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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
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
Competing interests: No competing interests