Diclofenac 150 mg / day was the most effective non-steroidal anti-inflammatory drug (NSAID) to improve both pain and function in knee or hip osteoarthritis (OA) and paracetamol was less effective and should not be used in this context. A new meta-analysis of the network published on March 17 in The Lancet.
“Based on available data, we see no role for the single agent paracetamol for the treatment of patients with osteoarthritis, regardless of dose,” write Sven Trelle, MD, University of Bern, Switzerland, and colleagues. “We provide strong evidence that diclofenac 150 mg / day is the most effective NSAID available today in terms of improving pain and function. However, in view of the safety profile of these drugs, clinicians should consider our results together with all known safety information when selecting the preparation and dosage for individual patients. ”
This study reinforces data previously reported by other investigators who showed similar lack of efficacy for acetaminophen in this setting.
The new report, which includes a substantially larger number of patients than the meta-analysis of the previous network, is likely to increase calls for reconsideration of OA treatment guidelines that position the drug as first-line treatment. The guidelines that recommend acetaminophen as a first-line treatment include those of the American College of Physicians, the American Pain Society, the European League against Rheumatism, the American College of Rheumatology, the International Osteoarthritis Research Society, and The UK National Institute of Health and Excellence in Care.
Dr. Trelle and his colleagues used network meta-analysis in an attempt to fill some of the gaps left by previous NSAID efficacy studies, most of which reported only on NSAID vs placebo pain relief “and therefore they are only of restricted use for the clinical practice ” write the authors. The network meta-analysis approach integrates data from all randomized controlled trials (RCTs) that compared different doses of NSAIDs head-to-head or placebo, respecting randomization, and therefore allows comparison between active agents .
In addition, the authors used an extension of multivariate Bayesian random effects models for mixed multiple treatment comparisons, allowing comparison of all treatments available between trials and representing multiple comparisons in trials with more than two treatment groups.
Eligible studies for inclusion were RCTs of patients with knee or hip OA who had at least 100 patients randomized to each treatment group. Treatments examined included acetaminophen, rofecoxib, lumiracoxib, etoricoxib, diclofenac, celecoxib, naproxen and ibuprofen.
The primary outcome was pain, evaluated at 1 week, 2 weeks, 4 weeks, 6 weeks, 3 months, 6 months and 12 months. The researchers defined minimal clinically significant difference as a decrease of 0.37 units, corresponding to a difference of 9 mm on a visual analog scale of 100 mm.
The secondary outcome was physical function, assessed at 1 week, 2 weeks and at the end of treatment.
The authors initially identified 8973 manuscripts, of which 74 RCTs comprising 58,556 patients were finally included in the analysis.
Among the maximum daily doses approved, diclofenac 150 mg / day and etoricoxib 60 mg / day were the most effective for reducing pain, both with a 100% chance of reaching the minimum clinically important difference.
Four other treatments had a 95% probability of reaching the prespecified threshold for clinically significant impact: etoricoxib 30 mg / day and 90 mg / day and rofecoxib 25 mg / day and 50 mg / day. The authors noted that etoricoxib is less available than diclofenac because it has marketing approval in fewer countries.
Five treatments were not superior to placebo using available data: acetaminophen
“The magnitude of estimates of the effect of treatment varied greatly between different NSAIDs and doses,” the authors write. “While paracetamol had almost no effect on pain symptoms at various doses (effect size -0.17, corresponding to a 4-mm difference on a 100-mm visual analogue scale), diclofenac 150 mg / day A moderate to large effect size of -0.57, corresponding to the difference in a visual analogue scale of 100 mm of 14 mm, equivalent to 1.5 times the minimum difference clinically important for chronic pain of -0.37 ” .
The efficacy of NSAIDs varied generally with dose, but acetaminophen was ineffective at all doses tested.
In contrast, diclofenac 150 mg / day was the most effective treatment for both pain and physical disability, and was superior to maximal doses of ibuprofen, naproxen and celecoxib.
In a press release, Dr. Trelle said: “NSAIDs are generally only used to treat short-term pain episodes in osteoarthritis because side effects are thought to outweigh benefits when used over a longer period. , uur results suggest that paracetamol at any dose is not effective in managing pain in osteoarthritis, but that certain NSAIDs are effective and can be used intermittently without paracetamol. ”
In a related commentary, Professor Nicholas Moore and colleagues in the pharmacology department of the University of Bordeaux, France, wrote that a limitation of the study was that widely used NSAIDs were not included in this meta-analysis, probably because there are no recent trials of these Drugs or because the recent trials that evaluated them were too small.
“The most notable result is that paracetamol does not appear to confer any demonstrable effect or benefit on osteoarthritis, at any dose. This finding is not entirely unexpected. Paracetamol has been on the market during the Time that most of its efficacy has never been adequately established or quantified in chronic diseases, and is likely not to be as large as many believe, and its safety is also questioned, not just overdose. ”
Commentators suggested that patients might be suffering unnecessarily due to perceived risks of NSAIDs and apparently nonexistent benefits of acetaminophen.
Dr. Moore and colleagues write that “short-term intermittent use of NSAIDs with gastroprotection may also explain why the risks of upper gastrointestinal bleeding from long-term full-dose trials without gastroprotection are not found in patients in real situations “.