Etodolac: A Reappraisal of its Pharmacology and Therapeutic Use in Rheumatic Diseases and Pain States

Abstract

Synopsis Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) effective in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, and in the alleviation of postoperative pain. Etodolac also provides relief of other types of pain, including that arising from gouty conditions and traumatic injury. In all indications, etodolac appears to be at least as effective as other NSAIDs. The incidence of clinical adverse effects other than abdominal pain and dyspepsia is similar to that observed with placebo, and etodolac has been associated with a low rate of gastrointestinal ulceration and other serious events. Data from preliminary animal studies have suggested that etodolac may provide more selective inhibition of prostaglandin synthesis at sites of inflammation than some other currently available NSAIDs. Thus, available evidence indicates that etodolac, with its low incidence of gastrointestinal events, is an effective and well tolerated alternative to other NSAIDs in the treatment of arthritic diseases and pain of various aetiologies and should be considered a first-line therapy. Pharmacodynamic Properties Etodolac is a pyranocarboxylic acid-derived nonsteroidal anti-inflammatory drug (NSAID), with analgesic activity. In common with other NSAIDs, etodolac inhibits biosynthesis of prostaglandins by inhibition of cyclo-oxygenase. Evidence from animal studies suggests that the drug may preferentially inhibit prostaglandin synthesis at sites of inflammation; macrophage accumulation at inflammatory sites also appears to be inhibited. The ratio of anti-inflammatory to gastric irritant activity in rats was more favourable for etodolac than for aspirin, sulindac, indomethacin or piroxicam, and studies in healthy subjects and arthritic patients have confirmed that etodolac (in dosages up to 1200 mg/day) causes less faecal blood loss and less endoscopically verified gastroduodenal irritation than aspirin, indomethacin, naproxen and ibuprofen. This low propensity of etodolac to cause gastric irritation, together with its lack of significant effects on renal function, may reflect a selective sparing of cytoprotective gastric mucosal prostaglandins, and of renal prostaglandins, as demonstrated in animals and humans. Etodolac appeared to reverse the pathological articular changes of established adjuvant arthritis in rats, whereas naproxen or ibuprofen merely inhibited these changes and aspirin had no effect. Moreover, etodolac slowed progression of joint disease in mice with collagen-induced arthritis, a model in which some other NSAIDs have shown little activity. Preliminary evidence of slowing of disease progression in patients with rheumatoid arthritis treated with etodolac has been reported in 1 study. Unlike a number of other NSAIDs, etodolac did not inhibit synthesis of proteoglycan, type II collagen and DNA by chondrocytes in vitro. However it is important to emphasise that these findings require confirmation, in large-scale clinical trials. A uricosuric effect has been observed in patients with rheumatoid arthritis receiving etodolac in clinical trials. Pharmacokinetic Properties Peak serum concentrations of around 12 to 15 mg/L and 21 mg/L are achieved within 2 hours of oral administration of etodolac 200 and 400mg, respectively. Concomitant administration of food may decrease the rate, but not the extent, of absorption of etodolac. Etodolac is extensively (> 99%) bound to plasma proteins and has an estimated volume of distribution of 0.41 L/kg. The drug penetrates rapidly into synovial fluid in patients with arthritis and data from animal studies have indicated that the uptake of etodolac may be enhanced in inflamed tissue. Excretion of etodolac occurs mainly by the renal route, around 60% of a dose being recovered in the urine within 24 hours and 73% within 7 days, mostly in the form of conjugated etodolac and hydroxylated metabolites. The elimination half-life of etodolac is around 6 hours in healthy subjects. The pharmacokinetic profile of etodolac in elderly subjects and those with impaired renal or hepatic function (including those with end-stage renal failure) is similar to that observed in young healthy subjects. Etodolac is not removed by haemodialysis. Therapeutic Use Clinical studies have established that etodolac is an effective analgesic and anti-inflammatory agent in the treatment of rheumatoid arthritis and osteoarthritis. In these indications, etodolac appears to be at least as effective as aspirin and has demonstrated comparable efficacy to other NSAIDs including indomethacin, naproxen, piroxicam, diclofenac and sulindac in small numbers of patients. During long term treatment (⩾ 1 year) the therapeutic efficacy of etodolac was maintained in patients with rheumatoid arthritis or osteoarthritis. Etodolac has been less extensively studied in ankylosing spondylitis, but appeared to be as effective as indomethacin, naproxen or piroxicam. In postoperative pain etodolac 100 to 400mg provides effective analgesia which is equal or superior to that of aspirin 650mg, while etodolac 400mg was superior to a combination of codeine 60mg and paracetamol 600mg in 1 study. In painful conditions such as gout, tendinitis, bursitis, acute sports injuries and pain of orthopaedic pathology, etodolac appeared to be as effective as diclofenac, naproxen or piroxicam, but in low back pain it was less effective than piroxicam-β-cyclodextrin. Adverse Effects Etodolac has been well tolerated in clinical trials. As with other NSAIDs, the most common adverse effects are gastrointestinal disturbances (dyspepsia, abdominal pain, nausea; 14% of patients), central nervous system effects (headache, dizziness; 3%) and dermatological reactions (pruritus, rash; 3%). With the exception of abdominal pain and dyspepsia, the incidence of such effects during etodolac treatment was similar to that observed with placebo. The incidence of adverse effects other than dyspepsia does not appear to be increased in elderly patients. The gastrointestinal tolerability of etodolac is superior to that of aspirin or indomethacin, and at least as good as that of sulindac or piroxicam. In particular, etodolac is associated with a low rate of gastrointestinal ulceration and other serious events. Fewer than 1% of patients withdrew from clinical trials because of altered hepatic, renal or haematological test values. Dosage and Administration The recommended adult dosage of etodolac for chronic arthritic pain is 400 to a maximum of 1200 mg/day in divided doses. A dosage of 200 to 400mg every 6 to 8 hours as required is recommended for acute pain. Patients concurrently receiving oral anticoagulants should be monitored for a possible effect on prothrombin time. © 1991, Adis International Limited. All rights reserved.