Comparison of ibuprofen and acetylsalicylic acid in the treatment of rheumatoid arthritis J. Dornan,* m.b., ch.b., f.r.cp.[c] and W. J. Reynolds,f m.d., f.r.cp.[c], Toronto Summary: A double-blind crossover caused by the accumulation of acetic tiveness,3"5 while in other studies acetyl¬ study of ibuprofen and acetylsalicylic derivatives in body tissues. salicylic acid appeared to be a more acid was carried out in 27 patients Early animal experiments revealed effective anti-inflammatory drug.6"8 Pa- with rheumatoid arthritis. Patients that ibuprofen possessed analgesic, velka et a? felt that ibuprofen com¬ were evaluated by joint counts, anti-inflammatory and antipyretic prop¬ pared favourably with phenylbutazone grip-strength determination, erythrocyte erties.1 The drug was found to be more in the treatment of rheumatoid arthri¬ sedimentation rate, and number of effective than acetylsalicylic acid in tis. Boardman, Nuki and Hart10 con¬ acetamkiophen tablets required in reducing the inflammation caused by sidered that the analgesic effect of addition to the test drug, as well as ultraviolet irradiation in guinea pigs,2 ibuprofen was less than that of acetyl¬ by various biochemical measurements. although in animal models of chronic salicylic acid in the control of pain in In the doses used ibuprofen and proliferative inflammation or inflam¬ osteoarthritis. In all trials reported acetylsalicylic acid appeared comparable mation of immunologic origin ibupro¬ side effects were less with ibuprofen in anti-inflammatory effect, but fen was not as effective as phenyl- than with acetylsalicylic acid.11 statistically fewer side effects were butazone or indomethacin. The study The purpose of the present study was observed during administration of of analgesic and antipyretic activity to compare the efficacy of 1200 mg ibuprofen. demonstrated that ibuprofen was many ibuprofen with 3600 mg acetylsalicylic times more effective than acetylsalicylic acid in patients with rheumatoid arthri¬ Resume: Comparaison entre I'ibuprofene acid in the animal models used. tis. et I'acide acetylsalicylique dans le Metabolic studies in animals and traitement de la polyarthrite man have shown that ibuprofen is well Patient selection, materials rhumatoide absorbed both from the stomach and and methods the intestine with maximum Nous avons procede chez 27 malades blood souffrant d'arthrite rhumatoide a levels occurring at 45 minutes after Patients selected were outpatients of une etude a double insu et ingestion when in the fasting state. the Rheumatic Disease Unit exhibiting chasse-croise de I'ibuprofene et de More than 90% of the drug is bound continuing active disease. All patients I'acide to plasma albumin. The half-life is were adults with classical or definite acetylsalicylique (AAS). short with Nous avons evalue les malades disappearance of all meta¬ rheumatoid arthritis according to the par bolites of the in 24 hours.1 The American le nombre d'articulations, par la force drug Rheumatism Association de prehension, la vitesse de usual route of excretion is the kidneys, criterion of more than six months' in some animals it is also duration.12 Patients who were sedimentation des erythrocytes et le although pregnant nombre de excreted into bile. and those with other concomitant dis¬ comprimes d'acetaminophene In contrast to the earlier eases were excluded from the trial. In qu'il fallait administrer en plus des compounds of this series ibuprofen has shown no addition, patients were excluded from medicaments etudies, ainsi que par At dose levels the if had received divers parametres biochimiques. Aux hepatic toxicity. high study they systemic both short- and long-term oral adminis¬ or intra-articular corticosteroids, phe¬ doses utilisees, I'effet anti-inflammatoire tration de produced gastrointestinal irrita- nylbutazone or indomethacin during I'ibuprofene et de I'AAS etait tion in the rat and the Parenteral the week before the of the mais, au de vue dog. beginning comparable, point administration ulceration trial. Two had been on anti- a produced sug¬ patients purement statistique, I'ibuprofene a mechanism. No malarial but these had been dis¬ donne lieu a gesting systemic drugs moins d'effets secondaires. evidence of carcinogenicity has been continued prior to their acceptance The search has continued for many detected experimentally. into the trial. Maintenance gold ther¬ years for safe and effective nonsteroid- Studies in patients with rheumatoid apy was continued in patients on this al drugs that combine a high level arthritis have been less clear cut in treatment. Acetaminophen tablets were of antirheumatic activity with a signi¬ documenting an anti-inflammatory supplied separately for pain relief when ficant reduction in side effects. One effect superior to that of acetylsalicylic required and patients were not per¬ of the newest such drugs recently intro¬ acid. In several double-blind studies mitted to use additional analgesic drugs. duced into the Canadian pharmaceu¬ ibuprofen in doses of 300, 600 and Nineteen patients with classical and tical market is ibuprofen [2-(4-isobutyl- 900 mg daily was found to be com¬ eight with definite rheumatoid arthritis phenyl) propionic acid], a substituted parable to acetylsalicylic acid in effec¬ took part in the study. phenylalkanoic acid (Fig. 1). The sub¬ stitution of propionic acid for the acetic acid used in earlier similar compounds eliminated the problem of toxicity From the Rheumatic Disease Unit, Toronto Western Hospital ?Assistant Professor of Medicine and CH.COOH Rehabilitation Medicine, University of Toronto; active attending staff, Toronto Western Hospital tAssistant Professor of Medicine, University of Toronto; Director, Rheumatic Disease Unit, Toronto Western Hospital Reprint requests to: Dr. W. John Reynolds, Toronto Western Hospital, 399 Bathurst St., Toronto, Ont. M5T 2S8 FIG. 1.Structural formula for ibuprofen. 1370 CMA JOURNAL/JUNE 22, 1974/VOL. 110 Both ibuprofen and acetylsalicylic eight tablets per day should adequate made of the study drugs to ensure that acid were supplied as capsules identical relief of pain not be obtained from the full dosage had been taken. Laboratory in appearance. Patients were randomly study drugs. evaluation included examination of given either drug for four weeks and Patients were examined at two-week blood smear, measurement of hemo¬ then changed to the alternative drug intervals by the same clinician. Clinical globin, leukocyte count and erythrocyte for the remaining four weeks. Neither evaluation included a count of swollen sedimentation rate (ESR), and SMA-12 the patient nor the clinician was aware and/or tender joints weighted accord¬ multiphasic estimation of total protein, which drug was being administered. ing to the Lansbury index,13 measure¬ albumin, calcium, cholesterol, glucose, One week before the start of the trial ment of the grip strength using a stand¬ BUN, creatinine, alkaline phosphatase, a complete clinical and laboratory as¬ ard sphygmomanometer, a recording uric acid, total bilirubin, LDH and sessment was carried out. For 72 hours of side effects and a documentation of SGOT. When the trial had been com¬ preceding the start of the trial all the patient's own estimation of the pleted for all 27 patients the code was drugs were discontinued and patients status of his or her disease. At no broken and results were analysed by were permitted to take only acetamino- time were the types of side effects to variance. phen for pain relief. This drug was be expected discussed with the patients. given to patients throughout the trial The number of acetaminophen tablets Results and they were permitted to take up to used was recorded and counts were Ali entered the Table I.Results patients who study (mean values) completed it. Results are recorded in Table I. Baseline refers to the evalua¬ tion carried out following the 72 hours during which anti-inflammatory drugs were discontinued. Although a numer¬ ical improvement was noted during the ibuprofen and acetylsalicylic acid peri¬ ods for grip-strength and joint-count de¬ terminations, the difference from base¬ line values was not significant statis¬ tically. A statistical difference (P<0.01) from baseline was recorded for both S.D. = standard deviation drugs in the average number of ace¬ ?Mean values with both drugs numerically but not statistically different from baseline values taminophen tablets taken per person fSignificant difference for both drugs over baseline (P < 0.01) week. It was found that the aver¬ JMean for acetylsalicylic acid significantly greater than mean for baseline or ibuprofen (P < 0.05) per 1fMean for ibuprofen significantly greater than mean for acetylsalicylic acid or baseline (P < 0.01) age ESR during the acetylsalicylic Provide basic nutritional needs IPMAC1 during pregnancy and lactation Prenavite1 tablet per day Prenavite Forte Each Prenavite film-coated tablet supplies: 150 mg. ferrous fumarate, 4,000 I.U.VIT.A acetate.4001.U.VIT. D2.100 mg. ascorbic acid (as ascor- bate), 2.5 mg. folic acid, 125 mg. calcium carbonate. Prenavite Forte has 50% more iron. Full information available on request. BDH Pharmaceuticals a Glaxo Canada Ltd. Co. Toronto. Montreal. Vancouver, Winnipeg.

CMA JOURNAL/JUNE 22, 1974/VOL. 110 1371 tablets at each visit. The high incidence acid period was significantly greater and found it to be a satisfactory clin- of recognized side effects reported b3 (P<0.05) than the average for either ical method of evaluating the effects patients while on acetylsalicylic aci( the baseline or ibuprofen period. Other of drugs on inflammation in rheuma- seemed to bear out claims that the hematological and biochemical de- toid arthritis. In the present study the drug was being taken regularly and thal terminations gave results that were nor- duration of morning stiffness was not adequate blood levels were achieved mal or unchanged throughout the study sufficiently sensitive as a measurable The efficacy of acetylsalicylic acid except for uric acid levels which were parameter and was therefore discarded. in the management of rheumatoid ar significantly higher during the ibupro- Although there was a numerical im- thritis has been well documented."'," fen period (P<0.01), although in no provement in the values for the mean This fact is accepted by clinical rheu- instance did the level rise above nor- grip strength and joint count, it is of matologists and acetylsalicylic acid has mal. interest that in neither of these para- come to be used as a standard by Side effects, as recorded in Table II, meters was there a statistically signi- which other drugs with anti-inflam- were considerably more frequent dur- ficant improvement over the baseline matory, antipyretic or analgesic effects ing acetylsalicylic acid administration. period. The difference might have are compared. The present study in- Nineteen patients complained of side reached significance if the baseline dicates that ibuprofen is equally effi- effects while taking acetylsalicylic acid: period had been longer than 72 hours. cacious and has significantly fewer seven complained of tinnitus and/or The amount of acetaminophen used side effects. It may prove to be useful deafness, eight of gastrointestinal symp- during the baseline period was statis- in patients who are allergic to acetyl- toms and seven of fatigue or lack of tically different from that used during salicylic acid or in whom side effects energy. In contrast, six patients com- the ibuprofen and acetylsalicylic acid prevent the administration of adequate plained of side effects while on ibu- periods, indicating a genuine analgesic doses of acetylsalicylic acid. profen: one complained of tinnitus, effect of both drugs. No difference in three experienced some gastrointestinal the degree of analgesia produced could The authors are indebted to the Upjohn discomfort and only two complained be detected between acetylsalicylic acid Company of Canada for their support, to of tiredness. The difference in fre- and ibuprofen. Drs. J. S. Crawford and W. M. Franks quency of side effects between the It is of interest that the ESR during for permission to use their patients, and two drugs was statistically significant. the period on acetylsalicylic acid was to Dr. Wood and Mrs. Cruikshank of the Thirteen patients felt they had a significantly higher than during either Department of Biostatistics of The Hospi- better response during the period on tal for Sick Children, Toronto for the the ibuprofen or baseline periods. This statistical analysis of the data. ibuprofen, while nine preferred acetyl- is difficult to explain, but it is well salicylic acid and five could detect no known that changes in the ESR follow difference. The clinician considered clinical deterioration or improvement References that eight patients responded more to and, again, a significant difference ibuprofen, nine had a superior response might have occurred for ibuprofen as 1. ADAMS SS, BOUGH RG, CLwF EE, et al: to acetylsalicylic acid and 10 responded well if the baseline period had been Some aspects of the pharmacology, meta- bolism and toxicology of ibuprofen. I. Phar- equally to each drug. Twelve patients longer than 72 hours. The serum uric macology and metabolism in Symposium on felt they could tolerate the ibuprofen Ibuprofen. Rheumatol Phys Med 10 (suppi acid levels were lower while the pa- 10): 9, 1970 better, 12 could detect no difference, tients were taking acetylsalicylic acid 2. BucKLER JW, ADAMS SS: The phenylalkanoic acids. Med Proc 14: 574, 1968 and only two felt that acetylsalicylic which has a well known uricosuric ac- 3. CHALMERS TM: Clinical experience with ibu- acid was more easily tolerated. Simi- profen in the treatment of rheumatoid ar- tion at this dosage level. thritis. Ann Rheum Dis 28: 513, 1969 larly, the investigator thought that 14 One major difference between acetyl- 4. THOMPSON M, Fox M, NEWELL DH: Ibu- profen in the treatment of arthritis. Med patients tolerated ibuprofen better, two salicylic acid and ibuprofen is the inci- Proc 14: 579, 1968 seemed to tolerate acetylsalicylic acid 5. JASANI MK, DowNIB WW, SAMUELS BM, dence of side effects; almost four times et al: Ibuprofen in rheumatoid arthritis: better, while in 11 no difference be- as many occurred when patients were clinical study of analgesic and anti-inflam- matory activity. Ann Rheum Dis 27: 475, tween the two drugs was evident. The on acetylsalicylic acid as when on 1968 frequency of side effects was not af- 6. DIcK-SMITH JB: Ibuprofen, aspirin and pla- ibuprofen. At no time was any patient cebo in the treatment of rheumatoid ar- fected by the sequence in which the thritis - a double-blind clinical trial. Med prompted regarding the type of side J Aust II: 853, 1969 drugs were administered. effects to be expected. Two patients 7. BRooKs CD, ScHMmD FR, BIUNDO J, et al: Ibuprofen and aspirn in the treatment of had to have their dosage of acetyl- rheumatoid arthritis. A cooperative double- Discussion cut of the blind trial, in Symposium on Ibuprofen. salicylic acid back because Rheumatol Phys Med 10 (suppl 10): 48, 1970 development of severe deafness, and 8. SASAKI S: Clinical trials of ibuprofen in Japan, in Ibid, p 32 The method of assessment used in a number of patients had to take anta- 9. PAVELKA K, SUSTA A, VosTisEK 0, et al: the present study was adopted from cids four-week on Double blind comparison of ibuprofen and during their period phenylbutazone in the short term treatment that developed by the Co-operating acetylsalicylic acid. One feature which of rheumatoid arthritis. Rheumatol Rehabil 12: 68, 1973 Clinics Committee of the American emerged from the study was the dif- 10. BOARDMAN PL, NuKi G, HART SD: Ibuprofen This com- in treatment of rheumatoid arthritis and Rheumatism Association."4 ference in incidence of fatigue. In osteoarthritis. Ann Rheum Dis 26: 560, 1967 mittee employed a composite index patients with rheumatoid arthritis, fa- 11. THOMPSON M, BELL D: Further experience with ibuprofen in the treatment of arthritis, consisting of joint count, grip strength, tigue is usually considered an effect of in Symposium on Ibuprofen. Rheumatol Phys and ESR Med 10 (suppl 10): 100, 1970 duration of morning stiffness the disease. However, while eight pa- 12. ROPES MW, BENNET GA? CoBB S, et al: tients complained of fatigue while tak- Proposed diagnostic critena for rheumatoid arthritis. Bull Rheum Dis 9: 175, 1958 Table II-Side effects ing acetylsalicylic acid, only three of 13. LANSBURY J: Methods for evaluating rheuma- toid arthritis, in Arthritis and Allied Condi- the eight taking ibuprofen voiced the tions, seventh ed, edited by HOLLANDER JL, same complaint. This is not a widely Philadelphia, Lea & Febiger, 1966, p 269 Acetylsalicylic 14. The Co-operating Clinics Committee of the acid Ibuprofen recognized complication of acetylsali- American Rheumatism Association: A seven-day variability study of 499 patients Gastrointestinal cylic acid ingestion. with peripheral rheumatoid arthritis. Arthrtits Serum concentrations of acetylsali- Rheum 8: 302, 1965 disturbances 10 3 15. FREMONTr-SMITH K, BAYLES TB: Saiieylate cylic acid and ibuprofen were not es- therapy in rheumatoid arthritis. JAMA 192: Auditory difficulties 9 1 103, 1965 timated during the study period. That 16. BAYLES TB: Salicylate therapy for rheuma- Fatigue 8 3 the patients were, in fact, taking medi- told arthritis, in Arthritis and Allied Condi- toins, eighth ed, edited by HOLLANDER JL, Others 1 1 cation regularly in prescribed dosage Philadelphia, Lea & Febiger, 1966, p 448 was checked by a count of unused 1372 CMA JOURNAL/JUNE 22, 1974/VOL. 110