analgesia in France, and there was no indica- and durations in this population, the GI risk was tion of lesser activity of ibuprofen: there were no not higher than that of paracetamol, and its acute more premature withdrawals because of treatment toxicity during intended or accidental overdose is inefficacy, the proportion of patients stopping much lower.[24-26] treatment because of pain relief was the same, and This study, as that of Lesko and Mitchell in the overall patient rating was significantly better children,[13] demonstrates that tolerability and for ibuprofen. Although efficacy was not the main safety aspects of widely used drugs may be assess- objective of the study, it appears that at the very ed with large interventional studies.

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Conclusion 9. Furey SA, Waksman JA, Dash BH. Nonprescription ibuprofen: side effect profile. Pharmacotherapy 1992; 12 (5): 403-7 In conclusion, this large-scale study in general 10. Moore N, Vuillemin N, Abiteboul M, et al. Large-scale safety study of ketoprofen 25mg (Toprec®) in febrile and painful practice, the first to compare directly the three most conditions. Pharmacoepidemiol Drug Saf 1996; 5: 292-302 commonly used first-line analgesics, aspirin, 11. Rainsford KD, Roberts SC, Brown S. Ibuprofen and paraceta- mol: relative safety in non-prescription dosages. J Pharm ibuprofen and paracetamol, at their approved OTC Pharmacol 1997; 49 (4): 345-76 doses, confirms the equivalent tolerability of 12.DunnettC,GoldsmithC.Whenandhowtodomultiple ibuprofen and paracetamol, which were better comparisons. In: Buncher C, Tsay J, editors. Statistics in the pharmaceutical industry. New York: Dekker, 1981: 397-433 tolerated than aspirin. In addition, ibuprofen was 13. Lesko SM, Mitchell AA. An assessment of the safety of associated with fewer GI events than paracetamol. pediatric ibuprofen. A practitioner-based randomized clinical trial. JAMA 1995; 273 (12): 929-33 These findings could lead to a reassessment of 14. Lanza FL. Endoscopic studies of gastric and duodenal injury the use of first-line analgesics for the short-term after the use of ibuprofen, aspirin, and other nonsteroidal anti- management of painful conditions in general inflammatory agents. Am J Med 1984; 77 (1A): 19-24 15. Misra R, Pandey H, Chandra M, et al. Effects of commonly used practice, recommending ibuprofen before aspirin NSAIDs on gastric mucosa. A clinico-endoscopic and histo- or paracetamol, because of the poor tolerability of pathological study. J Assoc Physicians India 1990; 38 (12): 913-5 aspirin and the potential risks of paracetamol 16. Strom BL, Schinnar R, Bilker WB, et al. Gastrointestinal tract overdose. bleeding associated with sodium vs ibuprofen. Arch Intern Med 1997; 157 (22): 2626-31 17. Zhang WY, Li Wan Po A. Efficacy of minor analgesics in primary dysmenorrhoea: a systematic review. Br J Obstet Acknowledgements Gynaecol 1998; 105 (7): 780-9 18. Cooper SA, Schachtel BP, Goldman E, et al. Ibuprofen and The authors would like to thank Dr J.K. Jones for acetaminophen in the relief of acute pain: a randomized, methodological assistance, the investigators and Therapharm double-blind, placebo-controlled study. J Clin Pharmacol for the quality of the trial and of the data, and Andrew 1989; 29 (11): 1026-30 Charlesworth of Nottingham Biostatistics Ltd for the 19. Schachtel BP, Furey SA, Thoden WR. Nonprescription ibuprofen and acetaminophen in the treatment of tension-type statistical analysis. The study was funded by Boots headache. J Clin Pharmacol 1996; 36 (12): 1120-5 Healthcare International. 20. Cooper SA. Five studies on ibuprofen for postsurgical dental pain. Am J Med 1984; 77 (1A): 70-7 References 21. McQuay H, Moore A, Justins D. Treating acute pain in hospital. 1. Fry SW, Seeff LB. of analgesics and anti- BMJ 1997; 314: 1531-5 inflammatory agents. Gastroenterol Clin North Am 1995; 24 22. Collins SL, Edwards JE, Moore RA, et al. Single-dose dextro- (4): 875-905 propoxyphene in postoperative pain: a quantitative systematic 2. Bray G. failure induced by paracetamol. BMJ 1993; 306: review. Eur J Clin Pharmacol 1998; 54 (2): 107-12 157-8 23. Durnas C, Cusack BJ. Salicylate intoxication in the elderly. 3. Bridger S, Henderson K, Glucksman E, et al. Deaths from low Recognition and recommendations on how to prevent it. dose . BMJ 1998; 316: 1724-5 Drugs Aging 1992; 2 (1): 20-34 4. Schiodt FV, Rochling FA, Casey DL, et al. Acetaminophen 24. Veltri JC, Rollins DE. A comparison of the frequency and toxicity in an urban county hospital. N Engl J Med 1997; 337 severity of poisoning cases for ingestion of acetaminophen, (16): 1112-7 aspirin, and ibuprofen. Am J Emerg Med 1988; 6 (2): 104-7 5. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin 25. Moore N, Noblet C, Breemeersch C. A review of the safety of and risk of peptic ulcer bleeding. BMJ 1995; 310 (6983): ibuprofen at the analgesic- dose. Therapie 1996; 51 827-30 (4): 458-63 6. Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin- 26. Halpern SM, Fitzpatrick R, Volans GN. Ibuprofen toxicity. A associated major upper-gastrointestinal bleeding with enteric- review of adverse reactions and overdose. Adverse Drug coated or buffered product. Lancet 1996; 348 (9039): 1413-6 React Toxicol Rev 1993; 12 (2): 107-28 7. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non- steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312 (7046): 1563-6 Correspondence and reprints: Prof. Nicholas Moore, 8. Haase W, Fischer M. Statistische Metaanalyse von multi- Department of Pharmacology, Université Victor Segalen, zentrischen klinischen Studien mit Ibuprofen in Hinblick auf Hôpital Pellegrin, 33076 Bordeaux, France. die Kohortengroβe. Z Rheumatol 1991; 50 Suppl 1.: 77-83 E-mail: [email protected]

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