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

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 pharmacokinetic profile of naproxen is generally unaffected to any clinically significant extent by age or the presence of disease. However, free plasma concentrations of naproxen may be increased in elderly patients with rheumatoid arthritis and in patients with hepatic impairment, due to decreased plasma albumin levels. Renal insufficiency has little effect on the pharmacokinetics of naproxen until it is severe. When creatinine clearance is less than 10 ml/min there is a significant decrease in plasma naproxen concentration but an increase in metabolite concentrations. Naproxen is not removed by haemodialysis. Dosage reductions are not therefore required in patients with mild to moderate renal impairment and neither is dose supplementation after haemodialysis. Naproxen, usually 500 to 1000 mg/day on a once or twice daily basis, administered orally or rectally, has been well studied in controlled clinical trials in patients with rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. The drug shows similar analgesic and anti-inflammatory efficacy to usual therapeutic dosages of other commonly used NSAIDs (e.g. aspirin, diclofenac, ibuprofen, indomethacin, ketoprofen, piroxicam), and other less frequently used or newer NSAIDs. As would be expected in such a large number of comparisons, statistically significant differences were found for some assessment parameters but these differences were not of clinical significance and usually related to comparison of therapeutically nonequivalent dosages. With appropriate dosage titration, clinical response to NSAIDs generally appears equivalent (although individual patients may inexplicably respond to or tolerate one NSAID and not others). The therapeutic efficacy of naproxen is maintained during long term treatment up to several years and is associated with a steroid-sparing effect in patients with rheumatoid arthritis. Several studies have shown that naproxen is effective in the treatment of acute gout and juvenile arthritis but further study is required to allow any definite conclusions concerning its efficacy and tolerability compared with other commonly used agents. Naproxen up to 1000 mg/day has been demonstrated to be an effective analgesic and anti-inflammatory agent for the treatment of acute or chronic nonarticular rheumatic conditions and soft tissue injuries. Its efficacy in these conditions is comparable to that of other commonly used agents. Naproxen is a useful analgesic in a variety of acute pain states, such as migraine, tension headache, postoperative pain, postpartum pain and pain associated with a variety of gynaecological procedures. In the treatment of acute migraine naproxen was comparable to ergotamine. In other acute pain states naproxen was at least as effective as some of the more commonly used ‘pure’ analgesics or their combinations [e.g. paracetamol (acetaminophen), codeine, dextropropoxyphene]. Naproxen has also been used successfully in the prophylaxis of migraine, reducing the severity and frequency of migraine attacks to a similar extent as pizotifen and propranolol. Naproxen is a well studied agent in the treatment of primary and secondary dysmenorrhoea, alleviating pain and associated symptoms. It reduces symptoms at least as well as other NSAIDs with which it has been compared. In addition, naproxen reduces blood loss and anaemia consequent to menorrhagia. Naproxen appears to be a particularly effective agent in the control of neoplastic fever and has been used to differentiate between neoplasm-related and infection-related pyrexia in cancer patients with fever of unknown origin. It may also be effective as a general antipyretic agent although further study is required to compare its efficacy relative to that of other standard treatments. The tolerability profile of naproxen is well established, as extensive experience has been gained with the drug over many years. The drug is generally well tolerated. In common with other NSAIDs the most frequent adverse effects include mild gastrointestinal disturbances and CNS effects, followed by occasional mild skin reactions. Increased age does not appear related to any increase in unwanted effects and there is little evidence to suggest that the nature, severity or frequency of adverse effects is any different with naproxen compared with other NSAIDs. Despite some claims of improved tolerability with some newer NSAIDs, there are no definitive findings to show this. Aspirin and indomethacin may produce a higher frequency of gastrointestinal symptoms and CNS effects compared with naproxen. As with any drug which has been used so extensively in clinical practice, a number of rare serious adverse effects have been associated with naproxen, which have also been associated with other NSAIDs. They include: gastrointestinal bleeding or ulceration, pseudoporphyria and other severe cutaneous reactions; acute renal failure including papillary necrosis, interstitial nephritis and hyperkalaemia; hepatitis; pulmonary infiltrates with eosinophilia; agranulocytosis; aplastic anaemia; haemolytic anaemia; peripheral neuropathy; aseptic meningitis; and corneal opacity. Patients exhibiting aspirin hypersensitivity may show cross-reactivity with naproxen. The following dosage schedule refers to naproxen administered as the free acid. If naproxen sodium is used, the dosage is increased by 10% to achieve bioequivalence (naproxen 500mg=naproxen sodium 550mg). The usual adult maintenance dosage of naproxen in patients with chronic rheumatic disease or chronic pain is 375 to 1000 mg/day after food and on a once or twice daily basis. This may be increased to 1500 mg/day in divided doses for up to 2 weeks to treat acute exacerbations of the disease. For children with juvenile arthritis the recommended dosage is 10 mg/kg in 2 divided doses; a suspension formulation is available to aid administration. In patients with acute conditions such as tendinitis, bursitis, dysmenorrhoea and mild to moderate pain an initial loading dose of 500mg should be administered and followed by 250mg every 6 to 8 hours as required (up to a maximum of 1250 mg/day).