Naproxen, a propionic acid derivative, is a nonsteroidal anti-inflammatory, antipyretic and analgesic agent which has been widely used in the treatment of rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis, acute gout, and periarticular diseases such as bursitis, tendinitis and tenosynovitis since 1973. It has also proved effective in the treatment of patients with painful states and with dysmenorrhoea. Pharmacology. Its activity in animal models of inflammation is presumed to be mediated through its demonstrated ability to inhibit prostaglandin synthesis although other actions of the drug may play a role. Its administration effectively blocks the erosion of cartilage and bone occurring in the adjuvant arthritis syndrome in the rat. It interferes with platelet aggregation both in animals and man. It blocks yeast-induced hyperpyrexia in the rodent and suppresses fever in man. Pharmacokinetics. The pharmacokinetics of naproxen in man are relatively simple. It is essentially completely absorbed after oral or rectal administration and reaches peak plasma concentrations in about two hours. The sodium salt is absorbed more rapidly than naproxen acid. Naproxen is extensively bound to plasma proteins. Its metabolic half-life averages 13 hours, justifying a loading dose regimen when acute effects are desired, and twice-daily administration for maintenance. Naproxen is excreted almost entirely in the urine as the native molecule, its oxidative 6-desmethyl metabolite and their respective conjugates. Its kinetics are dose dependent. As the dose is increased above one gram a day, plasma level increments are less than proportional to dose. Therapeutic trials. Naproxen, in doses of 500–700 mg daily, has been evaluated in comparative trials with aspirin and indomethacin in rheumatoid arthritis and degenerative joint disease. Its therapeutic efficacy has been similar to and sometimes superior to these agents; in most cases naproxen was better tolerated. In more limited trials it has also compared favourably to the newer NSAIs: ibuprofen, fenoprofen and ketoprofen. Initial results in patients with ankylosing spondylitis and gout showed efficacy comparable to phenylbutazone. Comparative trials against a wide variety of control agents have shown naproxen to be an effective analgesic in patients with moderate pain resulting from orthopaedic, dental, and other surgical procedures; it has been particularly useful in pain associated with uterine contractions. Side effects. Naproxen has been well tolerated in short and long term studies. Adverse effects necessitated the discontinuance of less than six per cent of a large cohort of rheumatoid arthritis patients in one year of treatment. Gastrointestinal side effects such as heartburn, nausea and dyspepsia have been most frequently reported; these occur significantly less frequently than when therapeutically equivalent doses of aspirin are administered. Potentially serious events such as gastrointestinal bleeding have been uncommon but a few fatalities have been reported. Other rare reactions reported include angioneurotic oedema, thrombocytopenia, agranulocytosis, and jaundice. Dosage. The usual adult dose in the treatment of rheumatic conditions is 500–750 mg daily, usually in two divided doses. Dosage may be adjusted according to individual requirements and response. Increasing the dose to one gram daily may provide a greater therapeutic effect without loss of tolerance. Doses over one gram a day have been used primarily in the treatment of acute gout and for the control of pain.