Indomethacin in rheumatoid arthritis: clinical effects, pharmacokinetics, and platelet studies in responders and nonresponders

N. Baber, L. D. C. Halliday, W. J. A. Van Den Heuvel, R. W. Walker, R. Sibeon, J. P. Keenan, T. Littler, M. L'E. Orme

Department of Pharmacology and Therapeutics, University of Liverpool, Moreton, Wirral, Merseyside
Department of Haematology, University of Liverpool, Moreton, Wirral, Merseyside
Regional Rheumatology Unit, Leasowe Hospital, Moreton, Wirral, Merseyside
Merck Sharpe and Dohme Ltd., Rahway, New Jersey, USA

Twenty patients with definite or classical rheumatoid arthritis entered and completed a sequential study of placebo for 1 week, oral indomethacin 25 mg 3 times a day for 3 weeks, and oral indomethacin 25 mg 3 times a day plus 100 mg indomethacin suppository at night for 3 weeks. Twelve of the patients had previously been classified as responders and eight as nonresponders to indomethacin by an independent assessor. At the end of each period patients were assessed by a blind observer for duration of morning stiffness, pain score, digital joint size, grip strength, articular index, analgesic tablet usage, and the patient's own overall global assessment and comparative global assessment. In 8 of the 9 tests used responders improved on indomethacin in comparison with placebo, while nonresponders did not improve. There were no significant differences between responders and nonresponders in the plasma half-life, plasma clearance of indomethacin, protein binding of indomethacin, or urinary excretion of free or conjugated indomethacin. There were no significant differences between responders and nonresponders in the urinary excretion of 7HDPA or in the platelet aggregation or platelet malonyldialdehyde production tests. In responders there was a significant positive correlation between the plasma indomethacin concentration (r=0·44, P<0·05) and the percentage inhibition of malonyldialdehyde production by the platelets. However, in nonresponders this correlation, while significant (P<0·05), was negative (r=–0·498). Both for responders and nonresponders there was a significant correlation between plasma indomethacin concentration and the percentage reduction in 7HDPA. There was no correlation between the clinical response and the plasma concentration of indomethacin. There appears to be a biochemical difference between responders and nonresponders, which, while not necessarily causally linked with the clinical response to indomethacin, is worthy of further study.

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