Topical NSAIDs for chronic musculoskeletal pain in adults
Use of topical nonsteroidal anti‐inflammatory drugs (NSAIDs) to treat chronic musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of 'Topical NSAIDs for chronic musculoskeletal pain in adults', originally published in Issue 9, 2012.
To review the evidence from randomised, double‐blind, controlled trials on the efficacy and safety of topically applied NSAIDs for chronic musculoskeletal pain in adults.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and our own in‐house database; the date of the last search was February 2016. We also searched the references lists of included studies and reviews, and sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' web sites.
We included randomised, double‐blind, active or inert carrier (placebo) controlled trials in which treatments were administered to adults with chronic musculoskeletal pain of moderate or severe intensity. Studies had to meet stringent quality criteria and there had to be at least 10 participants in each treatment arm, with application of treatment at least once daily.
Data collection and analysis
Two review authors independently assessed studies for inclusion and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat (NNT) or harm (NNH) compared to carrier or other active treatment. We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. The primary outcome was 'clinical success', defined as at least a 50% reduction in pain, or an equivalent measure such as a 'very good' or 'excellent' global assessment of treatment, or 'none' or 'slight' pain on rest or movement, measured on a categorical scale.
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.
Sheena Derry, Philip Conaghan, José António P Da Silva, Philip J Wiffen, R Andrew Moore
Plain language summary
Topical nonsteroidal anti‐inflammatory drugs for chronic musculoskeletal pain in adults
Topical diclofenac and topical ketoprofen can provide good levels of pain relief in osteoarthritis, but only for about 10% more people than get this result with topical placebo. There is no evidence for other chronic painful conditions.
Chronic musculoskeletal pain occurs in conditions like osteoarthritis. Pain is typically moderate or severe in intensity, lasting for three months or more.
Topical nonsteroidal anti‐inflammatory drugs (NSAIDs) are applied to unbroken skin where it hurts in the form of a gel, cream, spray, or plaster. Topical NSAIDs penetrate the skin, enter tissues or joints, and reduce processes that cause pain in the tissue. Drug levels in the blood with topical NSAIDs are very much lower than with the same drug taken by mouth. This minimises the risk of harmful effects.
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.
Quality of the evidence
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.
Sheena Derry, Philip Conaghan, José António P Da Silva, Philip J Wiffen, R Andrew Moore
Implications for practice
For people with chronic musculoskeletal pain
Topical diclofenac and topical ketoprofen can provide good levels of pain relief in knee osteoarthritis in people aged over 40 years, but only in about 10% more people than with carrier. Adverse events are minimal with topical nonsteroidal anti‐inflammatory drugs (NSAIDs).
Topical diclofenac and topical ketoprofen can provide good levels of pain relief in knee osteoarthritis, but only in about 10% more people than with carrier. Adverse events are minimal with topical NSAIDs. For this reason guidelines often suggest the use of topical NSAIDs before oral NSAIDs, particularly in older people. There is little good evidence for topical NSAIDs in other chronic musculoskeletal pain.
For policy makers
Topical NSAIDs are not associated with an increased incidence of local skin reactions compared with the inert carrier, and while the carrier may cause mild, transient irritation, it is rarely troublesome. Topical NSAIDs do not cause systemic (mainly gastrointestinal) problems commonly seen with oral NSAIDs, making them particularly useful for individuals with osteoarthritis who are unable to tolerate oral administration, or for whom it is contraindicated. The efficacy results we have are only applicable to knee osteoarthritis.
Topical diclofenac and topical ketoprofen preparations should be considered for treatment of chronic musculoskeletal painful conditions like knee osteoarthritis where there are no contraindications, such as damaged skin.
Formulations of topical NSAIDs are likely to change over time, therefore the relevant trials performed and reported over 25 years ago must be limited and may be questionable. Funders might wish to consider asking pharmaceutical companies without recent trial evidence for their products to produce it.
Implications for research
The general thrust of these findings is that gel formulations of topical diclofenac and topical ketoprofen can provide good levels of pain relief in patients with knee osteoarthritis, but only about 1 in 10 more will benefit with the topical NSAID than with topical placebo, or carrier. Response rates to topical placebo in relevant longer duration studies appear to be substantially higher than with oral placebo. The reason for this is not known, but the fact that 50% of osteoarthritis patients can report very high levels of pain relief without NSAID is not without importance.
There is little good evidence about other topical NSAIDs or topical NSAIDs in other chronic conditions, and research in other forms of chronic pain might be appropriate.
The design of the trials is generally good, and the knee osteoarthritis model appears to be reliable and reproducible. Modern studies have ensured that participants entering the trials have at least moderate pain, and this helps sensitivity to detect an analgesic response. Major changes to the design of these trials would not appear to be needed, other than ensuring an adequate duration because shorter studies consistently report higher efficacy.
A major issue is not in the measurement of pain, as most studies, especially modern ones, have used standard pain intensity and pain relief scales. However, reporting of average pain changes is inadequate, and the use of responder analyses (at least 50% pain intensity reduction, or patients experiencing mild or no pain) is preferred.
Comparison between active treatments
Indirect comparisons with carrier are probably as informative as use of an active comparator, for which there are few. However, comparisons between oral placebo and topical placebo (carrier only without NSAID) are an obvious target for future studies.