A Kinder, Gentler NSAID?

Abstract & Commentary

Synopsis: Meloxicam, at the daily dose chosen, was slightly less efficacious than diclofenac for osteoarthritis.

Source: Hawkey C, et al. Br J Rheumatol 1998;37:937-945.

Nsaids are widely used for patients with osteoarthritis. There is a small risk of serious gastrointestinal (GI) adverse effects such as gastric or duodenal ulceration associated with NSAID use. Ulcerations may be further complicated by perforation or bleeding. Both the beneficial and the adverse GI effects are believed to be due to reduction in the production of prostaglandins as a result of inhibition of cyclooxygenase, an enzyme that is known to exist in at least two isoenzymatic forms. These two isoenzymes are differentially inhibited by meloxicam, an NSAID that is currently available in Europe. Meloxicam has been shown in vitro to inhibit the COX-2 isoenzyme about 10 times more effectively than it inhibits COX-1.

Hawkey and colleagues compared 7.5 mg per day of meloxicam to 100 mg per day of sustained release diclofenac. Adverse drug reactions were recorded and efficacy in controlling arthritis symptoms was assessed by comparing baseline and four-week end points. Efficacy was quantified using a pain scale, patient and physician global ratings, and patient-reported change in arthritis symptoms. Some of the 10,051 subjects who enrolled never received study drugs. Only the data on the 9323 who received a study drug were analyzed. Of those, 4635 received meloxicam and 4688 received diclofenac. The two groups had no differences in baseline demographic or arthritis variables. Overall, there were fewer adverse events in the group receiving meloxicam (27%) than in the diclofenac group (32%). Dyspepsia, nausea, vomiting, abdominal pain, and diarrhea were all less frequent in the meloxicam group. There were fewer withdrawals in the meloxicam (5.48%) than in the diclofenac group (7.96%). Serious adverse drug reactions that were ascribed to the study drug occurred in 13 meloxicam-treated subjects and in 24 of those receiving diclofenac. Though too infrequent to be statistically significant, hospitalization for GI adverse events occurred in only three subjects in the meloxicam group resulting in a total of five hospital days. The diclofenac group had 10 subjects hospitalized for a total of 121 days for GI adverse events. In the meloxicam group, there were five subjects with serious GI adverse events: one with endoscopically documented gastric ulcer, one with duodenal ulcer, one with a reported episode of hematemesis, and two with episodes of melena but no source of bleeding found by endoscopy. The diclofenac group, by comparison, had seven subjects with serious GI adverse events: two subjects with perforated duodenal ulcers, one with a bleeding duodenal ulcer, three with endoscopically documented gastric ulcers (one with bleeding), and one with an episode of melena without an identified source of bleeding. GI adverse events were the only category of events that had a statistically significant difference in incidence (13.3% for meloxicam vs 18.7% for diclofenac).

Diclofenac was more efficacious in relieving arthritis pain than meloxicam and there were more dropouts due to lack of efficacy in the meloxicam (80) than in the diclofenac group (49).

Comment by Jerry M. Greene, MD

It appears likely that highly selective COX-2 inhibitors will become available in the United States in the not too distant future. The results of this European study of a moderately selective COX-2 inhibiting NSAID, meloxicam, are encouraging and suggest that there may be some significant safety advantage conferred by avoiding inhibition of the "housekeeping" isoenzyme COX-1. Meloxicam was less efficacious and one wonders if an increase in dosage of meloxicam would have made its efficacy more nearly comparable to diclofenac. If so, would it have been at the cost of an increased number of adverse events?

Although the relative number of GI adverse events in the two groups in Hawkey et al’s study only differed by about 20%, the severity of the events tended to be less in the meloxicam group, and hospital use was substantially less as a result. It will be interesting to see how the next generation of NSAIDs, which are highly selective in their inhibition of COX-2, will do in comparision to this mellifluously named NSAID, meloxicam. If their use can reduce the incidence of NSAID associated ulcers, bleeding, and perforation, while still providing symptomatic relief for arthritis sufferers, it will be sweet news indeed.