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Naproxen up to Date: A Review of its Pharmacological Properties and Therapeutic Efficacy and Use in Rheumatic Diseases and Pain States

Drugs volume 18, pages 241–277 (1979)Cite this article

Summary

Synopsis: Naproxen1 is a propionic acid derivative with analgesic and anti-inflammatory activity which has been widely used in the treatment of rheumatic diseases. Naproxen has been well studied in rheumatoid arthritis and is as effective as aspirin but better tolerated, thus enabling more patients to continue with treatment. For this reason some clinicians now prefer to try propionic acid derivatives, such as naproxen, before aspirin in arthritic patients. In comparative studies with other non-steroidal anti-inflammatory drugs, such as indomethacin, ibuprofen, fenoprofen and others, all drugs were usually of similar overall efficacy although naproxen was sometimes preferred: but as with other non-steroidal anti-inflammatory agents, not all patients will respond to naproxen and in such cases other agents should also be tried until the most satisfactory drug is found for each patient.

Naproxen is also effective in degenerative joint diseases of the hip and knee, although further well designed studies are needed to more clearly define its relative place compared with newer drugs such as diclofenac or diflunisal. Results of other comparative studies have shown that naproxen is a suitable alternative to phenylbutazone or indomethacin in ankylosing spondylitis and to aspirin in juvenile rheumatoid arthritis.

Naproxen appears to be effective in reducing pain and swelling in acute gout and is an effective analgesic in patients with pain following surgery or trauma and in pain of dysmenorrhoea.

Naproxen has generally been better tolerated than aspirin or indomethacin at the dosages used. Because of its relatively long plasma half-life, naproxen can with convenience be given twice daily, and there is some evidence that once daily dosage is as effective in rheumatoid arthritis.

Pharmacology: In animal models of inflammatory reactions oral naproxen possesses dose-related anti-inflammatory activity which is greater (weight for weight) than that of phenylbutazone or aspirin, and equal to or less than that of indomethacin. Oral naproxen has been demonstrated to possess analgesic and antipyretic activity. In humans, naproxen reduces radioactive pertechnetate (99mTc) uptake in arthritic joints.

Naproxen, like other non-steroidal anti-inflammatory agents, causes gastric erosions in fasted rats, but generally causes less gastrointestinal blood loss and fewer gastric lesions than aspirin in volunteers or patients with rheumatoid arthritis. When compared with other nonsteroidal anti-inflammatory agents naproxen caused less blood loss than ketoprofen, but caused greater blood loss and multiple small lesions in the antral part of the stomach more frequently than diclofenac. To date there have been no such comparisons in humans of naproxen with enteric-coated aspirin, aloxiprin or benorylate.

The mode of action of naproxen is not entirely clear, but at present, the most convincing explanation of its pharmacological activity centres around its capacity to inhibit prostaglandin synthesis and transport.

Pharmacokinetics: Open studies, and cross-over studies with oral and intravenous naproxen, suggest that naproxen is completely absorbed. Plasma levels rise proportionately with dosage after oral administration of single doses of up to 500mg, but thereafter the increase in plasma levels and in the area under the plasma level-time curve is less than linear. Naproxen is fully absorbed after rectal administration, but peak plasma concentrations are significantly lower than after the same dose given orally. Absorption of naproxen is not adversely affected by food or the concomitant administration of commercial magnesium aluminium hydroxide gel or sodium bicarbonate. However, naproxen absorption is clearly reduced by concomitant use of magnesium oxide and aluminium hydroxide.

Naproxen concentration in synovial fluid and membrane is 74 % and 30 % respectively of that in plasma 15 hours after administration. At therapeutic concentrations, naproxen is at least 99.5% bound to plasma protein.

Naproxen is eliminated from plasma largely by conversion to its glucuronide conjugate and to its inactive principal metabolite 6-0-desmethyl naproxen. The pattern of metabolism in children is closely similar to that in adults, about 10 % of a dose being excreted unchanged. Naproxen’s half-life of 12 to 15 hours makes it suitable for twice, or possibly once, daily administration.

Therapeutic Trials: Comparative controlled trials have shown that naproxen 500 to 750mg generally provides symptomatic relief in rheumatoid arthritis statistically indistinguishable from that obtained with aspirin 3.6 to 4g daily, indomethacin 100 to 150mg or diclofenac 100mg. Naproxen 500mg tended to be more effective than ibuprofen 1200 to 2400mg daily or ketoprofen 150mg daily and was more effective than placebo. Side effects have usually been less frequent with naproxen than with aspirin or indomethacin.

In recent studies the efficacy of once daily naproxen was not significantly different from that of a twice daily regimen using the same daily dosage.

Naproxen has been shown to be effective and well tolerated in degenerative joint disease of the hip and/or knee in which it has compared favourably with indomethacin, diclofenac, diflunisal and proquazone. There has been a tendency for naproxen 500 to 750mg daily to be slightly less effective than the same dosage of diflunisal, or benorylate 4.5g daily in some studies, but additional better designed studies in larger numbers of patients are needed to determine clearly the relative merits of these drugs.

Clinical impressions and brief periods of placebo substitution during long term open studies of naproxen in rheumatoid arthritis indicate that in most patients alleviation of symptoms is maintained over periods of up to several years. Long term open studies in patients with rheumatoid arthritis who had upper gastrointestinal tract disease and/or were intolerant of other commonly used non-steroidal anti-inflammatory agents, indicated that naproxen was well tolerated by most of these patients.

In patients with ankylosing spondylitis, naproxen 500 to 750mg daily was not significantly different from phenylbutazone 400 to 600mg or enteric-coated phenylbutazone 300mg daily. Naproxen 500mg suppositories were comparable with indomethacin 100mg suppositories in relieving night pain.

In acute gout, naproxen alleviated symptoms to an extent comparable with phenylbutazone. Good results are obtained when a loading dose of 750mg of naproxen was followed by 250mg 8-hourly for about 72 hours before tapering the dose.

Naproxen is also an effective analgesic in patients with acute pain following surgery, childbirth or trauma or in pain of dysmenorrhoea, and it has been effective in a small number of patients with chronic cancer pain.

At dosages used in the treatment of rheumatic diseases naproxen has generally been well tolerated during both long term and short term studies. Gastrointestinal effects such as indigestion, abdominal discomfort and pain, nausea, vomiting and heartburn, and central nervous system effects such as headache, vertigo or lightheadedness and drowsiness have been reported most frequently. These latter effects have generally been less frequent with naproxen than with indomethacin.

Although naproxen is highly bound to plasma protein and theoretically has a potential for interaction with other albumin-bound drugs, recent studies have not found evidence of a clinically significant interaction between naproxen and warfarin or tolbutamide. Although naproxen has been well tolerated by some patients exhibiting dyspepsia with other non-steroidal anti-inflammatory agents, episodes of gastrointestinal bleeding have been reported and naproxen should be given with caution in patients with a known or suspected history of upper gastrointestinal disease.

The usual starting dose, and maintenance dose, of naproxen is 250mg twice daily although there is some evidence that once daily dosage is effective in rheumatoid arthritis.

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Affiliations

  1. Australasian Drug Information Services, P.O. Box 34-030, Birkenhead, Auckland 10, New Zealand

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

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  1. R. N. Brogden
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  2. R. C. Heel
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  3. T. M. Speight
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  4. G. S. Avery
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Additional information

Manuscript reviewed by: H. Berry, King’s College Hospital, London, England; G.E. Ehrlich, Albert Einstein Medical Center, Philadelphia, USA; E.C. Huskisson, St. Bartholomew’s Hospital, London, England; B. Magnusson, Sahlgren’s Hospital, Goteborg, Sweden; Y. Mizushima, St. Marianna University School of Medicine, Kawasaki, Japan; S.H. Roth, Phoenix Arthritis Center, Arizona, USA; B. Tait, Christchurch Clinical School of Medicine, Christchurch, New Zealand.

‘Naprosyn’; ‘Naprosine’; ‘Naixan’; ‘Naxen’; ‘Proxen’; ‘Synaxsyn’ (Syntex)

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Brogden, R.N., Heel, R.C., Speight, T.M. et al. Naproxen up to Date: A Review of its Pharmacological Properties and Therapeutic Efficacy and Use in Rheumatic Diseases and Pain States. Drugs 18, 241–277 (1979). https://doi.org/10.2165/00003495-197918040-00001

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  • DOI: https://doi.org/10.2165/00003495-197918040-00001

Keywords

  • Rheumatoid Arthritis
  • Aspirin
  • Indomethacin
  • Naproxen
  • Ketoprofen