Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis

Abstract

Twenty-four patients with rheumatoid arthritis were tested in a randomized, double-blind. Latin-square comparison of 250, 750 and 1500 mg of naproxen daily. Each received each dose for 2 wk and baseline disease activity was established during withdrawal of medication before and after the study. Nine standard measures of efficacy were tested at each evaluation. No order effect or change in baseline was found. Total and unbound naproxen concentrations were measured by high-pressure liquid chromatography and equilibrium dialysis, respectively. A linear dose-response relationship (P less than 0.05) was demonstrated between naproxen and joint count, patient's pain assessment, activities of daily living index, physician's global assessment, and grip strength. The relationship to patients' global assessment was of uncertain significance (P less than 0.07). A positive dose to serum level correlation (1, 2, and 12 hr after dose) was apparent (r greater than 0.78). When patients were defined as responders or nonresponders by a summed efficacy score, there was a serum concentration-response relationship; the percentage of responding patients increased with each serum level quartile: 25%, 31%, 59%, and 75%. Patients with a trough total serum naproxen concentration under 18 micrograms/ml did not respond, while 76% of patients with trough total serum concentrations above 50 micrograms/ml responded. No serum naproxen toxicity level relationship was established.

The effect of concurrent aspirin upon plasma concentrations of tenoxicam.

“…This assumption remains unproven but is generally accepted. The observation that there is a linear relationship between dose or plasma concentration of NSAID and anti-inflammatory effect is supportive of this view, given that there is a direct relationship between unbound concentrations of NSAID and total concentrations (Day et al, 1982;Dunagan et al, 1986). However, other investigators have not found significant relationships between plasma concentrations of single NSAID and clinical efficacy (see Orme, 1982).…”

Quantitation of dose and concentration‐effect relationships for fenclofenac in rheumatoid arthritis.

“…Dose or concentration-effect studies of nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis are few and have rarely shown that significant clinical improvement can be detected with an increment in dose or in concentration (Brooks et al, 1975;Orme et al, 1976;Day et al, 1982;Grennan et al, 1983). Response to an increase in dose or in concentration has proved difficult to detect due to variability in the disease, differences between individuals and difficulties in the measurement of clinical effect.…”

Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis. Support for the concept of “responders” and “nonresponders”

“…Although the well-cited study by Day et a1 (30) does show such a relationship, there are some patients who do not seem to respond to higher drug doses, and 25-40% of the patients in the highest concentration quartile did not respond. It has also been hypothesized that differential metabolism or action of the enantiomers of these drugs is responsible for the phenomenon of response variability (22); however, our finding that there were both responders and nonresponders to piroxicam, which has no chiral center, and our finding of comparable proportions of responders to each drug in our study, suggests that this is not true.…”

“…It has also been hypothesized that differential metabolism or action of the enantiomers of these drugs is responsible for the phenomenon of response variability (22); however, our finding that there were both responders and nonresponders to piroxicam, which has no chiral center, and our finding of comparable proportions of responders to each drug in our study, suggests that this is not true. Furthermore, one of us (ROD) has previously found that a significant proportion of RA patients were nonresponders to naproxen, which is marketed only as the S-isomer (30). This is what might be predicted from our knowledge that the pharmacokinetic parameters for movement of S-and R-ibuprofen into and out of synovial and blister fluidthe presumed loci of action of such drugs-are the same (31,32).…”