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How good are trials and interventions in knee arthritis?

Systematic review
Results
Comment


The reason we do systematic reviews is not only to evaluate how good an intervention may be, but also to examine the clinical utility of the trials we do. The bottom line we have to recognise is that almost all drug trials are performed for some registration purpose, and that the requirements of drug registration are far removed from what is needed in clinical practice.


Those of a more practical bent have therefore either to throw up their hands and walk away from the evidence that exists or to look at that evidence with a cold and fishy eye and criticise constructively. A meta-analysis of interventions for knee osteoarthritis provides an excellent example [1].


Systematic review


The review had a wide search strategy that identified randomised, blinded, placebo-controlled trials of interventions in knee arthritis. The inclusion criteria included use of established diagnostic criteria, including symptom duration of more than three months, and an outcome measure of pain intensity both initially and within four weeks scored on WOMAC pain subscale or 100 mm VAS for global or walking pain.


The main analysis was for the difference between active and placebo during weeks 1-4, using the point with the maximum effect.


Results


The authors found 65 trials with information on 14,060 patients (Table 1, Figure 1). Though trials differed in number and number of patients for each intervention, they were generally similar in terms of the initial pain intensity and mean measurement time for maximum effect, though this was somewhat longer for glucosamine and chondroitin. All trials except two for intra-articular glucocorticoid were of adequate quality to avoid most sources of bias (scoring 3 or more on a five point scale for quality).



Table 1: Results for short-term interventions for knee osteoarthritis.

Best mean difference was the greatest difference between intervention and placebo in the period 1-4 weeks

Number of
Intervention
Trials
Patients
Mean initial pain
(mm VAS)
Mean time of measurement
(weeks)
Best mean difference from placebo
(mm VAS)
Intra-articular glucocorticoid (methylprednisolone 40 mg or equivalent)
6
221
57
1.5
15
Topical NSAID
9
749
55
1.6
12
Opioids (30 mg morphine sulphate or equivalent)
6
1057
73
2.8
11
Oral NSAIDs (diclofenac 100 mg or equivelent)
27
9964
64
2.3
10
Glucosamine sulphate (1500 mg)
7
401
58
4.0
5
Chondroitin sulphate (800 mg)
6
362
51
3.6
4
Paracetamol (4000 mg)
4
1306
55
1.3
3




Figure 1: Results for short-term interventions for knee osteoarthritis






What the results show is that some interventions (intra-articular glucocorticoids, topical NSAIDs, opioids, and oral NSAIDs) provide pain relief equivalent to 10-15 mm on a 100 mm VAS scale (Table 1), while others (glucosamine, chondroitin, paracetamol) provide under 5 mm.


Comment


What conclusion can we draw from this? One, which the authors draw, is that perhaps a 10 mm difference over placebo just isn't good enough, and they give some reasons for why we might think that. In essence, then, the conclusion is that the interventions are relatively ineffective.


An alternative view, provided by an accompanying editorial [2], is that common experience is that most of these interventions are known to work well for individual patients in clinical practice. Perhaps, then, the problem is that the trials are unable to capture that benefit, especially in terms of averages - when few patients are average. Here the advice is to question how we do trials or analyse them, and to perhaps consider blaming trial design rather than intervention efficacy.


This is exactly what we want from systematic review: argument, challenge, and new thinking. This is a particularly good example, because it will challenge guidelines, especially in the UK, which rate paracetamol as the first intervention to use, and relegates topical NSAIDs back to the shelf. The evidence makes it hard to justify that view: more thinking needed.


References:

  1. JM Bjordal et al. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: a meta-analysis of randomised placebo-controlled trials. European Journal of Pain 2007 11: 125-138.
  2. H McQuay, A Moore. Utility of clinical trial results for clinical practice. European Journal of Pain 2007 11: 123-124.

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