Alclofenac: A Review of its Pharmacological Properties and Therapeutic Efficacy in Rheumatoid Arthritis and Allied Rheumatic Disorders

Summary

Synopsis: Alclofenac¹ is a non-steroidal anti-inflammatory agent advocated for use in rheumatoid arthritis, degenerative joint disease and ankylosing spondylitis.

Published data to dale, suggest that alclofenac 3g daily is comparable in efficacy with aspirin 4.8g daily, phenylbutazone 300 to 600mg daily and indomethacin 150mg daily. In Welsh patients, gastro-intestinal side-effects have generally been less frequent and milder than with the standard comparison drugs, but in other populations differences in the overall incidence of these side-effects have been less marked. Results of a long-term trial, as evidenced by alterations in certain biochemical indications of disease activity, suggest that alclofenac may possibly reduce the severity of the disease itself, but further studies will be needed to confirm this. However, at present alclofenac should be considered along with the other drugs of its type in the initial treatment of the arthritic patient.

Skin rash is the most frequent side-effect, which in a small proportion of affected patients may be associated with systemic effects. A cutaneous reaction appears to be more likely in patients with a history of previous allergy to penicillin and other drugs.

Animal Pharmacology: Studies in rats have demonstrated the anti-inflammatory activity of alclofenac, as evidenced by its inhibition of paw oedema and abscess induced by carrageenin, granuloma formation induced by an implanted cotton pellet and the suppression of adjuvant-induced polyarthritis. In these screening tests of anti-inflammatory activity, alclofenac was comparable in efficacy with equal doses of phenylbutazone.

The analgesic potency of alclofenac relative to that of known analgesic compounds varies according to the nature of the stimulus used to produce pain in the rat. In rabbits with hyperthermia, the antipyretic effect of oral alclofenac 100 and 200mg/kg is greater than that of 250 and 500mg/kg of aspirin.

Alclofenac, like naproxen, fenoprofen, aspirin and indomethacin, inhibits prostaglandin biosynthesis in vitro. However, other actions associated with the displacement of endogenous anti-inflammatory substances from plasma may be of importance in the mechanism of action of alclofenac and other non-steroidal anti-inflammatory agents.

Pharmacokinetic studies with ¹⁴C-labelled alclofenac have been performed in the monkey, dog, rabbit and rat. The proportion of the drug absorbed, as reflected in the urinary excretion, varies according to the animal species studied. The pharmacokinetic handling of the drug in the monkey is similar to that in man.

Human Pharmacology: A study in healthy volunteers in which ⁵¹Cr-tagged erythrocytes were used to measure faecal blood loss, suggested that the gastrointestinal bleeding with alclofenac is less than that with aspirin.

Pharmacokinetic data on alclofenac in man indicate that the drug is variably absorbed after oral or rectal administration and is excreted in the urine, largely as the unchanged drug and glucuronide metabolite. In some patients, significant amounts of unchanged drug are recovered in the urine. After oral administration, peak plasma levels are attained 1 to 4 hours after a single dose. A simultaneous study of plasma and synovial fluid levels indicated that drug concentrations in synovial fluid were higher than in plasma at 6 hours and slightly higher 9 hours after a single 1g dose. The half-life of elimination is about 2.5 hours. Alclofenac is at least 99% protein-bound and has a very low volume of distribution. Urinary excretion accounted for 36 to 96 % of a single dose, most being excreted within the first 12 hours after a 400 or 800mg dose. In some patients, faecal excretion accounts for a significant proportion of the oral dose.

The mode of action of alclofenac, like that of other non-steroidal anti-inflammatory agents is still a matter of conjecture it has been proposed that the clinically useful drugs used in the treatment of rheumatoid arthritis and allied disorders possibly act by displacing endogenous anti-inflammatory substances from their protein-binding sites, and that the unbound forms of these endogenous substances protect tissues such as joints from chronic inflammatory stimuli. Much of the evidence in support of this hypothèsis has been based on observations of the behaviour of the binding of L-tryptophan. However, the exact relationship between the anti-inflammatory substance bound to circulating proteins and L-tryptophan has still to be clarified.

Therapeutic Trials: In short-term trials alclofenac tablets or capsules have been compared under double-blind conditions with aspirin, phenylbutazone, indomethacin and ibuprofen in patients with rheumatoid arthritis. Alclofenac has been compared with indomethacin in a long-term trial in patients with rheumatoid arthritis.

An anti-inflammatory effect as evidenced by a reduction in the circumference of proximal interphalangeal joints has been demonstrated in some studies but not in others. Patient selection may have contributed to the difference in findings between studies. Much of the investigation of alclofenac in rheumatoid arthritis has been performed in Welsh patients by the same investigators and further studies in other countries by other investigators are needed to supplement the present findings. Little difference in therapeutic efficacy has been detected between alclofenac 3g and aspirin 4.8g or phenylbutazone 300 and 600mg. Side-effects have been more frequent with indomethacin and phenylbutazone than with alclofenac in the Welsh studies, but the reverse has been true in others.

In a 13-month study comparing alclofenac and indomethacin in 80 patients with rheumatoid arthritis, alclofenac produced a greater improvement than indomethacin in the duration of relief of morning stiffness and in the articular index. Improvement in functional capacity was significantly greater at 6 months with alclofenac and was maintained throughout the remainder of the study. Improvement with alclofenac was reflected in a reduction in the severity of the disease as defined by the severity classes of the American Rheumatism Association.

No significant difference between alclofenac 3g and indomethacin 75mg or phenylbutazone 300mg was observed in osteoarthrosis or between alclofenac 3g daily and indomethacin 150mg daily in patients with low back pain and sciatica.

Side-effects: The most frequently reported side-effect with alclofenac is skin rash. The rash, often generalised and usually clinically significant, appears within the first 3 weeks of therapy and in a small proportion of instances is associated with systemic effects such as fever and feeling generally unwell. The likelihood of developing a skin rash appears greater in patients with a history of previous sensitivity to penicillin or other drugs. The rash usually subsides upon withdrawal of the drug. Vasculitis has been reported on 3 occasions in the United Kingdom. Gastrointestinal effects have been reported occasionally, but have seldom necessitated withdrawal of therapy. Other side-effects reported in a few cases include dizziness, frequency of micturition, headache and leucopenia.

Dosage: The usual adult dosage is 1 g 3 times daily.