Abstract: We identified five new studies for this update, which now has information from 10,857 participants in 39 studies, a 41% increase in participants from the earlier review; 32 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size. In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2353 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis. There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence). Clinical success with carrier occurred commonly - in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo. A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed. Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that.

Plain-language summary: This review is an update of 'Topical NSAIDs for chronic musculoskeletal pain in adults', originally published in 2012. We found 39 generally high-quality studies with 10,857 participants where topical NSAID was used at least once a day. These studies tested a number of different topical drugs, mostly against a topical placebo. We were interested in participants having good pain reduction (by about half), ideally 6 to 12 weeks after treatment started. Studies that last longer are more representative of the real world, because in these chronic conditions the pain almost never goes away if untreated. We looked at individual NSAIDs to see how effective they were. Diclofenac and ketoprofen were the only two with good quality and longer duration studies, mostly in people aged over 40 years with painful knee arthritis. The comparison was between topical diclofenac or ketoprofen in a solution or gel, and the solution or gel without any drug in it (topical placebo). For diclofenac and ketoprofen, about 6 people out of 10 with osteoarthritis had much reduced pain after 6 to 12 weeks, compared with 5 out of 10 with topical placebo (moderate quality evidence). Skin reactions (mostly mild) were more common (20 in 100) with topical diclofenac than topical placebo (5 in 100); there was no difference between topical ketoprofen and topical placebo (moderate quality evidence). Other adverse events, like stomach upsets, were poorly reported in these studies, but were no different between topical diclofenac or ketoprofen and topical placebo (very low quality evidence). Serious adverse events were uncommon. We rated the quality of the evidence for topical diclofenac and topical ketoprofen compared with placebo as moderate for efficacy, and very low for harmful effects. Moderate quality evidence means that further research may change our estimate of the effect, and very low quality evidence means that we are very uncertain about the accuracy of our estimate.