Adis Drugs; October 1984 - Volume 28 - Issue 4

Piroxicam A Reappraisal of its Pharmacology and Therapeutic Efficacy

Brogden, R.N.; Heel, R.C.; Speight, T.M.; Avery, G.S.

Abstract
Summary: Synopsis: Piroxicam 1 is a chemically different non-steroidal anti-inflammatory drug with a long half-life which enables it to be administered once daily. This member of the oxicam series of compounds is now well established in the treatment of rheumatoid arthritis and osteoarthritis and has been shown to be a suitable alternative to aspirin, indomethacin, naproxen, ibuprofen, ketoprofen, sulindac, phenylbutazone and diclofenac in the treatment of rheumatic diseases. Open trials in many thousands of patients in hospital clinics and in general practice have demonstrated its analgesic and anti-inflammatory efficacy in a wide cross-section of patients with rheumatic diseases, when administered once daily either at night or in the morning, and recent studies have demonstrated its usefulness in musculoskeletal disorders, dysmenorrhoea and postoperative pain. Such studies have also demonstrated the generally good tolerability of piroxicam 20mg daily. As with other nonsteroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. The frequency and severity of these effects are dose related. Thus, piroxicam is now well established in the treatment of rheumatic diseases and offers an alternative to other analgesics in various pain states. Pharmacodynamic Properties: In nonspecific animal models of inflammation, piroxicam is similar in potency to indomethacin. As an analgesic, piroxicam is more potent than aspirin, fenoprofen, ibuprofen, naproxen or phenylbutazone in inhibiting phenylquinone-induced writhing. The analgesic effect of piroxicam lasted for 7 hours in mice (phenylbenzquinone test) and for 48 hours in dogs (urate-induced knee pain). In animals, the ulcerogenic activity of piroxicam is less than that of indomethacin, phenylbutazone, diclofenac, ibuprofen and mefenamic acid, when ulcerogenic dosages are related to dosages that suppress experimental inflammation. In man, piroxicam 20mg daily caused less faecal blood loss than aspirin 3.9g daily, although comparisons with other non-steroidal antiinflammatory agents have not been conducted. Piroxicam, like many other non-steroidal antiinflammatory drugs, inhibits the secondary phase of platelet aggregation and synthesis of prostaglandins, but unlike indomethacin and aspirin, piroxicam is a selective reversible inhibitor of the cyclo-oxygenase step of arachidonic acid metabolism. At usual therapeutic dosages piroxicam decreases synovial fluid concentrations of PGE1 and PGF2[alpha] in patients with rheumatoid arthritis. Piroxicam also influences certain immunological mechanisms and has been shown to decrease production of IgM rheumatoid factor in vitro and to decrease serum IgM rheumatoid factor in patients with rheumatoid arthritis. Piroxicam, unlike indomethacin and ibuprofen, inhibited superoxide anion generation in vitro in stimulated polymorphonuclear cells. In vitro, piroxicam does not adversely affect the function of cartilage cells from dogs or humans. Pharmacokinetic Properties: Following administration of single doses, the pharmacokinetics of piroxicam are linear. Maximum plasma concentrations are usually attained in about 2 hours, but may vary between 1 and 6 hours in different subjects. Steady-state concentrations are generally achieved in 7 to 12 days, with peak plasma concentrations ranging from 4.5 to 7.2 mg/L and trough concentrations from 3.9 to 5.6 mg/L after repeated doses of 20mg daily. Plasma concentrations 75% of those at steady-state are achieved by the second day when a loading dose of 40mg daily is administered for the first 2 days, but up to 8 days are needed to achieve this plasma concentration 1/3

when a loading dose is not given. Omission of 1 day's dosage after 7 days of continuous medication results in only a minimal fall in the plasma concentration of piroxicam. In contrast, plasma concentrations of diclofenac, indomethacin, and flurbiprofen decrease markedly under the same conditions. Piroxicam penetrates into the synovial fluid of patients with rheumatoid arthritis where concentrations are about 40% of those in plasma. Concentrations of piroxicam in breast milk are about 1% of those in maternal plasma at the same time. Piroxicam is eliminated largely by biotransformation, the metabolites having little or no antiinflammatory activity. The elimination half-life is extended due to a low systemic clearance rate and often ranges from 30 to 60 hours in healthy subjects. Pharmacokinetics are not age related and renal function has a limited influence on elimination of piroxicam, but plasma concentrations are increased in patients with severe liver insufficiency. There is no close association between plasma concentration or joint fluid concentration and therapeutic effect. Therapeutic Trials: In patients with rheumatoid arthritis, piroxicam has been shown to be superior to placebo in practically all assessment criteria. Piroxicam 20mg daily was comparable with aspirin in maximum tolerated doses (2.65 to 6.3g daily) and with aloxiprin 4.8g daily. Studies comparing piroxicam with other non-steroidal anti-inflammatory drugs have generally indicated that piroxicam 20mg once daily or in divided doses is comparable in efficacy with indomethacin 75 to 200mg, ibuprofen 1200 and 2400mg daily, naproxen 500mg daily, diclofenac 75mg daily, ketoprofen 300mg daily, sulindac 400 to 800mg daily and phenylbutazone 400mg daily. As with other recently introduced non-steroidal drugs used in rheumatic diseases, piroxicam is better tolerated than aspirin, indomethacin or phenylbutazone. Long term open studies in rheumatoid arthritis have shown that the drug maintains its effectiveness for periods of up to 2 years. Recently reported open multicentre trials involving several thousands of patients with rheumatoid arthritis have confirmed the effectiveness of piroxicam in alleviating pain and functional incapacity. In patients with osteoarthritis, piroxicam 20mg daily was at least as effective as aspirin 2.6 to 3.9g daily, naproxen 500mg daily, diclofenac 150mg or fenbufen 600mg at night and comparable with indomethacin 75mg daily. In comparisons with controlled release indomethacin and diclofenac, piroxicam was at least as effective as diclofenac and appeared similar in efficacy to indomethacin. Piroxicam tended to be better tolerated than the controlled release preparations. Long term studies in adequate numbers of patients and short term trials in large groups of general practice patients have demonstrated that the effectiveness of the drug is maintained without an increase in dosage and that at a dosage of 20mg daily it is well tolerated by patients with osteoarthritis. Piroxicam has been shown to be a suitable alternative to indomethacin in ankylosing spondylitis, and open trials in gout have been promising. However, further comparative trials are necessary to determine the role of piroxicam relative to that of established drugs in acute gout. Placebo-controlled trials demonstrated the efficacy of piroxicam in acute musculo-skeletal injuries, and comparative studies indicate that piroxicam 40mg daily for the first 2 days, reducing to 20mg thereafter, is generally similar in efficacy to indomethacin 75 to 150mg daily in the treatment of acute musculoskeletal disease. Piroxicam 20mg daily was superior to placebo in dysmenorrhoea and comparable with aspirin 648mg daily in relieving pain resulting from surgery or trauma. Side Effects: The most frequently reported side effects have been gastrointestinal effects, but these have generally occurred less frequently with piroxicam than with therapeutically equivalent doses of aspirin, indomethacin or phenylbutazone. A survey of 73,000 patients treated with piroxicam indicated an overall side effect incidence of about 15%, with discontinuation of treatment necessary in

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about 5% of patients. Long term administration of doses of 30mg or higher is associated with an increased incidence of gastrointestinal side effects. Dosage: The usual initial and maintenance dosage in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis is 20mg daily given as a single dose. In acute musculoskeletal disorders treatment should be started with 40mg daily for the first 2 days, then reduced to 20mg daily thereafter. The same dosage regimen is recommended in post-operative and post-traumatic pain when an onset of effect more rapid than that achieved with an initial dose of 20mg daily is required. Treatment of acute gout is started with a single 40mg dose and continued with 40mg daily. Copyright 1984 Adis International http://adisonline.com/drugs/Abstract/1984/28040/Piroxicam_A_Reappraisal_of_its_Pharmacology_a nd.2.aspx

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