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• Cyclooxygenase-2 (COX-2) inhibitors constitute a new group of non-steroidal anti-inflammatory drugs (NSAIDs) which, at recommended doses, block prostaglandin production by cyclooxygenase-2, but not by cyclooxygenase-1.
  
• Two COX-2 inhibitors are currently available in Australia -- celecoxib, which is taken twice daily, and rofecoxib, which is taken once daily. Both drugs act rapidly in providing pain relief and their anti-inflammatory analgesic effect in osteoarthritis and rheumatoid arthritis is equivalent to standard doses of non-selective NSAIDs.
  
• Celecoxib and rofecoxib show significantly lower incidences of gastrotoxicity (as measured by endoscopic studies and gastrointestinal ulcers and bleeds) than non-selective NSAIDs.

  There is Level 2 evidence that COX-2 inhibitors:

  • reduce pain in classic pain models -- third-molar extraction, dysmenorrhoea and after orthopaedic surgery;
    
  • reduce pain and disability in osteoarthritis of the hip and knee; and
    
  • reduce pain and disability in rheumatoid arthritis.

  Other adverse effects, such as interference with antihypertensive agents and the potential to produce renal dysfunction in patients with compromised renal function by COX-2 inhibitors, seem similar to those of non-selective NSAIDs.

Until 10 years ago, it was accepted that NSAIDs acted by reducing prostaglandin synthesis through inhibition of cyclooxygenase (COX). Over the last decade the finding that cyclooxygenase activity increases in inflammation led to the identification of a new COX isoform, and the elucidation of its molecular structure.⁶ Recognition that cyclooxygenase consisted of two isoforms, COX-1 and COX-2, spawned an active, molecular-based drug development program for specific inhibitors of COX-2. The isoforms differ in that glucocorticoids inhibit synthesis of COX-2, but not COX-1, and COX-2 has a larger active site and a side pocket into which the new specific inhibitors fit.⁷

Inhibition by traditional NSAIDs and the selective COX-2 inhibitors (now classified as a separate class of NSAIDs -- the coxibs) is compared in Box 1. Coxibs should have the same efficacy as a traditional NSAID, but without the effects on haemostasis and gut mucosa.

Pain relief: Rofecoxib (50 mg) has been shown to be superior to placebo and equivalent to naproxen sodium (550 mg) in the 12 hours after being taken for orthopaedic surgical pain relief (E2) (see Box 3 for an explanation of level-of-evidence codes) and for dysmenorrhoea (E2), and equivalent to ibuprofen (400 mg) after third-molar tooth extraction (E2). Celecoxib in a dose of 100 mg or 200 mg was significantly better than placebo for pain after third-molar extraction, and no different than ibuprofen 400 mg or naproxen sodium 550 mg (E2).¹⁰

Osteoarthritis of hip and knee: In a 12-week trial of more than 1000 patients comparing 50 mg, 100 mg and 200 mg celecoxib twice daily with 500 mg naproxen twice daily or placebo, the 100 mg and 200 mg doses of celecoxib were as effective as the naproxen. Although 50 mg celecoxib twice daily was better than placebo, it was not as effective as the higher doses.¹¹

Rofecoxib in doses of 12.5 mg and 25 mg once daily has been shown to be significantly better than placebo, as effective as 2.4 g of ibuprofen daily (over six weeks)¹² and as effective as 150 mg of diclofenac daily (over one year) for osteoarthritis of the knee (E2).¹³

Rheumatoid arthritis: A three-month, double-blind, placebo-controlled study comparing naproxen 500 mg twice daily, placebo and celecoxib in doses of 100 mg, 200 mg or 400 mg twice daily in more than 1100 patients with rheumatoid arthritis showed that all celecoxib doses and naproxen were effective for pain and inflammation throughout the 12 weeks (E2).¹⁴ Interestingly, only 60% of patients completed this study. The reasons for failure to complete were not different between the active treatment groups, although those taking placebo showed a higher treatment failure rate. These patients also underwent endoscopy within a week of commencing treatment and at the end of the three months. The peptic ulceration rate (defined as any break in the mucosa at least 3 mm in diameter with unequivocal depth) was 4% for those taking placebo, and 6%, 4% and 6% for those taking 100 mg, 200 mg and 400 mg celecoxib, respectively; these incidences were not significantly different. However, the rate was significantly higher (26%) for those taking 500 mg naproxen (E2).¹⁴ A six-month study comparing 200 mg celecoxib twice daily with 75 mg diclofenac twice daily in 655 patients with adult-onset rheumatoid arthritis showed that celecoxib had similar efficacy to diclofenac, with a significantly lower incidence of gastrointestinal side effects. In this study 430 patients underwent endoscopy within seven days of the last treatment, and gastroduodenal ulcers (defined as any break in the mucosa of at least 3 mm in diameter with unequivocal depth) were found in 33 patients (15%) treated with diclofenac and eight (4%) in the celecoxib group. In this study, the rate of withdrawal for any gastrointestinal-related adverse event (most commonly abdominal pain, diarrhoea and dyspepsia) was nearly three times higher in the diclofenac-treated group than in the celecoxib group, and this was significant at P < 0.001 (E2).¹⁵

In an eight-week study, 648 patients with rheumatoid arthritis were randomly assigned to groups receiving either placebo or 5 mg, 25 mg or 50 mg of rofecoxib once daily. In this study the 5 mg dose was no different to placebo, while both larger doses were significantly better than placebo. No clinically significant oedema, hypertension or serious gastrointestinal effects were reported.¹⁶

Gastrointestinal: Carefully conducted endoscopy studies show a significantly lower incidence of endoscopically proven ulcers with up to 12 months of treatment with COX-2-specific agents. In patients with rheumatoid arthritis, celecoxib is associated with significantly less gastroduodenal ulceration than naproxen¹⁴ or diclofenac (E2).¹⁵ In a combined analysis of eight trials in patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of perforations, ulcers or bleeds than treatment with ibuprofen, diclofenac or nabumetone (E1).¹⁷ An endoscopic study in osteoarthritis showed an ulcer incidence at 12 weeks for rofecoxib equivalent to that for placebo and significantly lower than for ibuprofen.¹⁸ Large studies of gastrointestinal outcomes with both celecoxib and rofecoxib are currently in progress, and these data should be available in the next few months. There are also data suggesting that small bowel permeability is not affected by COX-2-specific agents, whereas it is increased with non-selective NSAIDs.

Renal: Although it was initially felt that COX-2-specific agents might be renal-sparing, there is COX-2 in the kidney¹⁹ and it can be induced in circumstances such as sodium depletion or in patients taking ACE inhibitors. COX-2-specific inhibitors may affect renal function in much the same way as traditional NSAIDs, and particular care should be taken in prescribing these drugs to patients with renal dysfunction or in those taking diuretics or antihypertensive agents, particularly ACE inhibitors.

Cardiovascular: The inhibitory effect on platelet function by traditional non-selective NSAIDs may play a contributory role in gastric bleeding. However, prostacyclin (PGI₂) is also thought to play an important role as an antithrombotic and vasodilator, and COX-2 is thought to play a role in the biosynthesis of both systemic and renal prostaglandin (PGE₂),²⁰ thus influencing PGI₂ synthesis. This may have important connotations in vascular disease. The implications of specific COX-2 inhibition on thrombosis are not known, although there have been several case reports of thromboses in patients with the antiphospholipid syndrome treated with celecoxib.²¹ As the COX-2 story unfolds it will be important to explore the effect of combinations of low-dose aspirin and specific COX-2 inhibitors in a wide range of patients.

Reproduction
COX-1 and COX-2 are both involved in various aspects of ovulation, implantation and parturition.²² COX-2-deficient mice are infertile and COX-2-specific inhibitors should not be taken by women wishing to become pregnant.

With the knowledge that COX-2 is overexpressed in bowel cancer and in Alzheimer disease and that non-selective NSAIDs retard both of these conditions comes the tantalising prospect that coxibs may have potential for wider use in the future.^1,7 Celecoxib has been approved in the US for patients with familial polyposis coli after a randomised placebo-controlled trial showed a 28% reduction in the number of polyps in patients who took 400 mg celecoxib twice daily.²³

The release of COX-2 inhibitors in Australia appears to be good news for sufferers of musculoskeletal conditions.²⁵ As with the introduction of any new drug, doctors should assess patients carefully, asking whether there are specific reasons for changing therapy (such as ineffectiveness or adverse events), and review patients taking the new drug at frequent intervals. In this way these drugs can be introduced cost effectively and benefit the maximum number of patients.

Disclaimer: Peter Brooks serves on Advisory Boards for Merck Sharp and Dohme for rofecoxib, and in the past has consulted and been a member of Advisory Boards for Pfizer and Searle. Richard Day serves on Advisory Boards on rofecoxib for Merck Sharp and Dohme and on Advisory Boards for celecoxib for Pfizer and Searle.

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University of New South Wales, St Vincent's Hospital, Sydney, NSW.
Richard O Day, MD, FRACP, Professor of Clinical Pharmacology.

Reprints will not be available from the authors.
Correspondence: Professor P M Brooks, Faculty of Health Sciences, University of Queensland, Edith Cavell Building, Royal Brisbane Hospital, Herston, QLD 4029.

©MJA 2000
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