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EDITORIALS: M M Skelly and C J Hawkey Potential alternatives to COX 2 inhibitors BMJ 2002; 324: 1289-1290 [Full text]

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Dont forget alternatives such as misoprostol and paracetamol

Jonathan L Underhill   (6 June 2002)

Dont forget alternatives such as misoprostol and paracetamol 6 June 2002
Jonathan L Underhill, Manager, Training the Trainers National Prescribing Centre, L69 3GF Send response to journal: Re: Dont forget alternatives such as misoprostol and paracetamol	The editorial by Skelly and Hawkey was useful and I share their concerns about the CLASS study. However, the last paragraph of their article requires clarification around the evidence base for GI cytoprotection. The authors state that "cyclo-oxygenase-2 inhibitors or prophylaxis with proton pump protection are the only realistic established options". This is misleading in that the evidence for the use of misoprostol as a cytoprotection agent is stronger than for PPIs. Misoprostol has evidence that it reduces the numbers of perforations, ulcers and bleeds (1) whereas the evidence for PPIs as cytoprotection has only been measured by their effect on reducing endoscopically detected lesions. (2,3) It is still unclear how surrogate markers such as endoscopically detected lesions relate to actual events such as perforations or bleeds. While some patients may not be able to tolerate misoprostol due to it causing diarrhoea (in around 20% of those taking it in the MUCOSA study vs. 16% on placebo), (1) many patients find it successful in practice. Not only it is the most evidence-based cytoprotective agent, it is also currently the cheapest. The authors also state that "it was possible to assert, probably wrongly, that paracetamol was as effective as NSAIDs, on the basis of a small number of underpowered studies." Compelling evidence does still not exist to show that NSAIDs or coxibs are more efficacious than 4g/day of paracetamol in patients with osteoarthritis. The study referenced to support their statement is by Geba et al (4) and compares the efficacy of celecoxib, two doses of rofecoxib and 4g/day of paracetamol in relieving pain in 382 patients with osteoarthritis. Importantly, 77% of these patients were already taking NSAIDs before being randomised to the new regimens. Only the higher dose of rofecoxib showed statistically significant benefit over paracetamol, and the clinical significance of the difference is debatable (9-14 points greater reduction on a 100 point visual analogue scale). The relative lack of evidence showing that NSAIDs are superior to simple analgesia supports the position of the North of England guidelines group. (5) They recommend that people with osteoarthritis should, where possible, avoid using potentially more toxic agents such as NSAIDs and try simple analgesics as first line pharmacotherapy. In addition, coxibs and NSAIDs have the potential to cause many other adverse effects other than those affecting the gastric mucosa. Indeed NSAID adverse effects such as heart failure, hypertension and renal failure may be associated with a larger burden of illness than that due to NSAID-induced GI damage. (6) As these effects are largely unrelated to the effect on the COX enzymes, it is unlikely that coxibs will hold any advantage over traditional NSAIDs in this respect. Furthermore, it is also worthwhile remembering that coxibs are black triangle drugs and their full adverse effect profile is not yet known. It remains the case that the best way of avoiding NSAID and coxib induced disease is to avoid their use in the first place wherever possible. 1. Silverstein FE, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Intern Med 1995; 123: 241-249. 2. Hawkey CJ, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. N Eng J Med 1998; 338: 727-734. 3. Yeomans N, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Eng J Med 1998; 338: 719-726. 4 Geba GP, et al Efficacy of Rofecoxib, celecoxib and acetaminophen in osteoarthritis of the knee: a randomised trial. JAMA 2002; 287: 64-71. 5. Eccles M, et al. North of England evidence based guideline development project: guidelines for non-steroidal anti-inflammatory drugs versus basic analgesia in treating the pain of degenerative arthritis. BMJ 1998; 317: 526-530. 6. Anon. More on NSAID adverse effects. Bandolier 2000; Number 79: 6- 8