Naproxen A Reappraisal of its Pharmacology, and Therapeutic Use in Rheumatic Diseases and Pain States

Publisher Website
Google Scholar
Abstract
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) advocated for use in painful and inflammatory rheumatic and certain nonrheumatic conditions. It may be administered orally or rectally using a convenient once or twice daily regimen. Dosage adjustments are not usually required in the elderly or those with mild renal or hepatic impairment although it is probably prudent to start treatment at a low dosage and titrate upwards in such groups of patients. Numerous clinical trials have confirmed that the analgesic and anti-inflammatory efficacy of naproxen is equivalent to that of the many newer and established NSAIDs with which it has been compared. The drug is effective in many rheumatic diseases such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and nonarticular rheumatism, in acute traumatic injury, and in the treatment of and prophylaxis against acute pain such as migraine, tension headache, postoperative pain, postpartum pain and pain associated with a variety of gynaecological procedures. Naproxen is also effective in treating the pain and associated symptoms of primary or secondary dysmenorrhoea, and decreases excessive blood loss in patients with menorrhagia. The adverse effect profile of naproxen is well established, particularly compared with that of many newer NSAIDs, and the drug is well tolerated. Thus, the efficacy and tolerability of naproxen have been clearly established over many years of clinical use, and it can therefore be considered as a first-line treatment for rheumatic diseases and various pain states. Naproxen possesses the typical pharmacodynamic properties of the nonsteroidal class of anti-inflammatory drugs. In animal studies it exhibits dose-related anti-inflammatory, analgesic and antipyretic effects: on a weight-for-weight basis it is more potent than aspirin and phenylbutazone, and equal to or less potent than indomethacin. Its anti-inflammatory effects are still apparent in adrenalectomised animals, indicating a nonsteroidal mechanism of action. The anti-inflammatory effects of naproxen, and most of its other pharmacological effects, are generally thought to be related to its inhibition of cyclo-oxygenase and consequent decrease in prostaglandin concentrations in various fluids and tissues, including the gastric mucosa, synovial fluid, urine and blood. In common with other NSAIDs naproxen may induce gastrointestinal microbleeding and endoscopically proven gastrointestinal lesions: it generally produces less effects than aspirin and indomethacin but more than diflunisal, etodolac, nabumetone and sulindac. In clinical practice, however, while the gastrointestinal tolerability of naproxen is better than that of aspirin and indomethacin, there is no definitive evidence to suggest significant differences in tolerability (minor complaints, bleeding or ulceration) between naproxen and other NSAIDs. Naproxen, like other NSAIDs, is a potent inhibitor of the secondary phase of platelet aggregation. However, at usual therapeutic dosages it has little effect on bleeding time in humans. In general, naproxen does not produce detrimental renal effects in patients with normal renal function although a few changes were reported in some patients with preexisting renal impairment or heart failure. Naproxen does not exert a uricosuric effect. In normal animals naproxen does not affect collagen metabolism but can inhibit cartilage and bone erosions in animals with adjuvant-induced arthritis. There is no definitive evidence in humans with rheumatic disease that naproxen or any other NSAID can inhibit the progression of cartilage or bone destruction. As occurs with other NSAIDs, naproxen affects leucocyte function reducing chemotaxis, and lysosomal and neutral protease, and collagenase activities in animals. Naproxen is available in 2 forms: the free acid or the sodium salt. Naproxen and naproxen sodium are pharmacologically and therapeutically equivalent at comparable dosages (naproxen 500mg equals naproxen sodium 550mg). The only difference between the 2 forms is their rate of absorption: naproxen sodium dissolves more rapidly in gastric juice and consequently produces earlier and higher plasma concentrations. Peak plasma concentrations are achieved in about 1 hour with naproxen sodium and 2 hours with naproxen. It is possible that this may provide a faster onset of action with the sodium salt after an initial dose; this would be of relevance in the treatment of acute pain states. Apart from this difference, the post-absorption phase pharmacokinetics of the sodium salt and its parent acid are identical. Naproxen is completely absorbed after oral and rectal administration. Concomitant administration of food may delay the absorption of orally administered naproxen but does not reduce the extent. Absorption is slower after rectal compared with oral administration, leading to a delay in and lower peak plasma concentrations. Plasma concentrations rise proportionately with dose after oral administration of single doses up to 500mg, but thereafter the increase is less than linear. This is related to increased clearance caused by saturable protein binding. Naproxen is highly protein bound (> 99.5%): the free fraction, however, increases significantly at higher plasma concentrations. The volume of distribution of naproxen is small, being about 10% of bodyweight. The drug readily reaches the synovial fluid and synovial membrane. Naproxen crosses the placental barrier, and minimal transfer occurs to breast milk (about 1% of maternal plasma samples). Approximately 95% of a radiolabelled dose of naproxen is recovered in urine and 3% or less in faeces. 70% of the drug is excreted as unchanged naproxen and the remainder is metabolised to an inactive 6-demethyl metabolite, probably by hepatic microsomal oxidation. The parent compound and metabolite are excreted free or as glucuronide or sulphate conjugates. The elimination half-life is about 12 to 15 hours. The...