da Costa BR, Reichenbach S, Keller N, et al.   Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.
Lancet. 2017 Jul 8;390(10090):e21-e33. doi: 10.1016/S0140-6736(17)31744-0.   (Systematic Review)   PMID: 28699595
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Special Interest - Pain -- Physician
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Internal Medicine
Surgery - Orthopaedics

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BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis.
METHODS: For this network meta-analysis, we considered randomised trials comparing any of the following
INTERVENTIONS: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose.
FINDINGS: We identified 8973 manuscripts from our search, of which 76 randomised trials with a total of 58 451 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0.37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0.57, 95% credibility interval [CrI] -0.69 to -0.45) and etoricoxib 60 mg/day (ES -0.58, -0.74 to -0.43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for naproxen (p=0.034). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis.
INTERPRETATION: On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients.
FUNDING: Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

Comments from Clinical Raters
Family Medicine (FM)/General Practice (GP)
This network meta-analysis shows that most NSAIDs and paracetamol are largely ineffective. The most effective drugs cluster around the minimum clinically effective mark. It supports the 2 important studies by Machado published recently in BMJ. Interestingly, the authors make something of diclofenac being more effective, but this is one of the less-studied NSAIDs
Family Medicine (FM)/General Practice (GP)
Acetaminophen being useless for osteoarthritis would be practice-changing.
Special Interest - Pain -- Physician
Unsurprising. For a geriatrician, the numbers needed to harm are more important data. Coxibs and NSAIDs are often poorly tolerated, let alone cardiac effects etc. Sadly, this study does not change my practice.
Surgery - Orthopaedics
The study would have been more interesting if authors had discussed publication bias related to financial support in the included studies.