Rapid responses Topic collections Primary care Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials

Abstract Objective To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee. Design Systematic review and meta-analysis of randomised placebo controlled trials. Studies reviewed 23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years. Main outcome measure Change in overall intensity of pain. Results Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31). Conclusion NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended

Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials

Objective To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee. Design Systematic review and meta-analysis of randomised placebo controlled trials. Studies reviewed 23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years. Main outcome measure Change in overall intensity of pain. Results Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31). Conclusion NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended

COMMENTS AND RESPONSE Overviews and Systematic Reviews on Low Back Pain Annals of Internal Medicine Letters

TO THE EDITOR: In a recent overview of systematic reviews and randomized trials of pharmacotherapy in low back pain, Chou and Huffman (1) concluded that there is good evidence that acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants provide moderate pain relief in acute low back pain. In the clinical practice guideline (2) in the same issue, the recommendations for acetaminophen and NSAIDs are extended to include chronic low back pain and tramadol, opioids, and benzodiazepines are recommended both in acute and chronic low back pain despite lack of "good" or even "fair" evidence. Chou and Huffman's method of reviewing literature relies too heavily on preexisting systematic reviews, some seriously outdated. As a result, previous work is reiterated without adequate scrutiny. In fact, methodological issues led to inclusion of studies not meeting the stated eligibility criteria and, more important, to erroneous conclusions. Acetaminophen: No direct evidence shows acetaminophen to be more effective than placebo for treating low back pain. A small (n ϭ 30) trial (3) found acetaminophen to be less effective than NSAIDs in treating acute low back pain. One low-quality trial (4) reported no difference between acetaminophen and no treatment, and another (5) showed ambiguous results. In an outdated Cochrane review (6) cited by Chou and Huffman, 2 low-quality trials (7, 8) found no difference between NSAIDs and acetaminophen. One of these trials (7) was not randomized. Comparative studies (9) of acetaminophen and nonpharmacologic treatments in high-quality randomized, controlled trials (RCTs) have shown that acetaminophen was inferior to superficial heat. In an old trial of lower quality (10), acetaminophen allegedly was slightly inferior to manipulation, but poor reporting of treatment allocation and handling of withdrawals obscured these results. As for evidence of the effectiveness of acetaminophen in nonlow back pain scenarios, the authors claim that 3 systematic reviews demonstrate the superiority of NSAIDs over acetaminophen in osteoarthritis, with a standardized mean difference of approximately 0.3. We have previously reported the effectiveness of NSAIDs over placebo in knee osteoarthritis, corresponding to a standardized mean difference of 0.31 (11), whereas acetaminophen had statistically significant but clinically insignificant effects in knee osteoarthritis, with a weighted mean difference for pain of 3.0 mm (95% CI, 1.4 to 4.7 mm) on a visual analogue scale (12). In summary, there is no direct evidence and a paucity of indirect evidence to prove the effectiveness of acetaminophen in low back pain. Chou and Huffman's claim of "good evidence of a moderate effect" of acetaminophen in this condition is, in our view, unsubstantiated. NSAIDs: The outdated Cochrane review (5, 13) cited by Chou and Huffman has several shortcomings. Most important, the standardized mean difference analysis for pain was statistically insignificant for NSAIDs in acute low back pain (Ϫ0.53 [CI, Ϫ2.74 to 1.69]). Chou and Huffman state that the Cochrane review included 6 trials in which NSAIDs were superior to placebo in acute low back pain, with a relative risk for benefit of 1.24 (CI, 1.10 to 1.41). Of these 6 trials, 4 found statistically insignificant differences, whereas 2 (14, 15) reported statistically significant positive results. In the first of these studies, groups of patients received intramuscular injections of dipyrone (metamizole), diclofenac, or saline (placebo). Dipyrone, the sodium sulfonate of the obsolete antipyretic agent antipyrine, is not licensed in the United States and many other countries because of serious side effects and is hardly a typical NSAID. However, only data for the dipyrone group in this particular study were entered into the Cochrane analysis. In addition, 1 of the trials (16) was not randomized and thus was not eligible for the overview. Removing this trial and substituting dipyrone data with diclofenac data in the other trial rendered global improvement statistically insignificant, with relative risk for benefit of 1.11 (CI, 0.98 to 1.26). The overview claims ibuprofen was superior to placebo in 1 trial of chronic low back pain, but this trial (17) actually states that both groups received ibuprofen, and additional medication was compared with placebo. Thus, on the basis of the cited material, the conclusion that there is good evidence for moderate effect of NSAIDs in low back pain is erroneous. Muscle relaxants, including benzodiazepines: On the basis of 4 RCTs summarized in a Cochrane review (18), the overview states that there is "good" evidence of a "moderate" effect of muscle relaxants in acute low back pain. However, 3 out of 4 RCTs in this relative risk analysis for pain have statistically insignificant results, with CIs less than 1. The positive overall result rests more or less on a single RCT from 1982 in which Merck & Co. personnel performed the statistical analysis. In the review, 79% of the weight in the statistical analysis came from this trial, which has a methodological quality score at the reviewers' cutoff value (6 out of 11). In other words, if this RCT had been rated 5 instead of 6 out of 11 and thereby was excluded from the analysis for poor methodological quality, the overall result of the meta-analysis would have been negative. The reported relative risks stated in the overview (1.25 and 1.72) differ from those reported in the Cochrane review (0.80 and 0.58), and the reason for this discrepancy remains obscure. Chou and Huffman also claim that tizanidine was efficacious in 8 trials, but according to the cited review (18), only 6 of the trials were placebo-controlled and just 3 of these reported statistically significant results. For benzodiazepines, the positive overall result in the overview rests on 2 RCTs. However, the analyses failed to include 51 patients who dropped out in 1 of these studies (19). The relative risk for pain relief by benzodiazepines became statistically insignificant at 1.38 (CI, 0.99 to 1.92) after inclusion of these withdrawals. Low-level laser therapy (LLLT): Chou and Huffman handled LLLT on a trial-by-trial basis because no suitable reviews of LLLT were identified. The overview states that the LLLT material is heterogeneous, although adequate doses of LLLT with wavelengths ranging from 600 to 1100 nm seem to offer an anti-inflammatory class effect We believe that the examples given are sufficient to support our key message: Overviews of systematic reviews are methodologically inferior to systematic reviews. The degree of transparency is low, errors often remain unacknowledged, and sensitive and unreliable data are propagated. With the small body of RCTs that eventually constitute the critical basis for guidelines, systematic review with updated meta-analyses should be mandatory. If the present overview's definition of "good evidence" is applie