risk factors for adverse events in analgesic drug users: results from the pain study

pharmacoepidemiology and drug safety 2003; 12: 601–610Published online 22 April 2003 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.842

ORIGINAL REPORT

Risk factors for adverse events in analgesic drug users: resultsfrom the PAIN study

Nicholas Moore*1{, Andrew Charlesworth2z, Eric Van Ganse3{, Jean-Marie LeParc4{,

Judith K. Jones5{, Richard Wall6{,§, Helene Schneid7§ and Francois Verriere7§

1Department of Pharmacology, Universite Victor Segalen, Bordeaux, France2Nottingham Clinical Research Limited, Nottingham, UK3Department of Pharmacology, CHU de Lyon, 69000 Lyon, France4Department of Rheumatology, Hopital Ambroise Pare, 92000 Boulogne, France5The Degge Group, Arlington, VA, USA6Boots Healthcare International, Nottingham, UK7Boots Healthcare France, Courbevoie, France

SUMMARY

Background The relative influence of various risk factors for adverse events (AE) in analgesics users have never beenprecisely quantified. Advantage was taken of data generated in the paracetamol, aspirin and ibuprofen new tolerability(PAIN) study, a large randomized double-blinded trial of paracetamol, aspirin or ibuprofen for common pain in generalpractice to attempt this.Objective Identify and quantify factors associated with the occurrence of AE in users of analgesic drugs.Method Multivariate logistic regression analysis of potential risk factors for all AE, clinically significant AE (SAE) andclinically significant gastro-intestinal AE (GI SAE).Results Of the 8677 patients included in the study, 8633 contributed data. The main risk factors for SAE were indication:compared to those treated for musculoskeletal pain, patients treated for menstrual pain had an odds ratio (95% ConfidenceInterval) of 0.4 (0.2–0.7), sore throat 0.6 (0.5–0.8), cold and flu 0.7 (0.6–0.8), headache 0.8 (0.7–1.0); concomitant use ofmedication contra-indicated in the drugs’ labeling (OR: 2.2; 1.6–2.9); increasing number of other concomitant medications:1: OR 1.5 (1.3–1.8); 2–3: OR 1.9 (1.6–2.3); more than 3: OR (2.7; 2.1–3.5); treatment with aspirin: OR 1.4; (1.2–1.6) but notibuprofen: OR 0.9; (0.8–1.1) compared to paracetamol; history of previous GI disorder OR 1.4 (1.0–1.8); female gender: OR 1.3(1.1–1.4). Age was not significantly associated with AE in the multivariate analysis. Risk factors for all AE and GI SAE weremostly the same as for significant AE, but there were fewer GI SAE with ibuprofen than with paracetamol (OR 0.8; 0.6–0.9).Conclusion Apart from the analgesic used and its indication, the main risk factors identified for AE in users of first-line analgesics for common pain were the number and nature of concomitant medication. Copyright # 2003 John Wiley& Sons, Ltd.

key words— adverse events; aspirin; paracetamol; ibuprofen; risk factors; medications

Received 7 October 2002Revised 4 December 2002

Copyright # 2003 John Wiley & Sons, Ltd. Accepted 20 February 2003

*Correspondence to: N. Moore, Department of Pharmacology, Universite Victor Segalen, 33076 Bordeaux, France.E-mail: [email protected]{Nicholas Moore (Professor of Clinical Pharmacology, Bordeaux), Eric Van Ganse (Associate Professor of Clinical Pharmacology andPharmacoepidemiology, Lyon), Judith K. Jones (Consultant, Washington) and Jean-Marie LeParc (Professor of Rheumatology, Paris) areindependent researchers or academics, with no financial link with Boots Healthcare other than occasional honoraria for specific tasks. Theywere involved in the initiation, design, surveillance, analysis and interpretation of this study, and in the writing of this article. NicholasMoore and Richard Wall are the guarantors of this study.zAndrew Charlesworth is a statistician in Nottingham Clinical Research, a contract organization that was commissioned to analyze thestudy, with input from the four above-mentioned researchers.§Richard Wall, Helene Schneid and Francois Verriere are or were Boots Healthcare employees who were involved at every stage of the study,from conception on. They were given and took the opportunity of reviewing the manuscript and approving the final version.

Contract/grant sponsor: Boots Healthcare International.

INTRODUCTION

Aspirin, ibuprofen and paracetamol are the threemain WHO step 1 analgesics, used daily on an over-the-counter (OTC) basis by millions of persons. Theyare generally well tolerated, but the sheer number ofusers makes even apparently minor adverse events(AE) significant from a public health point of view.In this context any factor, other than the drug itself,that increases the risk of AE, or that changes thebalance of risk between the drugs, is worthy ofexploration.

A number of factors are thought to increase the riskof AE in users of these drugs, such as gender, age,previous medical history, concomitant drugs bynumber or type or concomitant diseases. These areusually non-specific factors that are common to mostdrugs used for whatever indication.

Aspirin and ibuprofen are non-steroidal anti-inflam-matory drugs (NSAIDs), also used at higher doses andfor longer durations for the treatment of osteoarthritisand rheumatoid arthritis. Most studies of AE and riskfactors thereof relate to these indications and doses,and it is not generally known whether these are alsotrue for the lower doses and shorter durations of theirOTC analgesic use. Information on AE patterns andrisk factors come from small-scale efficacy studies andtheir meta-analyses, and from some larger epidemio-logical studies. Comparative efficacy studies areusually not designed to study AE, and large cohortstudies are usually not comparative, so that theinteractions between exposure to different analgesicdrugs and other risk factors for AE cannot be studied.In addition, the observational nature of the largeepidemiological studies, may they be cohort or case-control studies, entail a serious risk of confounding byprescription or by indication, justifying, if need be, alarge randomized controlled trial. Moreover, thesestudies usually concentrate on the more serious adversereactions such as GI bleeding, hepatic reactions orrenal failure, and not on the less serious events thatconstitute the mass of the patient burden associatedwith these drugs.

The paracetamol, aspirin and ibuprofen new toler-ability (PAIN) study was a randomized double-blindtrial of the tolerability of paracetamol (up to 3 g/day),aspirin (up to 3 g/day) and ibuprofen (up to 1200 mg/day), used for less than 7 days, for common painfulconditions, studying the frequency of AE as assessedprimarily by the patients themselves.1 A total of 8677patients were included, 8633 (99.5%) of whom wereevaluable. The primary results of this trial wereequivalent tolerability for paracetamol and ibuprofen,

both being better tolerated than aspirin. This was truefor all AE, for significant AE (SAE) (see definitionbelow), for gastro-intestinal (GI) events and specificevent terms such as abdominal pain or dyspepsia. ThePAIN study has the combined advantages of being alarge randomized double-blind clinical trial of thethree major WHO step 1 analgesics and of beingspecifically designed to study their relative tolerability.Few studies of analgesics, if any, have had the size ofthe PAIN study, or its specific focus on patientevaluation of common AE.

Though the primary objective of the study was asimple comparison of the rates of AE during the use ofthese drugs for common pain, its size and design gaveus the unique opportunity of studying the effects ofother potential risk factors for AE and their interactionswith the study drugs.

Because these drugs were used in conditions that arethe ones for which the drugs are used OTC, the resultsof this analysis could have consequences on therecommendations for safer use of the drugs.

METHOD

The PAIN study has been described elsewhere indetail.1 A reprint of this article can be obtained fromthe authors of the present work upon request.

To summarize the salient points of the studymethodology, it was a randomized double-blind clinicaltrial comparing the tolerability of aspirin, paracetamoland ibuprofen, given for conditions of common painaccording to the approved indications of these drugs.Non-inclusion criteria were essentially the contra-indications cited in the drugs’ summary of productcharacteristics and labeling, to be as close as possible tothe real-life use of these drugs. The list of prohibitedconcomitant medication is given in Table 1. Patientswere given 42 tablets, i.e. treatment for a maximum of 7days, at a maximum of 6 tablets per day: paracetamol or

Table 1. Prohibited medication: the use of the following agentswas not permitted during the study period

i Aspirinii Paracetamol

iii Any NSAID at analgesic or anti-inflammatory dosesiv Corticosteroid anti-inflammatory drugsv Oral anticoagulants or heparinvi Ticlopidinevii Digoxin

viii Lithium saltsix Methotrexatex Interferon

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Copyright # 2003 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2003; 12: 601–610

aspirin up to 3 g/day, ibuprofen up to 1200 mg/day.These were the doses authorized for OTC use in France.However, the mean total quantity of the drugs used was20.5 tablets over 5 days and was similar for the threestudy drugs. Patients were seen only once by the generalpractitioner (GP) investigator at inclusion, unlessadverse or other events warranted a second visit. TheGP called the patient 24 hours and 7–9 days afterinclusion, to ensure compliance with the study. Patientscompleted a diary indicating quantities of drug used,concomitant medications (excluding those used to treatthe AE) and diseases, and description and grading ofAE. The main objective of the study was thecomparison of the frequency of SAE between treatmentgroups. Significant events were those events that wereserious according to the internationally approvedregulatory definitions (i.e. those that were fatal or life-threatening, that caused or prolonged hospitalization,that resulted in disability), of severe (preventing dailyactivity), moderate (interfering with daily activity) orunknown intensity, or that resulted in the treatmentbeing stopped or in a second GP visit.

The main analysis concerned the comparison of therates of SAE between treatment groups, with priorhypotheses of superiority of ibuprofen over aspirin, andof equivalence of ibuprofen and paracetamol, whichwere both confirmed by the study. Previously reportedsecondary analyses compared the rates of specific eventcategories, of all events and GI events, includingdyspepsia and abdominal pain, between treatments,with the same results as for the primary analysis.

The present analysis concerns potential risk factorsother than treatment and their possible interaction withthe treatment.

Data from the PAIN study were therefore furtheranalyzed, using, as dependent variables:

� all adverse events,� significant adverse events (as defined above),� significant gastro-intestinal events;

and as exploratory variables:

� treatment group (paracetamol, aspirin, ibuprofen),� potential risk factors for adverse events, as listed in

Table 2.

In addition, the time course of AE rates by treatmentwas analyzed using the actual time from treatmentonset and number of tablets taken.

Statistical analysis

All analyses were done using the Splus 2000 statisti-cal analysis package. These include descriptive analy-

sis (Table 2), univariate logistic regression (Table 3)and multivariate logistic regression analysis (Table 4).

These analyses were done for all AE, for SAE asdefined above and for significant GI events.

All numbers are of patients with at least one event.Even if a patient had several events, he/she was onlycounted once for that event or event class.

Univariate analyses of individual potential riskfactors were done using logistic regression. For eachrisk factor, the presence of any statistical interactionwith treatment group was also assessed. Odds ratios aregiven for the presence of the factor (compared to itsabsence) for dichotomous risks. In the case ofpolychotomous risk factors (e.g. indication or numberof concomitant medications), the baseline category ofthe risk factor is indicated as having an odds ratio of 1.In all cases, the bilateral 95% confidence intervalaround the odds ratio was computed.

The multivariate logistic regression analyses wereperformed using all potential risk factors regardless oftheir univariate significance. The final models weredetermined using backward and forward stepwiseprocedures, with 0.05 as the threshold for entry intoor eviction from the model. Both stepwise proceduresgenerally gave the same model, but where smalldifferences existed, these were carefully consideredand the most appropriate model chosen. Havingdetermined the multivariate models for each type ofevent, one further exploratory analysis was performed.The significance of all two way interactions wereassessed and the findings are discussed below.

RESULT

Of 8677 patients who were included in the study, 8633(99.5%) contributed data to this analysis. Because thestudy was a randomized controlled trial, there was nodifference in the distribution of the different potentialrisk factors between the treatment groups.

The results are summarized in Tables 2 (descriptive),3 (univariate analysis) and 4 (multivariate analysis).

Effects of treatment group (main study results)

As reported previously,1 aspirin had the worst toler-ability: respectively 25.9%, 18.7% and 10.6% of thepatients had at least one AE for respectively all AE,SAE and GI SAE, compared to paracetamol (21.4,14.5 and 7.3%) and ibuprofen (19.5, 13.7 and 5.8%,respectively). Aspirin was significantly worse thanthe two other treatments ( p< 0.01). Ibuprofen andparacetamol were statistically equivalent for signifi-cant events.1 This was also true for all events. For

risk factors for adverse events in analgesic users 603


Table 2. Distribution of risk factors and adverse events (AE)

All patients All AE SAE GI AE

Number %* Number** %{ Number** %{Num-ber** %{

All patients 8633 100 1923 22.3 1347 15.6 684 7.9Paracetamol 2874 33.3 615 21.4 416 14.5 211 7.3ASA 2890 33.5 748 25.9 539 18.7 307 10.6Ibuprofen 2869 33.2 560 19.5 392 13.7 166 5.8Gender

Male 3611 41.8 708 19.6 487 13.5 241 6.7Female 5009 58.0 1214 24.2 859 17.1 443 8.8

Age�45 years 4921 57.0 993 20.2 682 13.9 323 6.646–65 years 2839 32.9 671 23.6 476 16.8 255 9.0>65 years 864 10.0 257 29.7 188 21.8 105 12.2

Clinical findingsT� 378C 3192 37.0 778 24.4 539 16.9 288 9.0T>378C 4198 48.6 836 19.9 590 14.1 290 6.9Diastolic BP�80 mmHG

7322 84.8 1607 21.9 1123 15.3 577 7.9

Diastolic BP>80 mmHg

1270 14.7 305 24.0 215 16.9 103 8.1

Weight � 65 kg 3940 45.6 909 23.1 647 16.4 336 8.5Weight >65 kg 4686 54.3 1014 21.6 700 14.9 348 7.4Height � 160 cm 2013 23.3 547 27.2 383 19.0 210 10.4Height >160 cm 6610 76.6 1373 20.8 962 14.6 473 7.2

IndicationBack pain 1368 15.8 311 22.7 220 16.1 116 8.5Cold/flu 1705 19.7 323 18.9 227 13.3 112 6.6Headache 892 10.3 192 21.5 136 15.2 71 8.0Menstrual pain 179 2.1 20 11.2 13 7.3 5 2.8Musculoskeletal pain 2786 32.3 737 26.5 510 18.3 266 9.5Sore throat 990 11.5 184 18.6 127 12.8 55 5.6Toothache 341 3.9 54 15.8 43 12.6 23 6.7Other 354 4.1 98 27.7 69 19.5 34 9.6

Concomitant medicationForbidden comeds 215 2.5 92 42.8 68 31.6 29 13.5No forbidden comeds 8418 97.5 1831 21.8 1279 15.2 655 7.8

Number of concomitant medications, not including prohibited medications0 4760 55.1 800 16.8 546 11.5 262 5.51 1802 20.9 450 25.0 323 17.9 175 9.72–3 1601 18.5 493 30.8 343 21.4 184 11.5>3 470 5.4 180 38.3 135 28.7 63 13.4

Previous history and concomitant diseasesPrevious GI history 371 4.3 127 34.2 91 24.5 52 14.0No previous GI history 8262 95.7 1796 21.7 1256 15.2 632 7.6

Number of concomitant diseases0 6163 71.4 1184 19.2 813 13.2 401 6.51 1537 17.8 440 28.6 320 20.8 170 11.12 592 6.9 184 31.1 133 22.5 74 12.53–4 300 3.5 101 33.7 68 22.7 35 11.7>4 41 0.5 14 34.1 13 31.7 4 9.8

*percentage of total population exposed/not exposed; **Number of patients with at least one AE of the category; {Frequency of AE in thesubgroup.AE, adverse events; GI, gastro-intestinal; comed, concomitant medication.

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GI events, the event rate was in fact lower with ibupro-fen than with paracetamol (p< 0.05).

These results were apparent from the first day oftreatment and from the first tablet taken and remainedconsistent thereafter (Figures 1 and 2).

Univariate analysis of other risk factors(Tables 2 and 3)

a. Demographic and initial descriptive factors, indi-cations for drug use. Other than the analgesic used,many individual factors increased the risk of having

AE, such as female gender, increasing age,height� 160 cm, indication for musculoskeletal pain,while use for menstrual cramps, sore throat or tooth-ache and the presence of fever were associated with alower frequency of AE.

b. Concomitant medication and diseases. Use of pro-hibited medication or concomitant use of other medi-cations were the most important risk factors, the latterexhibiting increasingly great odds ratios for theassociation with increasing numbers of concomitantmedication. In the same way, the risk of AE increased

Table 3. Univariate logistic regression analysis for risk factors for all AE, significant AE (SAE) and significant GI AE in the PAIN study

All AE SAE Significant GI AE

OR CI� CIþ OR CI� CIþ OR CI� CIþ

Paracetamol 1 1 1Aspirin 1.28 1.14 1.45 1.35 1.18 1.56 1.5 1.25 1.8Ibuprofen 0.89 0.78 1.01 0.94 0.81 1.09 0.78 0.63 0.95Female gender 1.31 1.18 1.46 1.33 1.18 1.5 1.36 1.15 1.59Age

�45 1 1 146–65 1.22 1.1 1.37 1.25 1.1 1.42 1.4 1.18 1.66>65 1.67 1.42 1.97 1.73 1.44 2.07 1.97 1.56 2.48

Temperature >378C 0.77 0.69 0.86 0.8 0.71 0.91 0.75 0.63 0.89Heart rate >80 bpm 0.97 0.85 1.1 0.98 0.84 1.13 0.85 0.7 1.04Systolic BP >120 mmHg 1.09 0.98 1.21 1.11 0.98 1.25 1.13 0.96 1.32Diastolic BP >80 mmHg 1.12 0.98 1.29 1.12 0.96 1.32 1.03 0.83 1.28Weight �65 kg 1.09 0.98 1.2 1.12 1.00 1.26 1.16 0.99 1.36Height �160 cm 1.42 1.27 1.6 1.38 1.21 1.57 1.51 1.27 1.79Indications

Musculoskeletal 1 1 1Menstrual pain 0.35 0.22 0.55 0.35 0.20 0.62 0.28 0.12 0.63Toothache 0.52 0.39 0.71 0.64 0.46 0.90 0.69 0.44 1.06Sore throat 0.63 0.53 0.76 0.66 0.53 0.81 0.56 0.42 0.75Cold/flu 0.65 0.56 0.75 0.69 0.58 0.81 0.67 0.53 0.84Headache 0.76 0.64 0.91 0.80 0.65 0.99 0.82 0.62 1.08Back pain 0.82 0.70 0.95 0.86 0.72 1.02 0.88 0.70 1.10Other indications 1.06 0.83 1.36 1.08 0.82 1.43 1.01 0.69 1.46

Concomitant and forbidden medicationsForbidden medications 2.69 2.04 3.54 2.58 1.93 3.46 1.85 1.24 2.75

Number of concomitant medications (not including forbidden medication)0 1 1 11 1.71 1.5 1.94 1.72 1.48 2 1.88 1.54 2.32–3 2.22 1.95 2.53 2.14 1.84 2.48 2.29 1.88 2.79>3 3.24 2.66 3.94 3.23 2.61 4.01 2.6 1.94 3.48

Previous GI history 1.87 1.5 2.34 1.81 1.42 2.31 1.97 1.45 2.67Number of concomitant diseases

0 1 1 11 1.69 1.48 1.92 1.73 1.5 2 1.79 1.48 2.162 1.9 1.58 2.28 1.91 1.55 2.34 2.05 1.58 2.673–4 2.13 1.67 2.73 1.93 1.46 2.55 1.9 1.32 2.74>4 2.18 1.14 4.17 3.06 1.58 5.92 1.55 0.55 4.37

Odds ratios (OR) and 95% confidence interval limits (CIþ, CI�).The odds ratio is considered different from 1 when the 95% confidence interval does not include 1.



Table 4. Multivariate logistic regression analysis of risk factors for all, significant and GI AE in the PAIN study

All AE SAE GI AE

OR CI� CIþ OR CI� CIþ OR CI� CIþ

Treatment groupParacetamol 1 1 1Aspirin 1.33 1.16 1.52 1.35 1.17 1.56 1.48 1.23 1.78Ibuprofen 0.89 0.77 1.02 0.92 0.79 1.07 0.76 0.62 0.94Female gender 1.14 1 1.3 1.26 1.12 1.43 /Temperature >378C 0.85 0.75 0.97 / /Height �160 cm 1.22 1.06 1.41 / 1.34 1.13 1.6Indication

Musculoskeletal 1 1 1Menstrual pain 0.38 0.23 0.66 0.4 0.22 0.71 0.34 0.14 0.82Sore throat 0.66 0.54 0.82 0.63 0.51 0.78 0.52 0.38 0.7Cold/flu 0.68 0.57 0.81 0.66 0.55 0.79 0.66 0.52 0.83Toothache 0.68 0.49 0.94 0.72 0.51 1.01 0.77 0.49 1.2Headache 0.7 0.57 0.87 0.8 0.65 0.99 0.83 0.63 1.1Back pain 0.83 0.7 0.99 0.88 0.74 1.05 0.91 0.72 1.15Other indications 1.09 0.83 1.43 1 0.75 1.33 0.93 0.64 1.36

Concomitant and forbidden medicationsForbidden medications 2.39 1.75 3.26 2.16 1.6 2.93 1.53 1.01 2.3

Number of concomitant medications (not including forbidden medications)0 1 1 11 1.65 1.42 1.91 1.54 1.31 1.81 1.87 1.52 2.292–3 2.16 1.87 2.5 1.89 1.59 2.25 2.14 1.75 2.63>3 2.53 2.01 3.18 2.72 2.09 3.53 2.35 1.73 3.18

Previous GI history 1.45 1.13 1.87 1.35 1.04 1.76 1.42 0.61 2.5Number of concomitant diseases

0 / 1 /1 / 1.21 1.03 1.43 /2 / 1.04 0.82 1.32 /3–4 / 0.84 0.6 1.16 />4 / 1.23 0.61 2.5 /

Odds ratios (OR) and 95% confidence interval limits (CIþ, CI�). Empty cells (/) represent items that did not enter the stepwise logistic regres-sion model. The odds ratio is considered different from 1 when the 95% confidence interval does not include 1.

Figure 1. Cumulative frequency of patients with a first SAE, bytreatment day

Figure 2. Cumulative frequency of patients with a first SAE, bynumber of tablets taken

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with the number of concomitant diseases (Table 3).Further analysis of the interaction between concomi-tant diseases and concomitant medication showed theexpected correlation between the two, with an effectthat was not additive. When the number of concomi-tant medication was taken into account in multivariateanalyses, the effect of concomitant diseases essen-tially disappeared.

The most common concomitant medications were,by decreasing order of frequency antibiotics (11.4% ofthe patients), oral contraceptives (6%), cough prepara-tions (5.3%), lipid-lowering agents (5.1%), psycho-leptics (5%), ACE inhibitors or angiotensin IIantagonists (4.2%), beta-blockers (3.7%), venotonicagents (3.2%), cold preparations (3.1%), calciumantagonists (2.8%), antidepressants and psycho-analeptics (2.7%) etc. The top individual subclasseswere oral penicillins (5.2%), betablockers (3.7%),macrolide antibiotics (3.2%), benzodiazepines (3.1%),fibrates (2.9%), venotonics (2.9%), expectorants(2.7%), antidepressants (2.6%), single componentcalcium antagonists (2.6%), cephalosporins (2.2%).

Interactions between individual risk factorsand treatment groups

For SAE, the main outcome measure in the trial, therewas an interaction between the effects of the treatment

groups and the number of concomitant medication( p¼ 0.012) (Figure 3). Overall, increasing use of con-comitant medications was associated with a largeincrease in event rates, but this pattern was not thesame for the three analgesics. Gradual increases wereseen for ibuprofen and paracetamol. The slope wassteeper for paracetamol than ibuprofen so that formore than three concomitant medications, the highestrate of AE was observed in patients treated with para-cetamol. For aspirin, the increased rate of AE wasobserved from the first concomitant medication andremained approximately constant thereafter.

For other risk factors, there was no interaction withtreatment group: the effect of the risk factor was thesame in all treatment groups, or the effect of treatmentwas the same regardless of the risk factor status (i.e.equivalent tolerability of ibuprofen and paracetamol,worse tolerability with aspirin) (data not shown).

Multivariate models

The results of the multivariate analyses of the risk fac-tors for AE are shown in Table 4. These analyses takeinto account the relations between individual risk fac-tors, such as increasing concomitant diseases andmedications with advancing age, or the relationshipbetween age and indication. Inclusion in the models,as described above, was determined by their contribu-tion to overall risk. Some factors such as indication,

Figure 3. Effect of concomitant and prohibited medication (Table 1) on SAE rate. PARA, paracetamol; ASA, aspirin; IBU, ibuprofen.There was a significant interaction between number of concomitant medications and treatment group ( p< 0.01)



concomitant use of prohibited or other medication, orprevious history of GI disorders appeared in the finalmodels for the three types of AEs (all AE, SAE, GIAE). Others such as gender, height, initial temperatureor number of concomitant diseases appeared in onlyone or two of the models. Though age, for example,appeared significant in univariate analyses, it nolonger had any significant influence on risk for anyof the models, once concomitant medications wereincluded in the model.

The factors that influenced the risk of having (or not)AE during short-term treatment of common pain werethe treatment itself as shown in Table 4, with a higherrisk of any type of AE with aspirin compared toparacetamol or ibuprofen, and a lower risk of GI AEwith ibuprofen than with paracetamol (OR: 0.74; 95%CI: 0.62–0.94, p¼ 0.01). Other risk factors for AEwere indication (e.g. compared to use for musculo-skeletal pain, use for menstrual pain had an OR of 0.34(GI AE)–0.4 (SGAE)), concomitant use of prohibitedmedication (OR: 1.53–2.39), or other medication, withan OR that increased with the number of medicationsused, from 1.54 to 1.87 for one medication to 2.35–2.72 for three or more medications (not includingprohibited medication). Previous history of GI dis-orders had less influence (OR: 1.35–1.45).

The female gender increased the risk of AE for allAE (OR: 1.14) and SAE (OR: 1.26), but not GI AE.Fever decreased the risk of all AE only and a height of�160 cm increased the risk of all and GI AE only.Concomitant diseases were a risk factor only for SAEand were significant only for one concomitant disease.Beyond this, the increased use of concomitantmedication could explain all of the increased risk ofAE seen in univariate analyses.

DISCUSSION

The risk factors involved in the emergence of GIulcers or bleeds during the use of NSAIDs have beenextensively studied in clinical trials, in cohort studies,and in case-control studies. These risk factors for theserious GI events during NSAID treatment at anti-inflammatory doses are drug, dose and duration ofNSAID treatment;2 age, previous history of GI disor-der and other measures of poor health,3,4 as well aspossibly concomitant H. pylori infection.5 These stu-dies however generally consider the higher anti-inflammatory doses of the drugs, used for longer dura-tions than for analgesia. How relevant are these riskfactors for the AE observed during the use for com-mon pain at OTC doses, events that are less seriousbut affect a much larger population?

There are very few studies of the risk factors for AEat the OTC or analgesic doses of these drugs as used forcommon pain. These rely mainly on observationaldata, on meta-analyses of smaller trials6 or on singlearm cohort studies. Because of the observational natureof most studies, prescription or channeling biases maypollute the estimation of the influence of various riskfactors and generate or cancel interactions. In addition,few include patient-generated data, a crucial element toassess drug tolerability.7 In this respect, the dataderived from the PAIN study, a randomized clinicaltrial using patient-derived data for AE collection andmedical data for risk factors, was a unique opportunityto study risk factors and their interactions with drugs:the treatment effect and interactions were not subject tobias, since drug attribution was random and the studywas blinded. This study was designed and powered tostudy tolerability: it was not designed to study GIbleeding, perforations or ulcers, nor serious AE. Onlysix serious events were observed, none drug-related,and six cases of minor GI bleeding (see Ref. 1).

Univariate analyses studying only the individual riskfactors and their interactions with treatment groups areshown here only for information, even though theseresults may be found individually interesting. Most ofthe risk factors are in some way confounded: treatedwomen are often older than men, and they are shorterand lighter. The older the patient, the more chance ofconcomitant diseases and therefore of concomitantdrugs; patients with fever tend to have ENT indicationsrather than musculoskeletal, to be younger, have fewerconcomitant medications, and be treated for a shorterperiod of time. Because of this widespread risk ofcross-confounding, we shall only discuss the multi-variate analysis.

In the multivariate analysis, the major risk factorswere the indication for treatment and the type andnumber of associated drugs, with weaker risks for theanalgesic assigned, female gender, normal tempera-ture, short height and concomitant diseases. Age wasnot a risk factor when the other factors were included,which is consistent with more general studies ofadverse reactions8 including with NSAIDs.9

In addition to the treatment group, the two main sour-ces of risk of AE were indication and co-medication.

The frequency of AE varied widely depending on theindication. Compared to use for musculoskeletalindications, the frequency of AE in women using thesedrugs for menstrual pain was about one third. The riskin patients using the drugs for dental pain, sore throat orflu was also significantly less than in those using thedrugs for muculoskeletal indications. Therefore con-clusions on the tolerability of analgesics derived from

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studies done on a patient population using these drugsfor an indication such as rheumatoid arthritis orosteoarthritis, included in this study in musculoskeletaldisorders, cannot be generalized to the whole popula-tion of analgesic users.10 This is especially the casewhen absolute frequencies are considered. Because ofthe absence of significant statistical interaction how-ever, relative risks between drugs may be the same. Theapparent difference in risk of AE between indicationscould be related to differences in the actual occurrencerate of events related to the disease itself (related e.g. tometabolic changes). It could also be related to adifference in the perception or reporting of AE betweenacute, very painful diseases where the pain relief ismost effective, and chronic, recurrent diseases withmultiple discomforts and long-term or repeatedanalgesic use, where patients may be less tolerant ofand more prone to report non-serious AE.

The second main source of risk was the number andtype (forbidden or not) of concomitant medication:three or more concomitant drugs (not includingforbidden medication) were associated with a morethan doubled risk of AE of any kind. The risk related tothe number of medications used has also been found inmost studies of the frequency of adverse drugreactions, be they NSAID-related or other.8,11

Concomitant medications were used to treat back-ground diseases or conditions (antihypertensives, oralcontraceptives, lipid-lowering drugs) or the conditionfor which the analgesic was given (e.g. antibiotics,antitussives). None were, in principle, used to treat theAE so that the causality of the association, if any, wouldbe from the medication to the event rather than theopposite.

Concomitant use of forbidden medication alsodoubled the risk of having any or SAE and multipliedby 1.5 the risk of significant GI AE. The risk increasefor medication whose concomitant use is forbiddenwith aspirin and ibuprofen also appeared with para-cetamol, a fact not generally recognized.

Previous history of GI disorders was another riskfactor that appeared throughout the regression models,even though its influence was not as great as that ofconcomitant medication.

Other risk factors do not appear in all regressionmodels. Their role must remain putative. Increased riskof AE in women is found in other studies, includingthose of serious AE. Though the effect of fever couldhave been explained by the association with certaintypes of indications with lower AE rates, it persistedwhen indication is taken into account. The role ofpatient height in the AE rate, which persists for allevents in the multivariate analysis is also unexplained.

In the same way, the influence of concomitantdisease disappeared when concomitant medicationwas taken into account, as discussed above.

Beyond the description of risk factors for AE theinteractions or lack of interaction between these riskfactors and the treatment arms yielded interestingfindings. One could have expected treatment-factorinteractions, especially with previous GI history andconcomitant forbidden medication, to result in moreAE with aspirin and ibuprofen than with paracetamol.Our study showed that this was not the case:paracetamol is not better tolerated clinically thanibuprofen. This is true for all types of AE and for mostor all background risks including ‘prohibited’ drugs.Though these prohibited drugs (Table 1) are essentiallydrugs that are thought to interact with aspirin orNSAIDs, and not with paracetamol, their use inpatients taking paracetamol was also associated withan increased risk of AE to an even higher level thanaspirin (Figure 3). In the same way, the interaction(statistical) with other drugs is different betweentreatment arms: with aspirin, almost maximal effectoccurred from the first concomitant medication,whereas with paracetamol and ibuprofen, the rate ofAE increased progressively with increasing numbersof concomitant drugs (Figure 3). In the end, however,with more than three concomitant medications, thehighest rate of AE was observed in the paracetamolgroup. This cannot be due to selection or other biasessince treatment attribution was random. In the sameway, whereas one might have expected that theincrease would have been less with paracetamol, therewas no difference in the effects of such risk factors asprevious GI disorders. Care must be taken to under-stand that these interactions are statistical, notpharmacological, though the latter could be the reasonfor the statistical results.

From the results of this study, there is no demon-strable advantage or protection against any of thecommon risk factors for common AE by usingparacetamol instead of ibuprofen for short-termtreatment of common pain, when the labeling isrespected. Even when it was not, for example in thecase of the forbidden drugs, there was no difference intolerability between the drugs. Of course, this studycannot exclude better safety of paracetamol thanibuprofen at higher doses, for longer periods ofcontinuous use and for more serious AE such as GIbleeding, though some studies found that intermittentuse of low-dose ibuprofen (OTC pattern) does notincrease the risk of GI bleeding.2,12

There was no indication of a change in the riskpatterns over time or treatment duration (Figures 1



and 2) or of better tolerability of paracetamol over time.Again, it is possible that paracetamol may be safer inspecific populations such as the rheumatoid arthritispatients in ARAMIS,10 but these findings cannot beextended or generalized to other user populations.

Aspirin on the other hand had consistently worsetolerability than either ibuprofen or paracetamol, for allrisk factors, and maximal risk was reached from almostthe first concomitant medication.

CONCLUSION

These results could be starting points for further stu-dies, perhaps exploring the role of stature in AE, or thereason for the strong interaction of paracetamol withthe number of medications taken and with the forbid-den medication.

They clearly confirm the role of treatment indicationand of the number and nature of concomitantmedication in the risk of AE, and the validity ofexcluding associations with the drugs mentioned intheir labeling. It is interesting to note that though thesedrugs are mainly mentioned in the labeling of aspirinand other non-steroidals, they seem to interact at leastas much with paracetamol. This increasing risk of AEwith concomitant medication is a further argument forgiving clear instructions to patients when these drugsare purchased OTC, warning of the increased risk ofAE in the case of concomitant treatment of any natureand the advisability of seeking medical advice.

ACKNOWLEDGMENTS

The authors thank the investigators and the patientswho participated in this study, and the study monitors

who ensured the high response rates and high qualityof the data. This study was funded by Boots Health-care International. The funding organization wasinvolved in the design and conduct of the study.

REFERENCES

1. Moore N, Van Ganse E, Le Parc J, et al. The PAIN study: Para-cetamol, Aspirin and Ibuprofen New tolerability study. A largescale, randomized clinical trial comparing the tolerability ofaspirin, ibuprofen and paracetamol for short-term analgesia.Clin Drug Invest 1999; 18: 89–98.

2. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability inrisk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborativemeta-analysis. Br Med J 1996; 312(7046): 1563–1566.

3. Griffin MR. Epidemiology of nonsteroidal anti-inflammatorydrug-associated gastrointestinal injury. Am J Med 1998;104(3A): 23S–29S; [Discussion 41S–42S].

4. Cappell MS, Schein JR. Diagnosis and treatment of non-steroidal anti-inflammatory drug-associated upper gastroin-testinal toxicity. Gastroenterol Clin North Am 2000; 29(1):97–124, vi.

5. Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K,Lauritsen K. Helicobacter pylori and risk of ulcer bleedingamong users of nonsteroidal anti-inflammatory drugs: a case-control study. Gastroenterology 1999; 116(6): 1305–1309.

6. Rainsford KD, Roberts SC, Brown S. Ibuprofen and paraceta-mol: relative safety in non-prescription dosages. J PharmPharmacol 1997; 49(4): 345–376.

7. Ottervanger JP, Valkenburg HA, Grobbee DE, StrickerBH. Differences in perceived and presented adverse drug reac-tions in general practice. J Clin Epidemiol 1998; 51(9): 795–799.

8. Atkin PA, Veitch PC, Veitch EM, Ogle SJ. The epidemiologyof serious adverse drug reactions among the elderly. DrugsAging 1999; 14(2): 141–152.

9. Solomon DH, Gurwitz JH. Toxicity of nonsteroidal anti-inflammatory drugs in the elderly: is advanced age a risk fac-tor? Am J Med 1997; 102(2): 208–215.

10. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxi-city of nonsteroidal antiinflammatory drugs. N Engl J Med1999; 340(24): 1888–1899.

11. Moore N, Lecointre D, Noblet C, Mabille M. Frequencyand cost of serious adverse drug reactions in a departmentof general medicine. Br J Clin Pharmacol 1998; 45(3):301–308 .

12. Kaufman DW, Kelly JP, Wiholm BE, et al. The risk of acutemajor upper gastrointestinal bleeding among users of aspirinand ibuprofen at various levels of alcohol consumption. AmJ Gastroenterol 1999; 94(11): 3189–3196.

KEY POINT

� The main risk factors for AE in users ofanalgesic drugs were the medication itself, theindications for use, and the number and natureof concomitant medications.

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risk factors for adverse events in analgesic drug users: results from the pain study

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