Treatment of acute gout with oxaprozin

Acute Gout

Treatment of Acute Gout With Oxaprozin By Philip J. Mease and Robert F. Willkens Fifty patients with acute gouty arthritis entered into an S-day multicenter open study designed to evaluate the efficacy and safety of oxaprozln, a new nonsteroidal antiinflammatory drug (NSAID). Patients received 1.800 mg of oxaprozin daily in two divided doses (1.200 mg in the morning and 600 mg in the evening I for 2 days. followed by 1.200 mg daily until pain was relieved. Based on evaluation of pain intensity recorded on patient diary cards. 84% of the patients (P < .001) showed improvement during the 24 hours after receiving at least 2 doses 11.800 mg) of oxaprozin. At the final clinical visit. 93% reported

improvement (P < .001). Fourteen patients reported adverse effects. but only two discontinued treatment for that reason. Five patients discontinued because of an unsatisfactory response . A significant decrease (P < .0011 from baseline occurred in mean total leukocyte count by the eighth day. probably due to the antiinflammatory effect of oxaprozin. No clinically significant changes in renal or hepatic function test results or vital signs were observed. Oxaprozin was found to be effective and safe in the treatment of patients with acute gout. ~ 1986 by Grun9 & Stratton, Inc.

G

methods of treatment, block the phagocytosis of urate crystals by PMN but have no effect on CCF production.t? Although effective, these agents may produce upper gastrointestinal (GI) tract irritation or cause fluid retention, even during short-term administration; therefore, active peptic ulcers or severe congestive heart failure are contraindications to their use. In addition, phenylbutazone has been associated with leukopenia and bone marrow depression. At present, therefore, orally administered colchicine and these other agents have largely been supplanted by intravenously (IV) administered colchicine and by nonstero idal antiinflammatory drugs (NSAIDs) that cause fewer severe GI and other serious side effects.t" Naproxen, piroxicam, fenoprofen, meclofenamic acid, niflumic acid, and l-isopropyl-4-phenyl-7-methyl2(1H)quinazolone (agent 43·715) have been shown to be at least moderately effective in treating acute goUt.8 •10 In addition, GI side effects reported with some of the NSAIDs, specifically piroxicam and naproxen, have been mild and have not necessitated discontinuation of treatment. Oxaprozin is a propionic acid derivative (4,5diphenyl-2-oxazole propionic acid) that is safe and effective, in doses ranging from 600 to 1,800 mg/d, for the treatment of rheumatoid arthritis (RA),11 osteoarthritis," and tendinitis and bursitis." In addition, oxaprozin has demonstrated uricosuric properties in both preclinical and c1in-

OUT is characterized by recurrent episodes of severe arthritis associated with the presence of monosodium urate monohydrate crystals in the synovial fluid and, in many cases, the eventual appearance of gross urate deposits (tophi) in and about the joints, in the kidneys, and in subcutaneous sites. The acute episode is precipitated by crystal-induced chemotactic factor (CCF) released from polymorphonuclear leukocytes (PMN) during phagocytosis.' In contrast to most other types of arthritis, the onset of joint inflammation in acute gout is very rapid and, typicalIy, maximal pain and swelling occur in several hours. Colchicine, the traditional remedy for acute gouty arthritis, blocks the inflammatory reaction in the joint and the generation of CCF by the leukocyte.' However, colchicine also causes severe abdominal cramping, diarrhea, nausea, and vomiting in approximately 80% of the patients treated.' Phenylbutazone, oxyphenbutazone, and indomethacin, which have been used as alternate

From the Division of Arthritis, Department of MediCine, University of Washington Medical School; and Harborview Hospital. Seattle. Philip J. Mease, MD; Division ofArthritis. Department of Medicine. University of Washington Medical School: Robert F. Wilkens. MD : Harborview Hospital. Address reprint requests to Robert F. Willkens, MD. 715 Minor Ave, Seattle, WA 98103. CO 1986 by Grune & Stratton, Inc. 0049--()172/86/1 503...()() I0$5 .00/0 86

Seminars in Arthritis and Rheumatism. Vol 15. No 3, Suppl 2 (February), 1986: pp 86-89

87

TREATMENT OF ACUTE GOUT WITH OXAPROZIN

ical studies. 14•l s Specifically, when given in doses within its antiinflammatory range, oxaprozin delayed the excretion of phenol red from the blood of fasting rats, indicative of increased uric acid excretion." In patients with RA, oxaprozin lowered the mean serum uric acid level." The present study was performed to determine the drug's effectiveness in the treatment of patients with acute gout. PATIENTS AND METHODS Outpatients of either sex were enrolled in the study if they presented within 48 hours of the onset of acute gouty arthritis and had hyperuricemia or demonstrable uric acid crystals in synovial fluid. The presence of tophi and a history of documented gout were used as supportive evidence for the diagnosis. Institutional review committee approval of the protcol was granted and informed consent was obtained from each patient. Excluded from the study were women who were pregnant. breast feeding, or of childbearing potential; patients with known hypersensitivity to NSAIDs; patients receiving ant icoagulant or steroid thera py; those with malignancies. active peptic ulcers, or renal or hepatic disease; and those with rheumatic diseases resembling gout (for example, gonorrheal arthritis. cellulitis, Reiter syndrome) . Eligible patients were not permitted to receive analgesic or antiinflammatory agents, colchicine, or antihyperuricemic medication during the study . The patients received loading doses of 1,800 mg of oxaprozin per day for the first 2 days (1,200 mg in the morning followed by 600 mg in the evening) . On subsequent days, the da ily dose was fixed at 1,200 mg (600 mg twice daily). Therapy continued for S days and could be extended to 8 days at the discretion of the investigator. Clin ical data were collected on therapy days I, 3, S, 8 and at a follow-up visit on day 14. Efficacy was assessed daily by the patient's ranking of pain on a scale of 4 (extreme) to 0 (none) on a diary card in the evening of each day of therapy and at each clinical visit in an oral description to the physician. Since the efficacy data were of a categorical type, Friedman test was used to test for significant changes from baseline. The severity of adverse effects noted by either the patient or the physician was graded, and the physician recorded his impression of each effect as definitely, probably, possibly, or not related to therapy . Safety was assessed by laboratory tests that included preand post-treatment hematologic, blood chemistry, and serum ur ic acid determinations and urinalyses . The paired' test was used to test for significant changes in laboratory data over time .

RESULTS

Study Population Fifty patients were enrolled, There was a predominance of males (88%) and whites (76%), with a mean age of 54 years (28 to 84 years) and a mean weight of 186 Ib (98 to 299 lb). The

Table 1. Joint Involvement of Patients W ith Acute Gout Treated with Oxaprozin Joints Involved Great toe

Ankle Knee(s) Wrist Olecranon bursa Second distal interphalangeal Elbow Two or more joints involved

No.(%)

17 (341 9 (18) 5 (10) 4(8) 2(4) 1 (2)

1 (2)

11 (22)

degree of pain at the start of therapy was extreme in 19 patients (38%), severe in 25 (50%), moderate in five (10%), and not reported for one (2%). Joints involved are listed in Table 1. Twenty-nine patients had concurrent illnesses, with hypertension the most frequently reported (14 patients, 28%). Twenty-nine patients (58%) took other allowed medications concomitantly with oxaprozin, the most common being diuretics (16%) and other antihypertensive agents (24%).

Efficacy Assessments Forty-three patients were evaluated for efficacy; six who were excluded from the efficacy evaluation took unacceptable concomitant medications (indomethacin, colchicine, or probenecid), and one had no baseline data. Early response to therapy was evaluated using the patients' assessments of pain intensity recorded on the diary cards. Mean pain intensity remained at the baseline value (3.33) on day I, decreased to 2.21 on day 2 after at least two 1,800 mg doses of oxaprozin had been taken by each patient, and progressively decreased to 0.58 on day 8 (Fig I). By day 2, 36 patients (84%) reported improvement in their degree of pain (Table 2). With the exception of one patient on day 3 and one on day 5, all patients evaluated for efficacy had reduction of pain relative to baseline from days 3 through 8. Analysis of the degree of pain at each clinical visit (patient's oral description to the physician) showed a similar pattern of improvement. At the final clinical evaluation, 42 of 43 patients (98%) showed improvement in their clinical conditions, and that improvement was still evident at the follow-up visit on day 14.

Attrition and Safety Seven patients discontinued oxaprozin therapy for treatment-related reasons. Five patients with-

MEASE AND WILLKENS

88

.00l) in mean leukocyte count from 9,600/~L to which was consistent with the observed decrease in inflammation, and a slight decrease (-0.3 g/dL) in mean hemoglobin values (P < .05) were noted. The changes in hemoglobin levels were not associated with overt gastrointestinal bleeding and were of no clinical importance. Small decreases in mean uric acid levels were noted at each visit (-0.25 to -0.38 mg/dl.) but were not statistically significant. No clinically significant changes occurred in renal and hepatic function test results or in any other blood chemistry determination. 7,700/~L,

3-

I

1 43

2 43

I

1

i

3

4

5

6

7

B

DAYS

42

40

36

30

25

19

NO.

i

or

PATIENTS

Fig 1. Mean response scores for the degree of pain based on patient diary cards: patients with acute gout treated with oxaprozin. (Mean response: 0 - none: 1 - slight: 2 - moderate: 3 - severe: 4 - extreme.1

DISCUSSION

The new, long-acting NSAID oxaprozin has been shown to effectively reduce symptoms of various arthritic syndromes'"" with few untoward effects. During long-term studies lasting up to I year, the incidence of severe (GI) adverse effects (gastric ulcer or bleeding) was very low «I%)}6-20 In addition, oxaprozin caused no reduction in sodium excretion by healthy volunteers during sustained water diuresis" and only very slight mean weight gains in large, clinical trial populations (0.0 to 0.5 Ib) after 2 weeks of therapy.P:" The results of this study demonstrate that oxaprozin, given in doses of 1,800 mg/d initially, followed by 1,200 mg/d for up to 8 days, is a clinically effective and safe agent for the treatment of gout. Eighty-four percent of the patients (P < .00 I) showed improvement after having received at least two doses (1,800 mg) of oxaprozin, and at the final clinical evaluation on day 8, 93% reported improvement (P < .00l). In the opinion of the observers, 98% of patients showed improvement in their clinical conditions by day 8, and that improvement was still noted at the follow-up visit on day 14. Oxaprozin also proved to be safe, with the incidence of the most

drew because of unsatisfactory response, one withdrew because of adverse experience (swelling of the ankles and feet after discontinuing previous diuretic therapy), and one withdrew because of adverse experiences (epigastric distress and loose stools) in combination with an unsatisfactory response. A total of fourteen patients (28%), including the two previously mentioned who withdrew, reported adverse effects. Only three patients, including the one withdrawal who had epigastric distress and loose stools, had adverse effects that were judged to be definitely associated with oxaprozin. Adverse effects in the remaining II patients, including the above mentioned patient with swelling of the ankles and feet, were felt to be only possibly related to oxaprozin therapy. The most frequently reported averse effects among all 50 patients were headache (8%), abdominal pain and discomfort (6%), nausea (6%), and flatulence (4%). On the final day of treatment, a significant mean weight gain of 1.0 lb over baseline was noted (P < .05). A significant decrease (P <

Table 2. Patients With Decreases. no Change. or Increases in Pain Intensity as Assessed by Patient Diary Cards

Changes.n Pain Intensity

1 No.(%)

2 No. 1%1

3 No. (%1

4 No.(%)

6 No.(%)

6 No.(%)

7 No.(%)

8 No. 1%)

Final On-Therapy Evalustion No. 1%1

Decreased No change Increased Total patients-

3 (71 36 (84) 4 (9)

36 (84) 6 (14) 1(2)

41 (98) 1(2)

30 (1001 0 0 30

19(1001

40 (93)

43

35 (971 1(31 0 36

25 (1001

43

40(1001 0 0 40

Day

0 42

0 0 25

-Numbers of patients decreased over time because therapy could be withdrawn when pain was relieved.

0 0 19

2 (51 1 (21 43

89

TREATMENT OF ACUTE GOUT WITH OXAPROZIN

frequently reported adverse effects ranging from 4% (flatulence) to 8% (headache). Oxaprozin can therefore be expected to provide pain relief of acute gout attacks within 24 to 48 hours. Although the onset of this relief is somewhat delayed with oxaprozin as compared with some 7.8.10 but not all 7 NSAIDs. oxaprozin is not associated with the high incidence of GI side-effects commonly seen with oral colchicine or the potentially serious adverse effects asso-

ciated with oxyphenbutazone and phenylbutazone. ACKNOWLEDGMENT The following clinical investigators, in addition to the authors, conducted this multicenter stud y: Drs Roy D. Altman, Miami, Fla; Daniel J. Appelrouth, Atlanta; John T. Harrington, Madison. Wis; Richard S. Panush, Gainesville, Fla; Jeffrey E. Polley, Orlando. Fla: James E. Poteet, Montgomery, Ala; and Robert T. Reid, LaJolla, Calif.

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13. Bono RF, Finkel S, Goodman HF, et al: A multicenter, double-blind comparison of oxaprozin, phenylbutazone, and placebo therapy in patients with tend initis and bursitis. Clin Ther 6:79-85, 1983 14. Lewis AJ, Carlson RP. Chang J. et al: The pharmacological profile of oxaprozin, an antiinflammatory and analgesic agent with low gastrointestinal toxicity. Curr Ther Res 34:777-794, 1983 15. Goldfarb S, Walker BR, Agus ZS: The uricosuric effect of oxaprozin in humans . J Clin Pharmacol 25:144-148, 1985 16. Barber JV, Collins RL, Kitridou RC , et al: The efficacy and safety of single daily doses of oxaprozin in the treatment of rheumatoid arthritis: A comparison with aspirin. Semin Arthritis Rheum 15:47-53, 1986 (suppI2) 17. Appelrouth OJ , Chodock AL. Miller JL, et al: A comparison of single daily doses of oxaprozin with multiple dail y doses of ibuprofen for the treatment of rheumatoid arthritis. Sem in Arthritis Rheum 15:54-58, 1986 (suppl 2) 18. Poiley JE , Spindler JS, Clarke JP, et al: Nonsteroidal antiinflammatory drug therapy in rheumatoid arthritis: A comparison of oxaprozin and ibuprofen. Semin Arthritis Rheum 15:59-65, 1986 (suppl 2) 19. Vreede PO, Harper FE. Sheldon WB: Use of oxaprozin in the treatment of aspirin failures in rheumatoid arthritis. Semin Arthritis Rheum 15:66-71, 1986 (suppI2) 20. Kolodny AL, Klipper AR, Harri s BK, et al: The efficacy and safety of single daily doses of oxaprozin in the treatment of osteoarthritis: A comparison with aspirin. Semin Arthritis Rheum 15:72-79, 1986 (suppl 2) 21. Mitnick PO, Greenberg A, DeOreo PB, et al: Effect of two nonsteroidal antiinflammatory drugs, indomethacin and oxaproz in, on the kidney. Clin Pharmacol Ther 28:680-689, 1980