Aliment Pharmacol Ther 2000; 14: 187±191. Ibuprofen versus other non-steroidal anti-in ammatory drugs: use in general practice and patient perception C. J. HAWKEY 1,D.J.E.CULLEN 1,9,G.PEARSON 1,S.HOLMES 2,M.DOHERTY 3,J.V.WILSON 4, P. GARRUD 6,S.GARNER 7, A. MAYNARD 8 &R.F.A.LOGAN 5 1 Division of Gastroenterology, 6 Department of Behavioural Sciences, 7 Pharmacy Department, University Hospital; 2 Belvoir Health Group General Practice; 3 Division of Rheumatology, City Hospital; 4 Family Health Services Authority; 5 Department of Public Health Medicine & Epidemiology, University of Nottingham, Nottingham, UK; 8 Centre for Health Economics, York, UK; and 9 Freemantle Hospital, Western Australia Accepted for publication 18 October 1999 SUMMARY Objective: To investigate whether ibuprofen was as well-regarded by patients as other non-steroidal antiin ammatory drugs (NSAIDs). Design: Questionnaire sent to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six general practices with computerized records. Patient responses were subsequently linked to data held on the practice records. Setting: General practices in and around Nottingham, selected to re ect local variations in number of partners, list size, geographical location, deprivation, prescribing burden and prescribing rate. Subjects: Unselected patients receiving NSAIDs prescribed for all indications for use. Main outcome measures: Effectiveness of ibuprofen and other NSAIDs, possible drug related adverse events, patients' overall satisfaction with ibuprofen and other NSAIDs, factors associated with choice of ibuprofen, drug costs of ibuprofen and other NSAIDs. Results: The main NSAIDs used were ibuprofen, diclofenac and naproxen. Ibuprofen use ranged from 1.0% of prescriptions in one practice to 69.1% in another. Although ibuprofen was generally prescribed in low doses, it was perceived by patients as being as effective as the other NSAIDs used, even after allowing for severity of the pre-treatment condition. Overall, 50.5% of patients rated their NSAID the best treatment they had received for their condition with no differences between individual drugs. Conclusions: Ibuprofen is as highly regarded as other NSAIDs when used in similar circumstances. Switching patients to ibuprofen may be a realistic way of reducing nancial and medical costs associated with NSAIDs. INTRODUCTION Non-steroidal anti-in ammatory drugs (NSAIDs) are associated with a high incidence of side-effects, particularly gastrointestinal side-effects. 1±3 Epidemiological studies suggest that some NSAIDs are less likely to cause gastrointestinal complications than others. A systematic Correspondence to: Professor C. J. Hawkey, Division of Gastroenterology, University Hospital, Nottingham, NG7 2UH, UK. E-mail: cj.hawkey@nottingham.ac.uk review of studies that examined the relative risks of gastrointestinal complications associated with different NSAIDs found ibuprofen to be the least toxic NSAID. 4 Since ibuprofen is also cheaper than other NSAIDs, switching patients from more toxic NSAIDs to ibuprofen could achieve both nancial and medical savings. However, ibuprofen's lower toxicity may due to the fact that it is used in relatively low effective doses in clinical practice and it is not known how ibuprofen is perceived by patients in comparison to other NSAIDs when used for unselected indications in general practice. Ó 2000 Blackwell Science Ltd 187
188 C. J. HAWKEY et al. We therefore conducted a study using scrutiny of general practice records and a postal questionnaire of all patients receiving NSAIDs in six general practices in Nottingham to investigate patient perception of the effectiveness and tolerability of ibuprofen and other NSAIDs and overall patient satisfaction with treatment. METHODS As described in the accompanying paper, a research assistant visited six Nottingham General Practices every week over a 4-month period and identi ed recipients of an NSAID. Each of these patients was sent a questionnaire concerning the effectiveness, tolerability and sideeffects of their current NSAID. Other information (indication for use, no. of other medications, age, sex, history of ulcer disease and co-prescription of anti ulcer drugs) was extracted from the patient notes. For comparative purposes, drug doses were converted into de ned daily doses. 5 The de ned daily dose for ibuprofen is 800 mg, for diclofenac 75 mg and for naproxen 500 mg. Compliance (percentage of intended dose taken) was calculated from patient questionnaire replies and the general practitioner record, assuming that consumption started on the day following the prescription. Drug costs were calculated based on the data for the average doses, compliance and frequency of individual drug usage recorded during the study and minimum British National Formulary costs. The costs of individual NSAIDs used by less than 1% of patients was assumed to be a weighted average of the cost of all other NSAIDs. Statistical methods Descriptive statistics were computed using the SPSS-X statistical package. The v 2 -test (with Yates' continuity correction) was used to compare proportions. With comparisons for ordered categorical variables such as age, the v 2 -test for trend was used. In order to identify variables associated with speci c NSAID choice, drug effectiveness, drug adverse drug reactions (ADRs) and overall patient satisfaction, a number of potential determining variables were initially explored by multivariate analysis using a logistic regression model. A forward stepwise procedure was used to select model terms, including only those who made a signi cant contribution to the model (P < 0.05). Power calculations A large study was conducted to allow relatively small differences to be detected. The power of the study was speci cally calculated on the assumption that 1050 subjects would receive a questionnaire, with a 70% response rate (735 responses). The study had 90% power to detect a 10% difference between the proportion of subjects reporting good or complete relief of symptoms from ibuprofen compared to other NSAIDs. In practice because of a high response rate the study was somewhat more powerful than intended. RESULTS Patients studied A total of 1137 questionnaires were sent out; 947 patients replied (response rate 83%); of these 928 met the age criteria (18±80 years) of the study and provided analysable information. The average age of the respondents was 59.3 years (mean s.d. 15.8). Drug choice Ibuprofen (31.7%), diclofenac (31.8%) and naproxen (22.2%) accounted for 85.7% of prescriptions, with indomethacin (4.8%), piroxicam (3.0%), ketoprofen (1.6%) and benorylate (1.1%), being the only other drugs to be prescribed to more than 1% of patients. The prescribed average daily dose of ibuprofen, diclofenac and naproxen was 1131 314 mg, 116 32 mg and 806 254 mg, respectively (Table 1). Additional NSAIDs (other than the index drug) were prescribed to 6.8% of patients (including aspirin for cardiovascular prophylaxis in 3.8%). Factors in uencing prescription of ibuprofen Table 2 shows the factors associated with prescription of ibuprofen. The main factor in uencing the choice of ibuprofen was the individual practice (P < 0.000001), with one practice using ibuprofen for 1.0% of its prescriptions and another using it for 69.1% (compared to an overall average of 31.7%). Indication for use, number of other medications and age were also signi cant in uences, but sex, past history of ulcer disease and co-prescription of ulcer drugs were not. There was no obvious relationship to practice size,
IBUPROFEN VS. OTHER NSAIDS 189 Table 1. Drug exposure Ibuprofen n = 281 Diclofenac n = 294 Napraoxen n = 215 Mean daily dose 1131 116 806 In mg (s.d.) (314) (32) (254) Mean number of de ned daily doses prescribed 1.41 (0.39) 1.55 (0.43) 1.61 (0.51) per day (s.d.) Mean compliance rate (s.d.) 0.73 0.76 0.76 (0.55) (0.56) (0.55) Number of de ned daily dose units received 1.02 (0.88) 1.19 (0.87) 1.25 (1.05) per day (s.d.) Length of prescription 28.0 28.4 30.4 in days (s.d.) (13.0) (10.6) (13.2) location, deprivation index or prescribing burden that explained the difference in rates of ibuprofen prescribing between the practices under study. Ibuprofen was less likely to be used in in ammatory arthritis and in patients receiving multiple other drugs. Patients receiving ibuprofen tended to report severe or very severe pretreatment pain somewhat less frequently than those receiving other drugs (Table 3). The relationship of ibuprofen use to age was complex (Table 2). The odds ratio for ibuprofen choice, adjusted for other factors in the model, was higher in older than in younger patients. However, actual use was lower in the elderly because these patients were less likely to have conditions associated with high ibuprofen usage. Exposure There was no signi cant difference in the prescription length for the three main drugs prescribed (Table 1). Compliance for each of the three drugs was similar. Patients who were prescribed ibuprofen were generally prescribed a low daily dose (1131 314 mg). Effectiveness of ibuprofen compared to other NSAIDs Table 4 shows that 49.4% of patients reported good or complete relief, with no signi cant differences between individual NSAIDs (P > 0.2). Ibuprofen tended to be used in patients with a lower pre-treatment severity. However, when patients were strati ed for initial severity, the proportion reporting good or complete relief still did not vary signi cantly between the individual NSAIDs (P > 0.2). Similarly, if the analysis was restricted to those with in ammatory arthritis the amount of reported relief did not differ signi cantly between individual NSAIDs (P > 0.2). In the logistic regression analysis, symptom relief was not signi cantly in uenced by the initial diagnosis or severity, age, sex, practice or mode of usage (regularly vs. as required). Adverse drug experiences Fewer patients taking ibuprofen reported adverse effects compared to patients taking diclofenac and naproxen (an average of 0.49, 0.57 and 0.57 side-effects were reported per patient, respectively) although the Table 2. Factors associated with choice of ibuprofen Variable P-value Ibuprofen % prescriptions Odds ratio (95% CI) Practice 0.000001 Practice 1 39.8% 1* Practice 2 69.1 3.5 (1.9±6.3) Practice 3 1.0% 0.01 (0.002±0.05) Indication 0.0001 In ammatory arthritis 21.5% 1* Osteoarthritis 27.9% 1.1 (0.6±2.0) Other musculoskeletal 33.9% 2.4 (1.4±4.2) Miscellaneous 44.3% 3.2 (1.5±7.1) Number of 0.0003 < 3 36.3% 1* other drugs 3+ 22.9% 0.5 (0.3±0.7) Age group 0.008 18±44 34.8% 1* 45±64 29.2% 1.41 (0.87±2.27) 65±74 29.3% 2.56 (1.42±4.55) * Reference category. Some non-signi cant pair-wise comparisons are omitted for clarity.
190 C. J. HAWKEY et al. Table 3. Severity of initial condition according to drug choice Overall Ibuprofen Diclofenac Naproxen Other % using 100% 31.7% 31.8% 22.2% 14.3% Condition described as very severe/severe pre-treatment 61.2% 55.5% 62.9% 61.6% 68.6% Unable to dress unaided pre-treatment 8.5% 7.0% 10.8% 8.0% 6.9% Able to do normal work/housework pre-treatment 23.2% 28.5% 20.7% 21.8% 12.0% Unable to climb stairs unaided pre-treatment 39.7% 34.1% 42.1% 39.8% 46.9% Table 4. Drug effectiveness & tolerability Overall Ibuprofen Diclofenac Naproxen Other Condition severe/very severe pre treatment 62.9% 56.6% 66.4% 63.0% 67.4% post treatment 36.0% 31.9% 36.2% 36.2% 43.5% Good/complete relief 49.4% 52.7% 49.0% 44.9% 50.7% If condition initially severe/very severe 46.5% 50.0% 45.7% 41.2% 51.7% If used for in ammatory arthritis 56.3% 40.0% 46.7% 56.0% 73.1% Best treatment 50.5% 50.3% 50.5% 50.3% 51.5% Side-effects 54.9% 49.0% 58.2% 56.6% 56.9% GI side-effects 36.0% 31.1% 39.5% 36.2% 37.7% Upper GI side-effects 22.5% 18.7% 24.7% 25.0% 20.8% difference was not statistically signi cant (v 2 - test ˆ 2.428, P ˆ 0.119). No speci c pattern was associated with any of the individual NSAIDs. Overall NSAID satisfaction Approval for different NSAIDs was very similar with 50.3% rating ibuprofen as the best treatment recieved, vs. 50.5% for diclofenac, 50.3% for naproxen and 51.5% for other NSAIDs. Drug costs The average drug cost of an NSAID prescription, at the frequencies used in this study was 5.97 per prescription, varying from 2.29 for ibuprofen to 12.02 for diclofenac. Based on an annualized rate derived from the 3 months prior to the index prescription, patients in the study received 5.92 prescriptions per annum. In the patients studied, if ibuprofen use rose from 31.7% to 50% (and overall NSAID use remained the same), drug costs would fall by 16.5%. If half of non-ibuprofen NSAID users were switched to ibuprofen drug, costs would fall by 30.9%. Drugs costs would fall by 61.5% if all patients were switched to ibuprofen at the dosage used in this study. DISCUSSION Although the level of ibuprofen prescribing varied greatly from practice to practice, patients receiving ibuprofen appeared to experience similar levels of relief and to value it to the same extent as patients prescribed diclofenac and naproxen, regardless of practice, age, sex, indication for use, mode of usage (regular vs. `as required') or severity of underlying condition. Although the patients we studied were, to some extent, a population selected by satisfaction with their current treatment, it seems likely that more patients than at present could use ibuprofen. Using ibuprofen in favour of other NSAIDs would have direct economic consequences since ibuprofen at the doses used by the practices in this study costs less than all other commonly used NSAIDs, with the exception of generic indomethacin. In the patients studied, if ibuprofen use rose from 31.7% to 50% (and overall NSAID use remained the same), drug costs would fall by 16.5%. If half of non-ibuprofen NSAID users were switched to ibuprofen, drug costs would fall by 30.9%. For the calendar year 1998, in England, there were 18.3 million prescriptions for NSAIDs at a total cost of 157.5 million. 6 A reduction of 30.9% would represent a saving of approximately 48.7 million.
IBUPROFEN VS. OTHER NSAIDS 191 Indirect savings may also accrue from ibuprofen usage because of its lower toxicity. Symptomatically ibuprofen was somewhat better tolerated by our patients than other NSAIDs but these differences did not reach signi cance and the potential savings that could accrue from any reduction in current levels of co-prescription of anti-ulcer drugs that might occur would be relatively limited. More important are the reductions in costs, morbidity and mortality arising from the now well recognized lower risk of ulcer complications for ibuprofen compared to other NSAIDs. It has been suggested that ibuprofen is less likely to cause gastrointestinal complications because it is prescribed at relatively low doses. 4 Although ibuprofen was used at a relative low mean daily dose in our study, patients receiving ibuprofen appeared to experience similar levels of relief and to value it to the same extent as other NSAIDs. Low NSAID doses may achieve genuine therapeutic selectivity. Whilst several studies have shown a relentless and linear rise in the incidence of ulcer complications with increasing NSAID doses, there is evidence that the analgesic bene ts of NSAIDs are achieved at relatively low doses. 7 Our study does suggest that considerable savings, both economic and medical could be made by switching as many NSAID users as possible to ibuprofen, and we are presently undertaking studies to test this proposition directly. We thank the general practitioners, their practice managers, receptionists and nurses who helped with data collection, the patients for providing the primary data, Dr Sarah Smith for help with statistical analysis, and Miss Donna Hall and Mrs Rosemary Dainty for typing the manuscript. REFERENCES 1 Hawkey CJ, Hudson N. Mucosal injury induced by drugs, chemicals and stress. In: Haubrich W, Snaffer F, eds. Bockus Gastroenterology, 5th edn. Philadelphia: WB Saunders, 1994. 2 Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non steroidal anti in ammatory drugs. Lancet 1994; 343: 769±73. 3 Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non steroidal anti in ammatory drugs. Lancet 1994; 343: 1075±8. 4 Henry D, Lim LL-Y, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-in ammatory drugs: results of a collaborative metaanalysis. Br Med J 1996; 312: 1563±6. 5 WHO Collaborating Centre For Drug Statistics Methodology. Anatomical Therapeutic Chemical Classi cation Index. Oslo: WHO Collaborating Centre for Drug Statistics Methodology, 1996. 6 Roberts D. Prescribing Support Unit, Leeds. Personal Communication, 1999. 7 Gotzsche PC. Review of dose±response studies of NSAIDs in rheumatoid arthritis. Dan Med Bull 1989; 36: 395±9. ACKNOWLEDGEMENTS This study was funded by Trent Locally Organized Research Fund.