1. PIERRE PIGEON, ERIC ROBILLARD, GEOFFREY D.
CLARKE, IAN BURNETT
A PROSPECTIVE SURVEY TO COMPARE THE
SUITABILITY PROFILES OF OVER-THE-COUNTER
IBUPROFEN AND PARACETAMOL USE IN A
FRENCH GENERAL PRACTITIONER-CONTROLLED
POPULATION

2. BACKGROUND & OBJECTIVES
The PAIN (Paracetamol, Aspirin and Ibuprofen New tolerability) study published in 1999
assessed the tolerability of over-the- counter (OTC) analgesics in a French general practitioner
(GP)-controlled population and found no apparent difference between the tolerability of
ibuprofen and paracetamol (acetaminophen). However, patient selection in that study could
cast doubt over the relevance of the results to a more generalized OTC population.
The aim of our survey was to prospectively determine what proportion of a French GP-
controlled population is able to take ibuprofen and paracetamol in order to allow appropriate
interpretation of the PAIN study.
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3. METHODS
This was a prospective survey to identify all contraindications/warnings on product
labelling for ibuprofen and paracetamol in 5000 patients aged 18-75 years. 100 French
GPs each collected anonymized data on 50 patients over a 1-week period using a
standardized form.
GPs were stratified by geographical location and size of practice.
Demographic data for patients were summarized.
Contraindications/warnings for ibuprofen and paracetamol were summarized overall and
by individual criterion.
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4. RESULTS
The mean age of patients was 45.8 (± 16.5) years; 42% were males and 58% females.
Of these patients, 49.9% would have been ineligible for the PAIN study because of at
least one contraindication/warning for ibuprofen, whereas only 6.8% would have been
ineligible because of at least one contraindication/warning for paracetamol.
More specifically, contraindications to use of ibuprofen was noted in 12.3% of patients
and 37.6% of patients should have consulted a doctor before use of this drug.
In contrast, contraindications to use of paracetamol were noted in only 0.7% of patients
and only 6.1% should have consulted a doctor before use of this drug.
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5. CONCLUSIONS I
Our survey demonstrates how careful patient selection can limit the generalizability of a study. The
PAIN study excluded individuals 'at-risk' from ibuprofen and the tolerability results of this study
should therefore be interpreted with extreme caution because the patient population may not be
representative of unsupervised OTC analgesic users.
Pain and discomfort are often treated with over-the-counter (OTC) analgesic medications; it has been
estimated that up to 70% of the population in Western countries use such medications regularly.
However, because of the relatively unrestricted access to these drugs, many consumers believe that
such medications are innocuous and often do not inform their doctors when they use them. As a
consequence, consumers may purchase and use OTC analgesics without due consideration of their
contraindications, precautions and drug interactions.
In the prescription setting, adverse effects of NSAIDs, including gastrointestinal (GI)
bleeding, cardiovascular complications and renal toxicity, are widely documented and their use
requires careful assessment of the risks and benefits. These NSAID-related adverse effects are drug
and dose dependent with the risk of GI bleeding increasing with dose.
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6. CONCLUSIONS II
The widespread use of OTC analgesics means that any adverse event associated with the use of these products can
present a significant public health concern. For example, the American College of Gastroenterology Bleeding Registry
has indicated that OTC NSAIDs are used significantly more often in patients with GI bleeding (48%) than in matched
controls (19%). Recent data from the US indicate that some 23 million Americans are using OTC NSAIDs daily, and that
one in four users exceeds the recommended dose of OTC medications.
Paracetamol (acetaminophen) has been regarded as a first-line analgesic of choice for many years, and there is a
general consensus that based on its excellent risk-benefit profile at therapeutic doses, paracetamol should be
continued to be regarded as such, particularly in those patients at increased risk of GI, cardiovascular or renal
complications associated with NSAIDs. In addition, and in contrast to NSAIDs, there are very few clinically significant
drug interactions with paracetamol.
Many of the data pertaining to the relative safety profiles of OTC paracetamol and ibuprofen are derived from patient
populations and conditions that are not necessarily reflective of the general OTC analgesic-using population. In
recognition of this, the PAIN (Paracetamol, Aspirin and Ibuprofen New tolerability) study was an attempt to compare
directly the tolerability of aspirin, paracetamol and ibuprofen in situations that mimicked everyday use at OTC doses
and durations in common, mild to moderate acute pain states.
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7. CONCLUSIONS III
This large study involved 8677 patients recruited by 1108 French general practitioners (GPs). The results appeared to
support equal tolerability for ibuprofen and paracetamol, leading the investigators to suggest that a reassessment of
the use of these analgesics could be warranted, with ibuprofen replacing paracetamol as the first-line analgesic of
choice.
Concerns have since been raised about methodological deficiencies in the original published research that may have
adversely impacted on interpretation of the results. In particular, there are no data describing patient disposition from
screening through to randomization, making it difficult to draw conclusions regarding the applicability of the data to
the general population of OTC analgesic users. The present research was therefore designed to compare the suitability
profiles of OTC ibuprofen and paracetamol in a population of patients screened through a French GP database network
in order to allow appropriate interpretation of the PAIN study results. The objective of the survey was to determine the
relative incidence rates of contraindications to and/or warnings relating to the use of OTC ibuprofen and
paracetamol, with the primary hypothesis being that the rate would be higher with ibuprofen than with paracetamol.
This was a prospective survey of 5000 patients aged 18-75 years aimed at identifying contraindications and warnings as
listed on the Summary of Product Characteristics (SmPC) for OTC paracetamol and ibuprofen. A total of 100 GPs were
enrolled into the audit, with each GP completing 50 patient records over a 1-week period using a standardized form.
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8. CONCLUSIONS IV
Physicians were recruited into the survey based on a quota approach to ensure stratification by geographical location and size of
practice. A total of 100 GPs were recruited into the survey, 65% of whom were male and 35% of whom were female.
The only patient inclusion criterion employed in this research was age between 18 and 75 years inclusive. GPs were required to
collect data for every patient who met the age criterion, up to a total of 50 patients, regardless of the purpose of their visit to the
GP.
The primary outcome measure was the overall screening failure rate for ibuprofen and for paracetamol (i.e. the percentage of
patients presenting with at least one contraindication or warning related to use of ibuprofen or paracetamol). Secondary
outcome measures included quantification of the screening failure rate by individual criterion and by age group.
This survey tested the primary hypothesis that there would be a difference in screening failure rate between ibuprofen and
paracetamol. The demographic profile of the audit population was summarized by age and sex. The number of patients failing
screening (overall and by individual exclusion criterion) was summarized descriptively for ibuprofen and paracetamol. The overall
screening failure rates for ibuprofen and paracetamol were compared using a chi-squared (χ2) test to establish whether there was
a statistically significant difference between the two groups.
Five thousand patients were recruited into the study, 42.3% of whom were male and 57.7% female. The mean age of these
patients was 45.8 (± 16.5) years; age was evenly distributed throughout the audit population.
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9. CONCLUSIONS V
Statistically significantly more patients were found to have at least one contraindication/warning for ibuprofen
compared with paracetamol (2494 [49.9%] vs 340 [6.8%], p = 0.005, figure 1). This confirmed the primary hypothesis
that a higher proportion of this French GP-controlled population should exercise caution before using OTC ibuprofen
compared with paracetamol
Overall screening failure rate (proportion of patients with at least one contraindication to or warning related to use of
either ibuprofen or paracetamol [acetaminophen]).
More specifically, use of ibuprofen was contraindicated in 12.3% of patients. In contrast, use of paracetamol was
contraindicated in only 0.7% of patients. The details of patients with contraindications are presented more fully in
Table III . Additionally, 37.6% of the patients assessed should have consulted a doctor before using ibuprofen because
of warnings on the product labelling. Again, this was in stark contrast to paracetamol: only 6.1% of patients should
have consulted a doctor before using this drug.
There were differences with respect to patient age, with the data showing a positive upwards trend between
increasing age and more patients presenting with at least one contraindication or warning.
Overall screening failure rate (proportion of patients with at least one contraindication to or warning related to use of
either ibuprofen or paracetamol [acetaminophen]).
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10. CONCLUSIONS VI
This prospective survey of 5000 patients in general practice has shown that, based on an evaluation of the SmPC
contraindications and warnings, OTC paracetamol is suitable for use by many more people than is OTC ibuprofen.
Importantly, these results may have implications with regard to the use and safety perceptions of OTC analgesics.
The primary outcome results were as expected. Given that the product labelling for ibuprofen carries substantially
more contraindications, warnings and precautions than does that for paracetamol, it is not surprising that a higher
proportion of patients would be excluded from using OTC ibuprofen on this basis alone. Our study findings indicate
that particular care needs to be taken in the community to ensure that the labelled instructions are properly followed
so as to limit the possibility of inappropriate use.
Our results provide interesting data on the relative suitability profiles of two commonly used OTC analgesics. In
addition, they provide further insight into the interpretation of the PAIN study,and subsequent re-analyses of these
data. The PAIN study was a blinded, multicenter study that evaluated a French GP-based population of almost 9000
patients in an attempt to mimic the everyday use of aspirin, paracetamol and ibuprofen at OTC doses and durations.
Participants received up to 7 days' treatment with aspirin (3000mg daily), paracetamol (3000mg daily) or ibuprofen
(1200mg daily) for the symptomatic relief of common painful conditions, including musculoskeletal or back pain
(48%), sore throat, the common cold and flu (31%).
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11. CONCLUSIONS VII
The main outcome measure was the rate of significant (serious, severe or moderate) adverse events resulting in
treatment discontinuation or a visit to a doctor. The rate of significant adverse events for ibuprofen was reported to be
statistically equivalent to that of paracetamol, with both drugs being significantly better tolerated than aspirin.
Our data show that the patient population evaluated in the PAIN study may not have been representative of the
general adult population of OTC analgesic users. Based on our analysis, almost 50% of patients aged 18-75 years
presenting to their GP may have been excluded from the PAIN study because of contraindications, warnings or
precautions listed in the SmPC for ibuprofen. This would go some way to explaining why it took 1108 GPs just over 6
months to recruit 8677 patients in the PAIN study (i.e. a recruitment rate of only 1.3 patients per GP per month).
Hence, the claimed result of equal tolerability for ibuprofen and paracetamol should be interpreted with caution when
applied to an OTC user population rather than a GP-controlled population.
While OTC analgesics are substantially safe for the vast majority of the population, our research has demonstrated that
contraindications, warnings and precautions to OTC ibuprofen apply to 49.9% of the French adult audit population. In
contrast, such exclusions to OTC paracetamol apply to only 6.8% of this population. Therefore, OTC paracetamol is
more suitable for use by a wider proportion of the general population than is OTC ibuprofen.
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