Flurbiprofen: A Review of its Pharmacological Properties and Therapeutic Use in Rheumatic Diseases

Summary

Synopsis: Flurbiprofen¹, a phenylalkanoic acid derivative, is a non-steroidal anti-inflammatory, antipyretic, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and allied conditions.

Published data suggest that flurbiprofen 120 to 150mg daily is comparable in effectiveness with therapeutic doses of aspirin (3 to 4g) in rheumatoid arthritis, but generally causes fewer side effects. Flurbiprofen 150 to 300mg appears to be comparable with 75 to 150mg of indomethacin in rheumatoid arthritis and degenerative joint disease, and comparable with phenylbutazone or indomethacin in ankylosing spondylitis. In comparison with other non-steroidal agents, flurbiprofen appears to be at least as effective as naproxen, ibuprofen or sulindac, but generally causes more side effects than these drugs. However, as no one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, flurbiprofen should be considered along with other drugs of its type in the arthritic patient.

Pharmacodynamic Studies: In experimental studies in animals, flurbiprofen has been shown to possess anti-inflammatory, analgesic and antipyretic activity. It is a particularly potent inhibitor of prostaglandin synthetase. In humans, flurbiprofen produced an improvement in thermographic index in rheumatoid arthritics, and a 25mg dose lowered body temperature for a longer period than a single 300mg dose of aspirin in patients with fever caused by various infections.

An endoscopic study in volunteers showed gastrointestinal damage caused by aspirin 2.1g daily to be more severe and extensive than that caused by flurbiprofen 300mg daily, phenylbutazone 600mg daily or placebo.

Flurbiprofen causes marked inhibition of the secondary phase of platelet aggregation induced by adenosine diphosphate and adrenaline as well as collagen-induced aggregation in vitro and in vivo. Generally, flurbiprofen has not been found to influence platelet adhesiveness and except in one study, there has been no prolongation of bleeding time.

Flurbiprofen is a potent non-selective inhibitor of prostaglandin biosynthesis in vitro and in vivo, due possibly to the inhibition of endoperoxygenase, which catalyses conversion of arachidonic acid to cyclic endoperoxide. Like other commonly used non-steroidal anti-inflammatory agents, flurbiprofen inhibits prostaglandin synthesis in human rheumatoid synovium.

Pharmacokinetics: Flurbiprofen appears to be readily absorbed after oral administration, and plasma concentration is related to dosage in the range 15 to 150mg. Peak plasma concentration is about 12μg/ml after a 100mg dose and is usually attained 1.5 to 3 hours after ingestion. There are few data on the distribution of flurbiprofen in man, but a mean concentration of 1.92μg/ml was present in synovial fluid at 6 hours after ingestion of a single 100mg oral dose of flurbiprofen, whereas mean serum concentration was 7.90μg/ml at 1.5 hours and 1.96μg/ml at 6 hours. At 12 hours the concentration in synovial fluid was higher than in serum. Flurbiprofen is at least 99 % bound to human serum albumin at therapeutic concentration and appears to be bound specifically to site II. Metabolites of flurbiprofen have not been detected in human plasma although are present in that of some animals. 20 to 25 % of a dose is recovered in the urine unchanged and its principal metabolites are devoid of pharmacological activity in animals. 60 to 70 % of flurbiprofen and its metabolites are present in urine as glucuronide and sulphate conjugates. The half-life of elimination is about 3.5 hours during repeated doses. Preliminary data suggest that differences in the degree of response of rheumatic disease to flurbiprofen are not closely related to dosage.

Therapeutic Trials: Short term therapeutic trials published to date have shown the efficacy of flurbiprofen to be significantly greater than that of placebo and generally indistinguishable from that of aspirin or indomethacin in patients with active rheumatoid arthritis. In most studies, flurbiprofen 100 to 150mg daily has been compared with ordinary aspirin 3.0 to 4g daily, but no significant differences between the drugs could be detected by the usual subjective and objective assessment criteria. Almost invariably, side effects have been more frequent with aspirin than with flurbiprofen at the dosages used. Similarly, no statistically significant difference between the therapeutic efficacy of flurbiprofen 150 to 300mg and 75 to 150mg of indomethacin could generally be detected in rather small numbers of patients with rheumatoid arthritis. Flurbiprofen has generally been better tolerated than indomethacin, those studies reporting a very similar incidence of side effects having excluded patients known to be intolerant of indomethacin. Fixed dosages of both drugs have been used in all studies to date. Although not all studies have been able to demonstrate a significant decrease in the circumference of proximal interphalangeal joints during treatment, a significant decrease has been recorded in patients stated to have potentially reversible joint swelling.

In degenerative joint disease, flurbiprofen has been compared with placebo, indomethacin, naproxen, ibuprofen and paracetamol. No statistically significant difference could be detected between flurbiprofen 120 to 300mg daily and indomethacin 75 to 100mg daily, but flurbiprofen was superior to paracetamol and placebo.

In comparisons with other phenylalkanoic acid derivatives, flurbiprofen 300mg daily was at least as effective as naproxen 750mg, and 80mg flurbiprofen was comparable with ibuprofen 1600mg daily given over a 6-week period. However, gastrointestinal side effects were more frequent and more often severe with flurbiprofen than with naproxen, which, like indomethacin, was preferred by the patients. Further studies extending over longer periods are needed comparing flurbiprofen and other commonly used non-steroidal anti-inflammatory drugs, to determine their relative efficacy and tolerance.

In patients with radiologically confirmed ankylosing spondylitis, flurbiprofen has been shown to be superior to placebo. A dose of 150 to 200mg daily appears to be closely comparable in efficacy with indomethacin 75 to 100mg or phenylbutazone 300 to 400mg daily. As has generally been the case in other rheumatic conditions, studies in ankylosing spondylitis have been of only 2 to 6 weeks duration and longer trials are necessary to determine the relative efficacy and tolerance of flurbiprofen and the standard drugs.

Side Effects: As with other phenylalkanoic acid derivatives introduced in recent years, flurbiprofen has generally been better tolerated than moderate doses of aspirin, and central nervous system effects have occurred less frequently than with indomethacin. Abdominal discomfort, dyspepsia and constipation have been the most frequently reported side effects of flurbiprofen, and along with other gastrointestinal effects, have been reported in a total of 15 to 20 % of patients. Central nervous system effects have occurred in fewer than 5 % of patients in short term studies compared with 18 % of those receiving indomethacin under the same clinical conditions.

Flurbiprofen should be given only under close supervision to patients with a history of upper gastrointestinal disease and should be avoided in patients with active peptic ulcer.

Dosage: The usual initial adult dose of flurbiprofen is 150 to 200mg daily in 3 or 4 divided doses. If necessary the dosage may be increased to 300mg daily in divided doses.