1 In the first of a series of trials with naproxen sodium it was shown that patients achieved significantly earlier and higher plasma levels of naproxen when naproxen sodium was administered. 2 In a second study comparing naproxen with naproxen sodium in patients with post‐partum pain, pain intensity was consistently lower for the group receiving naproxen sodium. However, statistically significant differences were not seen until 4 to 5 h after medication. 3 A final study documented that a more frequent dosage schedule of every 6 h led to clearly higher plasma levels than those achieved with an every 8 h regimen; plasma levels did not plateau. Doses up to 1,375 mg/day were well tolerated. 4 In conclusion, naproxen sodium appears to be an improved form of naproxen for use as a analgesic agent.

The plasma level curves of oral doses of naproxen ranging from 125 to 900 mg were studied in normal sub;ects. Areas under plasma concentration vs time curves increased linearly with dose incmments up to 500 mg twice a day, but larger doses resulted in a plateau effect. Experiments with tritium‐labeled naproxen showed that there was no difference in the fraction of drug excreted in the stools whether the dose was 250 or 900 mg, eliminating incomplete absorption as a factor. Accelerated renal clearance at high doses because of disproportionate increases in the amount of unbound drug appeared to be the most likely explanation for the plateau effect.

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subject without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of 1, 2, 3, or 4 gm (up to eight times the clinically effective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.

In a double-blind study, 198 outpatients with pain after oral surgery were randomly assigned to treatment with a single oral dose of naproxen sodium 550 mg, codeine sulfate 60 mg, a combination of naproxen sodium 550 mg with codeine sulfate 60 mg, aspirin 650 mg or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Orthogonal contrasts for the four treatments making up the factorial component showed that the naproxen effect was significant for every measurement of total and peak analgesia; the codeine effect was significant for total and peak pain relief and patients' overall evaluation. The naproxen-codeine interaction was not statistically significant for any measure, which suggests that the analgesic effect of the combination represents the additive effect of its constituents. Based on pairwise comparisons, aspirin was significantly superior to placebo for most measures of effect, naproxen was significantly superior to both aspirin and codeine for all measures and the combination was significantly superior to naproxen for patients' overall evaluation. No more patients experienced adverse effects with aspirin or naproxen than with placebo, but significantly more patients receiving the codeine-containing treatments experienced adverse effects than those receiving aspirin and naproxen.