Naproxen in the Treatment of Juvenile Rheumatoid Arthritis: Metabolism, safety and efficacy

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Abstract
Metabolism, safety and efficacy of naproxen in the treatment of children with juvenile rheumatoid arthritis (JRA) were the three main topics of this study. First, when treating children with naproxen, the metabolism of the drug was followed by estimating plasma levels and by determining naproxen and its metabolite, 6-demethylated naproxen, in the urine, both in conjugated and unconjugated form. Naproxen was administered for 14 days in tablet form to 21 children with JRA (18 girls and 3 boys). Their ages ranged from 5 to 16 years (mean 9.9 years). The daily dose of naproxen was approximately 10 mg/kg divided in two doses. The peak plasma level after the ingestion of the very first tablet was reached after 4 hours, on average. Steady state in naproxen plasma levels was achieved about 72 hours after the start of the treatment. Naproxen plasma levels in the morning samples during the steady state varied between 25 and 30 /μg/ml; 4 hours after the daily medication the peak levels were 39–41 μg/ml. These values correspond to those observed in adults after naproxen doses of 250 mg twice daily. 36 hours after discontinuation of the therapy the mean plasma level was approx. 50% of that observed in the morning samples during the steady state. Approx. 10% of the oral daily dose of naproxen is excreted unchanged in the urine. Both naproxen and its metabolite, 6-demethylated naproxen are excreted in 70–90% in their conjugated forms. Second, a double-blind cross-over study with naproxen and aspirin was made in 18 children with JRA. The children's ages varied between 7 and 15 years. Each of the two drugs was given for 2 months, the daily dose of naproxen being 6.5 mg/kg on average, and that of aspirin 60 mg/kg. Naproxen was best in 7 cases, ASA in 4, in 4 the drugs were equal. Three patients discontinued the trial, one of them showing a febrile relapse when the earlier naproxen treatment was replaced by ASA. Third, in a long-term open study naproxen was given (10.5±1.6 mg/kg/day) to 38 children with JRA. The ages of these children varied between 3 and 16 years. The duration of the treatment ranged from 1 to 26 months (mean 10 months). The frequency of side effects during naproxen treatment was compared with that during high-dosage salicylate therapy. Aspirin (ASA) was administered to 43 hospitalized children for 14 days, the dosage of ASA being 89±15 mg/kg/day. Naproxen was associated with significantly fewer side effects than the high-dosage ASA therapy. The elevated values of S-ASAT (serum aspartate aminotransferase) and the symptoms of salicylism were the most frequent side effects during salicylate treatment. During naproxen therapy none of the patients showed any pathological changes of S-ASAT. However, depressed values in the P+P prothrombin test were observed in 21% of the patients treated with naproxen, and prolonged bleeding time in 42% of the cases. According to the results of this study, naproxen appears to be at least as effective as aspirin in the treatment of children with JRA. Furthermore, naproxen provoked fewer adverse reactions than the high-dosage ASA therapy, even though the duration of ASA therapy was only 14 days and that of naproxen 10 months, on average.