Sulindac: A Review of its Pharmacological Properties and Therapeutic Efficacy in Rheumatic Diseases

SummarySynopsis: Sulindac1, a substituted indene acetic acid chemically related to indomethacin, is a new non-steroidal anti-inflammatory, antipyretic and analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis, acute gout and periarticular diseases such as bursitis, tendinitis and tenosynovitis.Published data suggest that in degenerative joint disease, sulindac 300 to 400mg daily is comparable in effectiveness to aspirin 2 to 4g and ibuprofen 600 to 1200mg daily. In rheumatoid arthritis sulindac has been as effective as, and in some studies more effective than, moderate doses of aspirin, but is generally better tolerated. Sulindac has not been compared with the more active members of the phenylalkanoic acid derivatives such as naproxen and fenoprofen, or with indomethacin in adequate numbers of patients. However, as sulindac is effective and is generally well tolerated and is given twice daily, it should be considered along with other drugs of its type in the treatment of osteoarthrosis or rheumatoid arthritis. The role of sulindac in acute gout and in ankylosing spondylitis relative to other agents has still to be clarified. Pharmacology: In animal models of inflammatory reactions, sulindac has anti-inflammatory activity equivalent to about half that of indomethacin on a weight for weight basis. There is evidence that the sulphide metabolite of sulindac possesses most, if not all, of the anti-inflammatory activity in vivo and that sulindac itself is essentially devoid of significant pharmacological activity. Oral sulindac, through the sulphide metabolite, has been demonstrated to possess analgesic and antipyretic activity. Sulindac 200mg inhibited collagen-induced platelet aggregation and prolonged bleeding time in healthy subjects, but the effect was less pronounced than that caused by aspirin 600mg.Sulindac has a lesser propensity to cause gastric haemorrhage and intestinal perforation in rats than indomethacin and appears to cause less gastric mucosal damage than aspirin. Faecal blood loss was not significantly different from placebo in healthy subjects given dosages similar to those used in the treatment of rheumatic disorders. To date, the effect of sulindac on gastrointestinal bleeding has not been compared with that of other forms of aspirin or with that of the phenylalkanoic acid derivatives. Pharmacokinetics: The disposition of sulindac is complex, but data from several studies in man indicate that about 90 % of an oral dose is absorbed. Sulindac is oxidised to the sulphone and reduced to the sulphide, the metabolite which appears to be responsible for the anti-inflammatory activity of the drug. Peak plasma concentrations of the drug and its metabolites are attained 1 to 2 hours after ingestion. Like most other non-steroidal anti-inflammatory drugs, sulindac is extensively bound to plasma proteins. Sulindac and the sulphone metabolite and their conjugates are the major products excreted in the urine. Significant concentrations of the sulphide, free or conjugated, are not present in human urine. About a quarter of the ingested radioactivity is recovered in the faeces. The plasma half-life is about 7 hours for sulindac and 18 hours for the sulphide, thus enabling twice daily administration. Therapeutic Trials: Sulindac at dosages of 200 to 400mg daily has been compared in formal comparative trials with aspirin in rheumatoid arthritis and with aspirin and/or ibuprofen in osteoarthrosis of the hip or knee.Although the between patient comparative studies have often involved small numbers of patients, the therapeutic efficacy of sulindac has generally been similar to, and sometimes superior to, moderate doses of aspirin in rheumatoid arthritis, but sulindac has been better tolerated in most instances. The efficacy of sulindac in osteoarthrosis has usually been statistically indistinguishable from that of aspirin 2 to 4g daily or ibuprofen 600 to 1200mg daily. Long term studies extending over periods of up to 2 years have demonstrated that the degree of response obtained in short term studies can be maintained and sometimes improved with continued therapy.To date, sulindac has not been compared under double-blind, controlled conditions with indomethacin in adequate numbers of patients, nor with the more active members of the phenylalkanoic acid derivates such as naproxen and fenoprofen, but as no one of the non-steroidal anti-inflammatory agents will best suit all patients, and the most suitable agent cannot be predicted, sulindac can in the meantime be considered along with the other drugs of its type, in the treatment of rheumatoid arthritis and osteoarthrosis.Results of studies in limited numbers of patients with ankylosing spondylitis have shown sulindac to be superior to placebo and comparable in efficacy to phenylbutazone 400 to 600mg daily.Initial studies in acute gout suggest that sulindac 400mg is effective, and comparable in efficacy to phenylbutazone 600mg daily, but further studies are required to clarify its role relative to that of other drugs commonly used to treat this condition. Side Effects: At dosages usually used in the treatment of rheumatic diseases, sulindac has generally been well tolerated in short and long term studies. The overall incidence of side effects has been about 25% and withdrawal of therapy because of adverse effects has been necessary in 5 to 7 % of patients. Potentially severe side effects such as upper gastrointestinal bleeding have been reported rarely. Gastrointestinal side effects such as abdominal pain, nausea and constipation have been the most frequently reported effects, but the frequency and severity of gastrointestinal side effects with sulindac has been less than with aspirin and similar to that with ibuprofen. Central nervous system effects such as dizziness, drowsiness and headache have occurred in 2.5 to 6.5% of patients in studies involving large numbers. Dosage: The usual adult dosage is 100 or 200mg twice daily taken with fluids or food. Dosage should however, be adjusted according to individual response and requirements.