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A single-blind, randomized, controlled trial to assess the efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute gouty arthritis
CLINICAL THERAPEUTICS® / VOL. 26, NO. 3, 2004
A Single-Blind, Randomized, Controlled Trial to Assess the Efficacy and Tolerability of Rofecoxib, Diclofenac Sodium, and Meloxicam in Patients with Acute Gouty Arthritis Tien-Tsai Cheng, MD,1,2 Han-Ming Lai, MD,1 Chun-Kai Chiu, MD,1 and Ying-Chou Chen, MD1 1Section of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial and 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, Taiwan, Republic of
Hospital, China
ABSTRACT
Background: Acute attacks of gouty arthritis are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint. Nonsteroidal anti-inflammatory drugs are considered the drugs of first choice for treating acute gout. Rofecoxib is a specific cyclooxygenase-2 inhibitor, which has demonstrated analgesic efficacy in the setting of acute pain. Whether it is effective in the treatment of acute gouty arthritis remains to be evaluated. Objective: The aim of this study was to assess the efficacy and tolerability of rofecoxib compared with diclofenac sodium sustained release (SR) and meloxicam in the treatment of acute gouty arthritis. Methods: In this single-blind, randomized, controlled, parallel-group study, patients aged ≥18 years with acute gout within 48 hours of onset were randomized to receive oral treatment with 2 tablets of rofecoxib (25 mg), diclofenac (75 mg), or meloxicam (7.5 mg) once daily for 7 days. The primary outcome measures were patient global assessment of response to therapy and investigator assessment of response to therapy on days 3 and 8. Other efficacy measurements included investigator assessment of total inflammatory scores on days 3 and 8 and patient assessment of pain intensity during the first 12 hours of treatment. Results: Sixty-two patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were assigned to receive rofecoxib (n = 20), diclofenac (n = 21), or meloxicam (n = 21). For patient global response to therapy on days 3 and 8, rofecoxib was associated with analgesic efficacy in significantly more patients compared with meloxicam (84.2% vs 40.0% of patients [P = 0.005] and 94.7% vs 60.0% of patients [P = 0.02], respectively); no significant differences versus diclofenac were found. Similarly, for investigator global assessment of response to therapy, a greater percentage of responders was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% of patients [P = 0.02]), but the difference was not significant on day 8. A greater percentage of responders was found in the rofecoxib group compared with the diclofenac group on day 3 (88.9% vs 47.3% [P = 0.007]), but the difference was not significant on day 8. Compared with baseline, all regimens showed significant improvement in total inflammatory scores on days 3 and 8 (all P < 0.01). During the first 12 hours after dosing, pain intensity score was significantly reduced with rofecoxib starting at 0.5 hour (P < 0.05), but not with diclofenac or meloxicam. Clinical adverse events (AEs) were reported in 4 (20.0%), 7 (33.3%), and 6 (28.6%) patients in the rofecoxib, diclofenac, and meloxicam groups, respectively; the most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal pain (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). No significant differences in tolerability were found among the 3 treatment groups. Accepted for publication January 11, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2004 Excerpta Medica, Inc.
0149-2918/04/$19.00
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Conclusions: In this study of patients with acute gouty arthritis, rofecoxib 50 mg once daily provided more effective treatment than diclofenac sodium SR 150 mg and meloxicam 15 mg administered orally once daily for 7 days in ≥1 efficacy assessment of overall analgesic effect on day 3 or day 8. Rofecoxib achieved a rapid onset of pain relief, demonstrating significant improvement 30 minutes after dosing. All of the regimens appeared well tolerated in the population studied. (Clin Ther. 2004;26:399–406) Copyright © 2004 Excerpta Medica, Inc. Key words: acute gouty arthritis, nonsteroidal antiinflammatory drugs.
INTRODUCTION
Gouty arthritis, the most common type of inflammatory joint disease in men aged >40 years, is caused by the deposition of monosodium urate (MSU) microcrystals into the affected joint space. Acute attacks of gout are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint, which can be disabling.1 Although pain is the primary symptom of acute gout, an effective treatment must target the pain and the underlying inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the drugs of choice for treating acute gout, with indomethacin, naproxen, and sulindac having received approval from the US Food and Drug Administration for this indication.2,3 Although indomethacin is widely used,4,5 its efficacy is based on a limited number of studies6–8 (according to a MEDLINE search [key terms, nonsteroidal anti-inflammatory drugs, gout, and gouty arthritis; years, 1966–2003]), and its associated gastrointestinal tract and central nervous system adverse events (AEs) are significant.9,10 Evidence has shown that cyclooxygenase-2 (COX-2) expression in monocytes is induced in response to MSU microcrystal formation.11 Therefore, it is likely that NSAIDs exert their efficacy in the treatment of gout by inhibiting the production of COX-2– mediated proinflammatory prostaglandins. Rofecoxib is a specific COX-2 inhibitor that has demonstrated analgesic efficacy in the setting of acute pain of postoperative dental surgery,12 in a postorthopedic surgical model,13 and in primary dysmenorrhea.14 Despite a thorough search of the literature, we were able 400
to find only 1 small-scale, uncontrolled study of the efficacy of rofecoxib in the treatment of acute gout.15 The use of once-daily dosing of many drugs, including NSAIDs, is a current trend in medical practice. Rofecoxib can be given as once-daily treatment due to its long half-life. Diclofenac sodium sustained release (SR) and meloxicam also can be given once daily in the treatment of various rheumatic disorders16,17 and certain diseases with acute pain.18,19 Because acute gouty arthritis is an extremely painful condition that should be controlled as rapidly as possible, the maximum recommended daily dosage of each of the 3 drugs was chosen for this study. The aim of this study was to compare the analgesic efficacy, anti-inflammatory efficacy, and tolerability of rofecoxib 50 mg, diclofenac sodium SR 150 mg, and meloxicam 15 mg given as a once-daily oral regimen for acute gouty arthritis. PATIENTS AND METHODS Study Population
Patients were recruited from the Section of Allergy, Immunology and Rheumatology outpatient clinic of Chang Gung Memorial Hospital (CGMH) (Kaohsiung, Taiwan) from December 2001 through July 2002. Patients aged ≥18 years were eligible for the study if they were experiencing an acute attack of gout based on the American Rheumatism Association criteria.20 Other patient entry criteria included a physicianassessed total inflammatory score of ≥5 on a 0- to 9point scale (the sum of the scores for restriction of function [0–3 points], tenderness [0–3 points], and swelling [0–3 points] of the most severely affected joint) as determined by investigators; patient assessment of pain intensity as moderate, severe, or extreme; onset of acute gout attack within 48 hours prior to randomization; and stable dose of any concomitant hypouricemic agent for >30 days. Finally, patients had to be in otherwise good health based on physical examination and medical history and had to be able to understand the study procedures and the agreement to participate in the study. Patients were excluded if they had a history of attacks of acute gout that were unresponsive to NSAIDs; a gouty arthritis attack involving ≥3 joints; allergic reactions to any component of the study drugs, other NSAIDs, or aspirin; a history of asthma associated with nasal polyps; a history of gastroin-
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testinal ulcer bleeding or perforation within 6 months prior to study entry; history of chronic analgesic or tranquilizer use or dependency within the 3 months before enrollment; uncontrolled hypertension, diabetes mellitus, renal disease, or neurologic disorder; a history of stroke; a history of gastric, biliary, or small intestinal surgery that resulted in clinical malabsorption; any significant cardiovascular, hepatic, or neoplastic disease or clinically significant abnormalities on the prestudy examination; significantly abnormal laboratory safety tests, such as serum aspartate aminotransferase levels >2-fold above the upper limit of normal or serum creatinine level >1.4 mg/dL. Pregnant, possibly pregnant, or breastfeeding women were excluded. Women of childbearing potential who were not using adequate contraception were also ineligible for the study, as were patients who regularly consumed alcohol. Finally, patients who had taken either oral or parenteral NSAIDs or systemic corticosteroids within 48 hours before the study, who required regular use of anticoagulant drugs (eg, ticlopidine or clopidogrel), or who had taken colchicine (>1 mg/d) within 8 days prior to study entry were also excluded from the study. Study Design
This was a single-blind, randomized, controlled, parallel-group study of patients with acute gouty arthritis. The protocol was reviewed and approved by the CGMH institutional review board. All patients provided written informed consent before being screened for eligibility. Eligible patients were consecutively randomly assigned in a 1:1:1 ratio to receive oral treatment with 2 tablets of either rofecoxib* (25 mg), diclofenac sodium SR† (75 mg), or meloxicam‡ (7.5 mg) once daily for 7 consecutive days according to a predetermined block randomization table with block factor of 6. Although the patients were not blinded to the treatment assignment, all of the medications were prepackaged and sealed to maintain blinding of the investigators and study staff. In addition, patients were requested not to discuss their treatments with the investigators or study staff. All patients were *Trademark:
Vioxx® (Merck & Co., Inc., Rahway, New Jersey). †Trademark: Voltaren® (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). ‡Trademark: Mobic® (Boehringer Ingelheim GmbH, Ingelheim, Germany).
scheduled to return to the clinic on days 3 and 8 for assessment. Efficacy Assessment
Overall analgesic effect was determined by patient global assessment of response to therapy (PGART) and investigator global assessment of response to therapy (IGART), as in the study by Schumacher et al,21 on days 3 and 8. For both assessments, the possible responses were no effect, poor, fair, good, or excellent (5-point verbal scale). Patients were considered to be responders if the assessments on PGART or IGART were good or excellent. The overall anti-inflammatory effect was assessed by the investigators on days 3 and 8 using the total inflammatory score, which was used to determine the tenderness, swelling, and restriction of function in the affected joints. The 10-point numeric score ranged from 0 (no pain, swelling, or restriction of movement) to 9 (extreme pain to which patient winces and withdraws, swelling and bulging beyond the joint margin, and complete joint immobilization). In addition, we asked the patients to assess their pain intensity as the secondary end point using a 5-point verbal scale of none, slight, moderate, severe, or extreme at baseline (predose) and 0.5, 1, 2, 6, and 12 hours after initial dosing of the study drug. If both the PGART and IGART were excellent on day 3, the study medications were discontinued. However, if both the PGART and IGART were recorded as poor or having no effect on day 3 and the patient elected to discontinue the study medication, rescue medication with prednisolone 10 mg TID was given in place of the study medication. Tolerability Assessment
The tolerability of the study medications was determined using physical examination by the investigators, vital signs measured by assisting nurses, outpatient laboratory testing (estimated serum creatinine clearance [CCr] and serum aspartate aminotransferase [AST] level), and spontaneous reporting of any AEs by the patient. Statistical Analysis
Efficacy analyses were based on a modified intentto-treat approach; all patients with a baseline assessment and ≥1 efficacy measurement either on day 3 or 401
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day 8 were included in the analyses. The percentage of patients who were responders (good or excellent response) as assessed by patient (PGART) and by investigator (IGART) on days 3 and 8 were tested using the Fisher exact test. The changes in pain intensity at various time points within treatment groups were tested using paired t tests, and comparisons among the 3 treatment groups were tested by analysis of variance. The changes in total inflammatory score from day 1 within groups were tested by paired t tests and comparisons among the 3 treatment groups by analysis of variance. For missing assessments, the last available observations were carried forward. All randomized patients were included in the tolerability analysis. All clinical AEs occurring during the study were summarized by types of event. The Fisher exact test was used to compare the treatment groups with respect to the number of patients with AEs. Patients who had any abnormal changes in laboratory values at the end of the study were assessed for clinical significance. Statistical analysis was performed using SAS software version 8e (SAS Institute Inc., Cary, North Carolina). For all efficacy and tolerability comparisons, the difference was considered to be statistically significant at P ≤ 0.05 (2-tailed).
Table I.
RESULTS
A total of 62 patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were enrolled in the study; 20 patients received rofecoxib, 21 received diclofenac sodium SR, and 21 received meloxicam. The baseline demographic characteristics were similar between the 3 groups (Table I). At baseline, 28 patients (45.2%) reported extreme pain, and 27 patients (43.5%) reported severe pain. In total, 5 patients, including 2 patients each from the rofecoxib (10.0%) and diclofenac (9.5%) groups and 1 patient (4.8%) from the meloxicam group, failed to return to the outpatient clinic on day 3. The reasons for withdrawal were study drug ineffectiveness on day 2 (1 patient each from the rofecoxib [5.0%] and meloxicam [4.8%] groups) and personal factors on day 3 (1 patient each from the rofecoxib [5.0%], diclofenac [4.8%], and meloxicam [4.8%] groups). PGART assessments on day 3 were collected using telephone interviews of these patients, except those who withdrew due to study drug ineffectiveness on day 2, but IGART and inflammatory score assessments were unobtainable from these 5 patients. Efficacy
For overall analgesic efficacy based on PGART, a greater percentage of responders (with good to excel-
Baseline demographic and clinical characteristics of the study patients.*
Characteristic
Rofecoxib (n = 20)
Diclofenac Sodium SR (n = 21)
Meloxicam (n = 21)
Total (N = 62)
Age, mean (SD), y
52.2 (14.5)
50.4 (11.6)
50.6 (10.5)
51.1 (12.1)
15 (75.0) 5 (25.0)
19 (90.5) 2 (9.5)
19 (90.5) 2 (9.5)
53 (85.5) 9 (14.5)
Sex, no. (%) Men Women BMI, mean (SD), kg/m2 Pain intensity, no. (%) Extreme Severe Moderate Total inflammatory score, mean (SD)†
24.3 (1.9) 9 (45.0) 7 (35.0) 4 (20.0) 6.0 (1.2)
24.9 (2.1)
25.5 (2.8)
24.9 (2.1)
9 (42.9) 11 (52.4) 1 (4.8)
10 (47.6) 9 (42.9) 2 (9.5)
28 (45.2) 27 (43.5) 7 (11.3)
5.7 (0.9)
6.2 (1.1)
6.0 (1.1)
SR = sustained release; BMI = body mass index. *No significant between-group differences were found (Fisher exact test). †Scale: 0 = no pain, swelling, or restriction of movement to 9 = extreme pain to which patient winces and withdraws, swelling and bulging beyond the joint margin, and complete joint immobilization.
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lent ratings) was found in the rofecoxib group compared with the meloxicam group on days 3 and 8 (84.2% vs 40.0% [P = 0.005]; 94.7% vs 60.0% [P = 0.02], respectively), but no statistically significant difference was found when compared with diclofenac on days 3 and 8 (84.2% vs 57.1%; 94.7% vs 81.0%, respectively) (Figure 1). Regarding the investigators’ perspectives, similar results were shown for the IGART end point. A greater percentage of responders (with good to excellent ratings) was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% [P = 0.02]), but the difference was not significant on day 8 (89.5% vs 61.9%). Rofecoxib provided a statistically greater response than diclofenac on day 3 (88.9% vs 47.3% [P = 0.007]) but not on day 8 (89.5% vs 85.7%) (Figure 2). Using logistic regression analysis, the PGART and IGART analyses confirmed the findings based on the percentages of responders (data not shown). The changes in pain intensity from baseline, as assessed by patients at different time points immediately after study drug dosing, are shown in Table II. Both rofecoxib and meloxicam demonstrated similar improvement in pain scores compared with diclofenac
during the first 2 hours. Only the rofecoxib group showed significant improvement at 30 minutes compared with baseline (P < 0.05), and pain relief was maintained throughout the 12-hour assessment period. Overall Anti-inflammatory Effect
Compared with baseline, all of the regimens showed significant response on days 3 and 8 based on the change in inflammatory scores (all P < 0.01). However, no obvious difference was noted between the treatment groups (Table III). Tolerability
No serious AEs were reported in any group. None of the patients withdrew from the study because of an AE. Clinical AEs were reported by 4 patients (20.0%) treated with rofecoxib compared with 6 (28.6%) treated with meloxicam and 7 (33.3%) treated with diclofenac; no significant differences were found among the 3 groups. The most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal pain (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). These AEs were considered probably treatment related. No laboratory AEs were Rofecoxib (n = 20) Diclofenac sodium SR (n = 21) Meloxicam (n = 21)
100
†
*
% Patients
80
60
40
20
0 Day 3
Day 8
Figure 1. Percentages of patients with good or excellent response to therapy by patient self-assessment. *P = 0.005 versus meloxicam; †P = 0.02 versus meloxicam. SR = sustained release. 403
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Rofecoxib (n = 20) Diclofenac sodium SR (n = 21) Meloxicam (n = 21)
100 *† *
% Patients
80
60
40
20
0 Day 3
Day 8
Figure 2. Percentages of patients with good or excellent response to therapy as assessed by investigators. *P = 0.02 versus meloxicam; †P = 0.007 versus diclofenac. SR = sustained release.
reported, including no significant changes in renal and liver function (estimated CCr and serum AST level). DISCUSSION
In the current study, we focused only on patients with acute gout, an extremely painful condition requiring rapid treatment. Rofecoxib 50 mg once daily (the dosage recommended for the treatment of acute pain) was used, because gout represents an acute pain model. Compared with 2 other widely
used once-daily NSAIDs, diclofenac sodium SR and meloxicam, rofecoxib demonstrated statistically higher overall analgesic responses, assessed either by investigators or patients on day 3. Approximately twice as many patients in the rofecoxib group compared with the other 2 groups achieved good and excellent responses on PGART and IGART. However, the improvement in the inflammatory score was shown to be comparable between the 3 treatment groups. Although the sample size was not large
Table II. Mean (SD) changes in pain intensity* from baseline at different time points after the first dose. Change in Pain Intensity Time After First Dose, h
Rofecoxib (n = 20)
0.5 1 2 6 12
–0.3 –0.6 –0.9 –1.3 –1.6
(0.1)† (0.1)‡ (0.1)‡ (0.1)‡ (0.2)‡
SR = sustained release. *Scale: 0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = extreme. †P < 0.05 versus baseline (paired t test). ‡P < 0.01 versus baseline (paired t test).
404
Diclofenac Sodium SR (n = 21)
–0.2 –0.5 –1.3 –1.8
0 (0.1)† (0.1)‡ (0.1)‡ (0.1)‡
Meloxicam (n = 21) –0.2 (0.1) –0.5 (0.1)‡ –0.8 (0.2)‡ –1.3 (0.2)‡ –1.5 (0.2)‡
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Table III. Changes in mean (SD) inflammatory scores from day 1 to day 8.* Score
Rofecoxib
Diclofenac Sodium SR
Meloxicam
P†
Day 1
6.0 (1.2) (n = 20)
5.7 (0.9) (n = 21)
6.2 (1.1) (n = 21)
0.242
Day 3
1.9 (1.5) (n = 18) –4.1 (0.3)§
2.4 (1.9) (n = 18) –3.3 (0.3)§
3.7 (2.5) (n = 20) –2.5 (0.67)§
0.024‡
1.0 (1.7) (n = 11) –5.2 (0.5)§
0.6 (0.7) (n = 14) –5.1 (0.3)§
1.1 (1.3) (n = 13) –5.4 (0.5)§
Change from day 1 Day 8 Change from day 1
0.074 0.642 0.922
SR = sustained release. *Scale: 0 = no pain, swelling, or restriction of movement to 9 = extreme pain to which patient winces and withdraws, swelling and bulging beyond the joint margin, and complete joint immobilization. †Analysis of variance. ‡P < 0.05 versus day 1 (paired t test). §P < 0.01 versus day 1 (paired t test).
enough to detect differences in pain intensity improvement during the first 12 hours, the efficacy analyses indicate that rofecoxib appeared to have a more rapid onset of action than meloxicam or diclofenac, and only rofecoxib demonstrated a significant improvement in pain at 30 minutes. Previous studies have shown that COX-2 selective inhibitors such as rofecoxib provide efficacy similar to that of nonselective NSAIDs in chronic inflammatory conditions such as rheumatoid arthritis,22 as well as in acute pain such as postorthopedic surgical pain13 and postoperative dental pain.12 In this study, we demonstrated that rofecoxib, in addition to etoricoxib,21 is an effective alternative COX-2 selective inhibitor to treat acute gouty arthritis. The limitations of this study include a small sample size and the lack of blinding of the patients. In addition, the results of the study cannot be extrapolated to the patients with acute gouty arthritis who meet the exclusion criteria of the study. Although the patients were not blinded to their treatment, the investigators and the study staff remained blinded to the treatment by prepackaging the study drugs. Furthermore, this study represents the first randomized clinical trial of rofecoxib for patients with acute gouty arthritis. With a larger sample size, rofecoxib might demonstrate superior efficacy in the onset of pain relief and inflammatory score improvement. In this study, diclofenac and meloxicam were chosen as active comparators instead of indo-
methacin for several reasons. Diclofenac is the most widely used NSAID, and it is effective in a variety of inflammatory conditions, including rheumatoid arthritis and ankylosing spondylitis.16 Meloxicam, as a COX-2 preferential inhibitor, represents a different type of NSAID and has been shown to be effective in treating rheumatoid arthritis and ankylosing spondylitis. 17 In addition, meloxicam can be given once daily and diclofenac can also be given once daily by using an SR formulation. On the other hand, indomethacin requires frequent dosing of 3 to 4 times a day, which would have hampered the blinding of the investigators and study staff. Based on the finding of this pilot study, a largescale, prospective, double-blind, randomized controlled study is warranted to support the efficacy of rofecoxib in the treatment of acute gouty arthritis. CONCLUSIONS
In this study of patients with acute gouty arthritis, rofecoxib 50 mg once daily provided more effective treatment than meloxicam 15 mg and diclofenac sodium SR 150 mg administered orally once daily for 7 days in ≥1 efficacy assessment of overall analgesic effect on day 3 or day 8. Rofecoxib achieved a rapid onset of pain relief, demonstrating significant improvement 30 minutes after dosing. All of the regimens appeared well tolerated in the population studied. 405
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ACKNOWLEDGMENTS
The authors are grateful for the drugs supplied by the manufacturers. We thank D.J. Chang, MD, PhD, for his comments on refining the wording of the manuscript. REFERENCES 1. Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am. 1990;16:539–550. 2. Kim KY, Schumacher RH, Hunsche E, et al. A literature review of the epidemiology and treatment of acute gout. Clin Ther. 2003;25:1593–1617. 3. Pittman JR, Bross MH. Diagnosis and management of gout. Am Fam Physician. 1999;59:1799–1806. 4. Stuart RA, Gow PJ, Bellamy N, et al. A survey of current prescribing practices of antiinflammatory and urate-lowering drugs in gouty arthritis. N Z Med J. 1991;104:115–117. 5. Bellamy N, Gilbert JR, Brooks PM, et al. A survey of current prescribing practices of antiinflammatory and urate lowering drugs in gouty arthritis in the province of Ontario. J Rheumatol. 1988;15:1841–1847. 6. Shrestha M, Morgan DL, Moreden JM, et al. Randomized double-blind comparison of the analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute gouty arthritis. Ann Emerg Med. 1995;26:682–686. 7. Altman RD, Honig S, Levin JM, Lightfoot RW. Ketoprofen versus indomethacin in patients with acute gouty arthritis: A multicenter, double blind comparative study. J Rheumatol. 1988;15:1422–1426. 8. Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum. 1988; 31:803–805. 9. Singh G, Rosen Ramey D, for the Arthritis, Rheumatism, and Aging Medical Information System. NSAID induced gastrointestinal complications: The ARAMIS perspective—1997. J Rheumatol Suppl. 1998;51:8– 16. 10. Thompson M, Percy JS. Further experience with indomethacin in the treatment of rheumatic disorders. BMJ. 1966;5479:80–83.
11. Pouliot M, James MJ, McColl SR, et al. Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. Blood. 1998;91:1769–1776. Chang DJ, Desjardins PJ, Chen E, et al. Comparison of 12. the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: A randomized, placebo-controlled clinical trial. Clin Ther. 2002;24:490–503. 13. Reicin A, Brown J, Jove M, et al. Efficacy of single-dose and multidose rofecoxib in the treatment of postorthopedic surgery pain. Am J Orthop. 2001;30:40–48. 14. Morrison BW, Daniels SE, Kotey P, et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: A randomized controlled trial. Obstet Gynecol. 1999;94:504–508. 15. Capraru MS, Ilie E. The efficacy of rofecoxib in the treatment of inflammatory arthropathies. Ann Rheum Dis. 2001;60(Suppl 1):SAT.0123. 16. Brogden RN, Heel RC, Pakes GE, et al. Diclofenac sodium: A review of its pharmacological properties and therapeutic use in rheumatic diseases and pain of varying origin. Drugs. 1980;20:24–48. 17. Fleischmann R, Iqbal I, Slobodin G. Meloxicam. Expert Opin Pharmacother. 2002;3:1501–1512. 18. Bosch HC, Sigmund R, Hettich M. Efficacy and tolerability of intramuscular and oral meloxicam in patients with acute lumbago: A comparison with intramuscular and oral piroxicam. Curr Med Res Opin. 1997;14:29–38. 19. Colombo G, Giombini A, Pamich T, et al. Diclofenac dispersible provides superior analgesia with faster onset of action compared to naproxen granular in patients with acute, painful, minor sports injuries. J Sports Med Phys Fitness. 1997;37:228–233. 20. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895–900. 21. Schumacher HR Jr, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indomethacin in treatment of acute gouty arthritis. BMJ. 2002;324:1488–1492. 22. Geusens PP, Truitt K, Sfikakis P, et al. A placebo and active comparator-controlled trial of rofecoxib for the treatment of rheumatoid arthritis. Scand J Rheumatol. 2002;31:230–238.
Address correspondence to: Tien-Tsai Cheng, MD, Section of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Tapei Road, Niao-Sung, Kaohsiung Hsien, Taiwan, Republic of China. E-mail: [email protected] 406
A Single-Blind, Randomized, Controlled Trial to Assess the Efficacy and Tolerability of Rofecoxib, Diclofenac Sodium, and Meloxicam in Patients with Acute Gouty Arthritis Tien-Tsai Cheng, MD,1,2 Han-Ming Lai, MD,1 Chun-Kai Chiu, MD,1 and Ying-Chou Chen, MD1 1Section of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial and 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, Taiwan, Republic of
Hospital, China
ABSTRACT
Background: Acute attacks of gouty arthritis are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint. Nonsteroidal anti-inflammatory drugs are considered the drugs of first choice for treating acute gout. Rofecoxib is a specific cyclooxygenase-2 inhibitor, which has demonstrated analgesic efficacy in the setting of acute pain. Whether it is effective in the treatment of acute gouty arthritis remains to be evaluated. Objective: The aim of this study was to assess the efficacy and tolerability of rofecoxib compared with diclofenac sodium sustained release (SR) and meloxicam in the treatment of acute gouty arthritis. Methods: In this single-blind, randomized, controlled, parallel-group study, patients aged ≥18 years with acute gout within 48 hours of onset were randomized to receive oral treatment with 2 tablets of rofecoxib (25 mg), diclofenac (75 mg), or meloxicam (7.5 mg) once daily for 7 days. The primary outcome measures were patient global assessment of response to therapy and investigator assessment of response to therapy on days 3 and 8. Other efficacy measurements included investigator assessment of total inflammatory scores on days 3 and 8 and patient assessment of pain intensity during the first 12 hours of treatment. Results: Sixty-two patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were assigned to receive rofecoxib (n = 20), diclofenac (n = 21), or meloxicam (n = 21). For patient global response to therapy on days 3 and 8, rofecoxib was associated with analgesic efficacy in significantly more patients compared with meloxicam (84.2% vs 40.0% of patients [P = 0.005] and 94.7% vs 60.0% of patients [P = 0.02], respectively); no significant differences versus diclofenac were found. Similarly, for investigator global assessment of response to therapy, a greater percentage of responders was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% of patients [P = 0.02]), but the difference was not significant on day 8. A greater percentage of responders was found in the rofecoxib group compared with the diclofenac group on day 3 (88.9% vs 47.3% [P = 0.007]), but the difference was not significant on day 8. Compared with baseline, all regimens showed significant improvement in total inflammatory scores on days 3 and 8 (all P < 0.01). During the first 12 hours after dosing, pain intensity score was significantly reduced with rofecoxib starting at 0.5 hour (P < 0.05), but not with diclofenac or meloxicam. Clinical adverse events (AEs) were reported in 4 (20.0%), 7 (33.3%), and 6 (28.6%) patients in the rofecoxib, diclofenac, and meloxicam groups, respectively; the most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal pain (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). No significant differences in tolerability were found among the 3 treatment groups. Accepted for publication January 11, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2004 Excerpta Medica, Inc.
0149-2918/04/$19.00
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Conclusions: In this study of patients with acute gouty arthritis, rofecoxib 50 mg once daily provided more effective treatment than diclofenac sodium SR 150 mg and meloxicam 15 mg administered orally once daily for 7 days in ≥1 efficacy assessment of overall analgesic effect on day 3 or day 8. Rofecoxib achieved a rapid onset of pain relief, demonstrating significant improvement 30 minutes after dosing. All of the regimens appeared well tolerated in the population studied. (Clin Ther. 2004;26:399–406) Copyright © 2004 Excerpta Medica, Inc. Key words: acute gouty arthritis, nonsteroidal antiinflammatory drugs.
INTRODUCTION
Gouty arthritis, the most common type of inflammatory joint disease in men aged >40 years, is caused by the deposition of monosodium urate (MSU) microcrystals into the affected joint space. Acute attacks of gout are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint, which can be disabling.1 Although pain is the primary symptom of acute gout, an effective treatment must target the pain and the underlying inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the drugs of choice for treating acute gout, with indomethacin, naproxen, and sulindac having received approval from the US Food and Drug Administration for this indication.2,3 Although indomethacin is widely used,4,5 its efficacy is based on a limited number of studies6–8 (according to a MEDLINE search [key terms, nonsteroidal anti-inflammatory drugs, gout, and gouty arthritis; years, 1966–2003]), and its associated gastrointestinal tract and central nervous system adverse events (AEs) are significant.9,10 Evidence has shown that cyclooxygenase-2 (COX-2) expression in monocytes is induced in response to MSU microcrystal formation.11 Therefore, it is likely that NSAIDs exert their efficacy in the treatment of gout by inhibiting the production of COX-2– mediated proinflammatory prostaglandins. Rofecoxib is a specific COX-2 inhibitor that has demonstrated analgesic efficacy in the setting of acute pain of postoperative dental surgery,12 in a postorthopedic surgical model,13 and in primary dysmenorrhea.14 Despite a thorough search of the literature, we were able 400
to find only 1 small-scale, uncontrolled study of the efficacy of rofecoxib in the treatment of acute gout.15 The use of once-daily dosing of many drugs, including NSAIDs, is a current trend in medical practice. Rofecoxib can be given as once-daily treatment due to its long half-life. Diclofenac sodium sustained release (SR) and meloxicam also can be given once daily in the treatment of various rheumatic disorders16,17 and certain diseases with acute pain.18,19 Because acute gouty arthritis is an extremely painful condition that should be controlled as rapidly as possible, the maximum recommended daily dosage of each of the 3 drugs was chosen for this study. The aim of this study was to compare the analgesic efficacy, anti-inflammatory efficacy, and tolerability of rofecoxib 50 mg, diclofenac sodium SR 150 mg, and meloxicam 15 mg given as a once-daily oral regimen for acute gouty arthritis. PATIENTS AND METHODS Study Population
Patients were recruited from the Section of Allergy, Immunology and Rheumatology outpatient clinic of Chang Gung Memorial Hospital (CGMH) (Kaohsiung, Taiwan) from December 2001 through July 2002. Patients aged ≥18 years were eligible for the study if they were experiencing an acute attack of gout based on the American Rheumatism Association criteria.20 Other patient entry criteria included a physicianassessed total inflammatory score of ≥5 on a 0- to 9point scale (the sum of the scores for restriction of function [0–3 points], tenderness [0–3 points], and swelling [0–3 points] of the most severely affected joint) as determined by investigators; patient assessment of pain intensity as moderate, severe, or extreme; onset of acute gout attack within 48 hours prior to randomization; and stable dose of any concomitant hypouricemic agent for >30 days. Finally, patients had to be in otherwise good health based on physical examination and medical history and had to be able to understand the study procedures and the agreement to participate in the study. Patients were excluded if they had a history of attacks of acute gout that were unresponsive to NSAIDs; a gouty arthritis attack involving ≥3 joints; allergic reactions to any component of the study drugs, other NSAIDs, or aspirin; a history of asthma associated with nasal polyps; a history of gastroin-
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testinal ulcer bleeding or perforation within 6 months prior to study entry; history of chronic analgesic or tranquilizer use or dependency within the 3 months before enrollment; uncontrolled hypertension, diabetes mellitus, renal disease, or neurologic disorder; a history of stroke; a history of gastric, biliary, or small intestinal surgery that resulted in clinical malabsorption; any significant cardiovascular, hepatic, or neoplastic disease or clinically significant abnormalities on the prestudy examination; significantly abnormal laboratory safety tests, such as serum aspartate aminotransferase levels >2-fold above the upper limit of normal or serum creatinine level >1.4 mg/dL. Pregnant, possibly pregnant, or breastfeeding women were excluded. Women of childbearing potential who were not using adequate contraception were also ineligible for the study, as were patients who regularly consumed alcohol. Finally, patients who had taken either oral or parenteral NSAIDs or systemic corticosteroids within 48 hours before the study, who required regular use of anticoagulant drugs (eg, ticlopidine or clopidogrel), or who had taken colchicine (>1 mg/d) within 8 days prior to study entry were also excluded from the study. Study Design
This was a single-blind, randomized, controlled, parallel-group study of patients with acute gouty arthritis. The protocol was reviewed and approved by the CGMH institutional review board. All patients provided written informed consent before being screened for eligibility. Eligible patients were consecutively randomly assigned in a 1:1:1 ratio to receive oral treatment with 2 tablets of either rofecoxib* (25 mg), diclofenac sodium SR† (75 mg), or meloxicam‡ (7.5 mg) once daily for 7 consecutive days according to a predetermined block randomization table with block factor of 6. Although the patients were not blinded to the treatment assignment, all of the medications were prepackaged and sealed to maintain blinding of the investigators and study staff. In addition, patients were requested not to discuss their treatments with the investigators or study staff. All patients were *Trademark:
Vioxx® (Merck & Co., Inc., Rahway, New Jersey). †Trademark: Voltaren® (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). ‡Trademark: Mobic® (Boehringer Ingelheim GmbH, Ingelheim, Germany).
scheduled to return to the clinic on days 3 and 8 for assessment. Efficacy Assessment
Overall analgesic effect was determined by patient global assessment of response to therapy (PGART) and investigator global assessment of response to therapy (IGART), as in the study by Schumacher et al,21 on days 3 and 8. For both assessments, the possible responses were no effect, poor, fair, good, or excellent (5-point verbal scale). Patients were considered to be responders if the assessments on PGART or IGART were good or excellent. The overall anti-inflammatory effect was assessed by the investigators on days 3 and 8 using the total inflammatory score, which was used to determine the tenderness, swelling, and restriction of function in the affected joints. The 10-point numeric score ranged from 0 (no pain, swelling, or restriction of movement) to 9 (extreme pain to which patient winces and withdraws, swelling and bulging beyond the joint margin, and complete joint immobilization). In addition, we asked the patients to assess their pain intensity as the secondary end point using a 5-point verbal scale of none, slight, moderate, severe, or extreme at baseline (predose) and 0.5, 1, 2, 6, and 12 hours after initial dosing of the study drug. If both the PGART and IGART were excellent on day 3, the study medications were discontinued. However, if both the PGART and IGART were recorded as poor or having no effect on day 3 and the patient elected to discontinue the study medication, rescue medication with prednisolone 10 mg TID was given in place of the study medication. Tolerability Assessment
The tolerability of the study medications was determined using physical examination by the investigators, vital signs measured by assisting nurses, outpatient laboratory testing (estimated serum creatinine clearance [CCr] and serum aspartate aminotransferase [AST] level), and spontaneous reporting of any AEs by the patient. Statistical Analysis
Efficacy analyses were based on a modified intentto-treat approach; all patients with a baseline assessment and ≥1 efficacy measurement either on day 3 or 401
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day 8 were included in the analyses. The percentage of patients who were responders (good or excellent response) as assessed by patient (PGART) and by investigator (IGART) on days 3 and 8 were tested using the Fisher exact test. The changes in pain intensity at various time points within treatment groups were tested using paired t tests, and comparisons among the 3 treatment groups were tested by analysis of variance. The changes in total inflammatory score from day 1 within groups were tested by paired t tests and comparisons among the 3 treatment groups by analysis of variance. For missing assessments, the last available observations were carried forward. All randomized patients were included in the tolerability analysis. All clinical AEs occurring during the study were summarized by types of event. The Fisher exact test was used to compare the treatment groups with respect to the number of patients with AEs. Patients who had any abnormal changes in laboratory values at the end of the study were assessed for clinical significance. Statistical analysis was performed using SAS software version 8e (SAS Institute Inc., Cary, North Carolina). For all efficacy and tolerability comparisons, the difference was considered to be statistically significant at P ≤ 0.05 (2-tailed).
Table I.
RESULTS
A total of 62 patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were enrolled in the study; 20 patients received rofecoxib, 21 received diclofenac sodium SR, and 21 received meloxicam. The baseline demographic characteristics were similar between the 3 groups (Table I). At baseline, 28 patients (45.2%) reported extreme pain, and 27 patients (43.5%) reported severe pain. In total, 5 patients, including 2 patients each from the rofecoxib (10.0%) and diclofenac (9.5%) groups and 1 patient (4.8%) from the meloxicam group, failed to return to the outpatient clinic on day 3. The reasons for withdrawal were study drug ineffectiveness on day 2 (1 patient each from the rofecoxib [5.0%] and meloxicam [4.8%] groups) and personal factors on day 3 (1 patient each from the rofecoxib [5.0%], diclofenac [4.8%], and meloxicam [4.8%] groups). PGART assessments on day 3 were collected using telephone interviews of these patients, except those who withdrew due to study drug ineffectiveness on day 2, but IGART and inflammatory score assessments were unobtainable from these 5 patients. Efficacy
For overall analgesic efficacy based on PGART, a greater percentage of responders (with good to excel-
Baseline demographic and clinical characteristics of the study patients.*
Characteristic
Rofecoxib (n = 20)
Diclofenac Sodium SR (n = 21)
Meloxicam (n = 21)
Total (N = 62)
Age, mean (SD), y
52.2 (14.5)
50.4 (11.6)
50.6 (10.5)
51.1 (12.1)
15 (75.0) 5 (25.0)
19 (90.5) 2 (9.5)
19 (90.5) 2 (9.5)
53 (85.5) 9 (14.5)
Sex, no. (%) Men Women BMI, mean (SD), kg/m2 Pain intensity, no. (%) Extreme Severe Moderate Total inflammatory score, mean (SD)†
24.3 (1.9) 9 (45.0) 7 (35.0) 4 (20.0) 6.0 (1.2)
24.9 (2.1)
25.5 (2.8)
24.9 (2.1)
9 (42.9) 11 (52.4) 1 (4.8)
10 (47.6) 9 (42.9) 2 (9.5)
28 (45.2) 27 (43.5) 7 (11.3)
5.7 (0.9)
6.2 (1.1)
6.0 (1.1)
SR = sustained release; BMI = body mass index. *No significant between-group differences were found (Fisher exact test). †Scale: 0 = no pain, swelling, or restriction of movement to 9 = extreme pain to which patient winces and withdraws, swelling and bulging beyond the joint margin, and complete joint immobilization.
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lent ratings) was found in the rofecoxib group compared with the meloxicam group on days 3 and 8 (84.2% vs 40.0% [P = 0.005]; 94.7% vs 60.0% [P = 0.02], respectively), but no statistically significant difference was found when compared with diclofenac on days 3 and 8 (84.2% vs 57.1%; 94.7% vs 81.0%, respectively) (Figure 1). Regarding the investigators’ perspectives, similar results were shown for the IGART end point. A greater percentage of responders (with good to excellent ratings) was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% [P = 0.02]), but the difference was not significant on day 8 (89.5% vs 61.9%). Rofecoxib provided a statistically greater response than diclofenac on day 3 (88.9% vs 47.3% [P = 0.007]) but not on day 8 (89.5% vs 85.7%) (Figure 2). Using logistic regression analysis, the PGART and IGART analyses confirmed the findings based on the percentages of responders (data not shown). The changes in pain intensity from baseline, as assessed by patients at different time points immediately after study drug dosing, are shown in Table II. Both rofecoxib and meloxicam demonstrated similar improvement in pain scores compared with diclofenac
during the first 2 hours. Only the rofecoxib group showed significant improvement at 30 minutes compared with baseline (P < 0.05), and pain relief was maintained throughout the 12-hour assessment period. Overall Anti-inflammatory Effect
Compared with baseline, all of the regimens showed significant response on days 3 and 8 based on the change in inflammatory scores (all P < 0.01). However, no obvious difference was noted between the treatment groups (Table III). Tolerability
No serious AEs were reported in any group. None of the patients withdrew from the study because of an AE. Clinical AEs were reported by 4 patients (20.0%) treated with rofecoxib compared with 6 (28.6%) treated with meloxicam and 7 (33.3%) treated with diclofenac; no significant differences were found among the 3 groups. The most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal pain (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). These AEs were considered probably treatment related. No laboratory AEs were Rofecoxib (n = 20) Diclofenac sodium SR (n = 21) Meloxicam (n = 21)
100
†
*
% Patients
80
60
40
20
0 Day 3
Day 8
Figure 1. Percentages of patients with good or excellent response to therapy by patient self-assessment. *P = 0.005 versus meloxicam; †P = 0.02 versus meloxicam. SR = sustained release. 403
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Rofecoxib (n = 20) Diclofenac sodium SR (n = 21) Meloxicam (n = 21)
100 *† *
% Patients
80
60
40
20
0 Day 3
Day 8
Figure 2. Percentages of patients with good or excellent response to therapy as assessed by investigators. *P = 0.02 versus meloxicam; †P = 0.007 versus diclofenac. SR = sustained release.
reported, including no significant changes in renal and liver function (estimated CCr and serum AST level). DISCUSSION
In the current study, we focused only on patients with acute gout, an extremely painful condition requiring rapid treatment. Rofecoxib 50 mg once daily (the dosage recommended for the treatment of acute pain) was used, because gout represents an acute pain model. Compared with 2 other widely
used once-daily NSAIDs, diclofenac sodium SR and meloxicam, rofecoxib demonstrated statistically higher overall analgesic responses, assessed either by investigators or patients on day 3. Approximately twice as many patients in the rofecoxib group compared with the other 2 groups achieved good and excellent responses on PGART and IGART. However, the improvement in the inflammatory score was shown to be comparable between the 3 treatment groups. Although the sample size was not large
Table II. Mean (SD) changes in pain intensity* from baseline at different time points after the first dose. Change in Pain Intensity Time After First Dose, h
Rofecoxib (n = 20)
0.5 1 2 6 12
–0.3 –0.6 –0.9 –1.3 –1.6
(0.1)† (0.1)‡ (0.1)‡ (0.1)‡ (0.2)‡
SR = sustained release. *Scale: 0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = extreme. †P < 0.05 versus baseline (paired t test). ‡P < 0.01 versus baseline (paired t test).
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Diclofenac Sodium SR (n = 21)
–0.2 –0.5 –1.3 –1.8
0 (0.1)† (0.1)‡ (0.1)‡ (0.1)‡
Meloxicam (n = 21) –0.2 (0.1) –0.5 (0.1)‡ –0.8 (0.2)‡ –1.3 (0.2)‡ –1.5 (0.2)‡
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Table III. Changes in mean (SD) inflammatory scores from day 1 to day 8.* Score
Rofecoxib
Diclofenac Sodium SR
Meloxicam
P†
Day 1
6.0 (1.2) (n = 20)
5.7 (0.9) (n = 21)
6.2 (1.1) (n = 21)
0.242
Day 3
1.9 (1.5) (n = 18) –4.1 (0.3)§
2.4 (1.9) (n = 18) –3.3 (0.3)§
3.7 (2.5) (n = 20) –2.5 (0.67)§
0.024‡
1.0 (1.7) (n = 11) –5.2 (0.5)§
0.6 (0.7) (n = 14) –5.1 (0.3)§
1.1 (1.3) (n = 13) –5.4 (0.5)§
Change from day 1 Day 8 Change from day 1
0.074 0.642 0.922
SR = sustained release. *Scale: 0 = no pain, swelling, or restriction of movement to 9 = extreme pain to which patient winces and withdraws, swelling and bulging beyond the joint margin, and complete joint immobilization. †Analysis of variance. ‡P < 0.05 versus day 1 (paired t test). §P < 0.01 versus day 1 (paired t test).
enough to detect differences in pain intensity improvement during the first 12 hours, the efficacy analyses indicate that rofecoxib appeared to have a more rapid onset of action than meloxicam or diclofenac, and only rofecoxib demonstrated a significant improvement in pain at 30 minutes. Previous studies have shown that COX-2 selective inhibitors such as rofecoxib provide efficacy similar to that of nonselective NSAIDs in chronic inflammatory conditions such as rheumatoid arthritis,22 as well as in acute pain such as postorthopedic surgical pain13 and postoperative dental pain.12 In this study, we demonstrated that rofecoxib, in addition to etoricoxib,21 is an effective alternative COX-2 selective inhibitor to treat acute gouty arthritis. The limitations of this study include a small sample size and the lack of blinding of the patients. In addition, the results of the study cannot be extrapolated to the patients with acute gouty arthritis who meet the exclusion criteria of the study. Although the patients were not blinded to their treatment, the investigators and the study staff remained blinded to the treatment by prepackaging the study drugs. Furthermore, this study represents the first randomized clinical trial of rofecoxib for patients with acute gouty arthritis. With a larger sample size, rofecoxib might demonstrate superior efficacy in the onset of pain relief and inflammatory score improvement. In this study, diclofenac and meloxicam were chosen as active comparators instead of indo-
methacin for several reasons. Diclofenac is the most widely used NSAID, and it is effective in a variety of inflammatory conditions, including rheumatoid arthritis and ankylosing spondylitis.16 Meloxicam, as a COX-2 preferential inhibitor, represents a different type of NSAID and has been shown to be effective in treating rheumatoid arthritis and ankylosing spondylitis. 17 In addition, meloxicam can be given once daily and diclofenac can also be given once daily by using an SR formulation. On the other hand, indomethacin requires frequent dosing of 3 to 4 times a day, which would have hampered the blinding of the investigators and study staff. Based on the finding of this pilot study, a largescale, prospective, double-blind, randomized controlled study is warranted to support the efficacy of rofecoxib in the treatment of acute gouty arthritis. CONCLUSIONS
In this study of patients with acute gouty arthritis, rofecoxib 50 mg once daily provided more effective treatment than meloxicam 15 mg and diclofenac sodium SR 150 mg administered orally once daily for 7 days in ≥1 efficacy assessment of overall analgesic effect on day 3 or day 8. Rofecoxib achieved a rapid onset of pain relief, demonstrating significant improvement 30 minutes after dosing. All of the regimens appeared well tolerated in the population studied. 405
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ACKNOWLEDGMENTS
The authors are grateful for the drugs supplied by the manufacturers. We thank D.J. Chang, MD, PhD, for his comments on refining the wording of the manuscript. REFERENCES 1. Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am. 1990;16:539–550. 2. Kim KY, Schumacher RH, Hunsche E, et al. A literature review of the epidemiology and treatment of acute gout. Clin Ther. 2003;25:1593–1617. 3. Pittman JR, Bross MH. Diagnosis and management of gout. Am Fam Physician. 1999;59:1799–1806. 4. Stuart RA, Gow PJ, Bellamy N, et al. A survey of current prescribing practices of antiinflammatory and urate-lowering drugs in gouty arthritis. N Z Med J. 1991;104:115–117. 5. Bellamy N, Gilbert JR, Brooks PM, et al. A survey of current prescribing practices of antiinflammatory and urate lowering drugs in gouty arthritis in the province of Ontario. J Rheumatol. 1988;15:1841–1847. 6. Shrestha M, Morgan DL, Moreden JM, et al. Randomized double-blind comparison of the analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute gouty arthritis. Ann Emerg Med. 1995;26:682–686. 7. Altman RD, Honig S, Levin JM, Lightfoot RW. Ketoprofen versus indomethacin in patients with acute gouty arthritis: A multicenter, double blind comparative study. J Rheumatol. 1988;15:1422–1426. 8. Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum. 1988; 31:803–805. 9. Singh G, Rosen Ramey D, for the Arthritis, Rheumatism, and Aging Medical Information System. NSAID induced gastrointestinal complications: The ARAMIS perspective—1997. J Rheumatol Suppl. 1998;51:8– 16. 10. Thompson M, Percy JS. Further experience with indomethacin in the treatment of rheumatic disorders. BMJ. 1966;5479:80–83.
11. Pouliot M, James MJ, McColl SR, et al. Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. Blood. 1998;91:1769–1776. Chang DJ, Desjardins PJ, Chen E, et al. Comparison of 12. the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: A randomized, placebo-controlled clinical trial. Clin Ther. 2002;24:490–503. 13. Reicin A, Brown J, Jove M, et al. Efficacy of single-dose and multidose rofecoxib in the treatment of postorthopedic surgery pain. Am J Orthop. 2001;30:40–48. 14. Morrison BW, Daniels SE, Kotey P, et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: A randomized controlled trial. Obstet Gynecol. 1999;94:504–508. 15. Capraru MS, Ilie E. The efficacy of rofecoxib in the treatment of inflammatory arthropathies. Ann Rheum Dis. 2001;60(Suppl 1):SAT.0123. 16. Brogden RN, Heel RC, Pakes GE, et al. Diclofenac sodium: A review of its pharmacological properties and therapeutic use in rheumatic diseases and pain of varying origin. Drugs. 1980;20:24–48. 17. Fleischmann R, Iqbal I, Slobodin G. Meloxicam. Expert Opin Pharmacother. 2002;3:1501–1512. 18. Bosch HC, Sigmund R, Hettich M. Efficacy and tolerability of intramuscular and oral meloxicam in patients with acute lumbago: A comparison with intramuscular and oral piroxicam. Curr Med Res Opin. 1997;14:29–38. 19. Colombo G, Giombini A, Pamich T, et al. Diclofenac dispersible provides superior analgesia with faster onset of action compared to naproxen granular in patients with acute, painful, minor sports injuries. J Sports Med Phys Fitness. 1997;37:228–233. 20. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895–900. 21. Schumacher HR Jr, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indomethacin in treatment of acute gouty arthritis. BMJ. 2002;324:1488–1492. 22. Geusens PP, Truitt K, Sfikakis P, et al. A placebo and active comparator-controlled trial of rofecoxib for the treatment of rheumatoid arthritis. Scand J Rheumatol. 2002;31:230–238.
Address correspondence to: Tien-Tsai Cheng, MD, Section of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Tapei Road, Niao-Sung, Kaohsiung Hsien, Taiwan, Republic of China. E-mail: [email protected] 406