Abstract

Background

Topical analgesic drugs are used for a variety of painful conditions. Some are acute, typically strains or sprains, tendinopathy, or muscle aches. Others are chronic, typically osteoarthritis of hand or knee, or neuropathic pain.

Objectives

To provide an overview of the analgesic efficacy and associated adverse events of topical analgesics (primarily nonsteroidal anti‐inflammatory drugs (NSAIDs), salicylate rubefacients, capsaicin, and lidocaine) applied to intact skin for the treatment of acute and chronic pain in adults.

Methods

We identified systematic reviews in acute and chronic pain published to February 2017 in the Cochrane Database of Systematic Reviews (the Cochrane Library). The primary outcome was at least 50% pain relief (participant‐reported) at an appropriate duration. We extracted the number needed to treat for one additional beneficial outcome (NNT) for efficacy outcomes for each topical analgesic or formulation, and the number needed to treat for one additional harmful outcome (NNH) for adverse events. We also extracted information on withdrawals due to lack of efficacy or adverse events, systemic and local adverse events, and serious adverse events. We required information from at least 200 participants, in at least two studies. We judged that there was potential for publication bias if the addition of four studies of typical size (400 participants) with zero effect increased NNT compared with placebo to 10 (minimal clinical utility). We extracted GRADE assessment in the original papers, and made our own GRADE assessment.

Main results

Thirteen Cochrane Reviews (206 studies with around 30,700 participants) assessed the efficacy and harms from a range of topical analgesics applied to intact skin in a number of acute and chronic painful conditions. Reviews were overseen by several Review Groups, and concentrated on evidence comparing topical analgesic with topical placebo; comparisons of topical and oral analgesics were rare.

For at least 50% pain relief, we considered evidence was moderate or high quality for several therapies, based on the underlying quality of studies and susceptibility to publication bias.

In acute musculoskeletal pain (strains and sprains) with assessment at about seven days, therapies were diclofenac Emulgel (78% Emulgel, 20% placebo; 2 studies, 314 participants, NNT 1.8 (95% confidence interval 1.5 to 2.1)), ketoprofen gel (72% ketoprofen, 33% placebo, 5 studies, 348 participants, NNT 2.5 (2.0 to 3.4)), piroxicam gel (70% piroxicam, 47% placebo, 3 studies, 522 participants, NNT 4.4 (3.2 to 6.9)), diclofenac Flector plaster (63% Flector, 41% placebo, 4 studies, 1030 participants, NNT 4.7 (3.7 to 6.5)), and diclofenac other plaster (88% diclofenac plaster, 57% placebo, 3 studies, 474 participants, NNT 3.2 (2.6 to 4.2)).

In chronic musculoskeletal pain (mainly hand and knee osteoarthritis) therapies were topical diclofenac preparations for less than six weeks (43% diclofenac, 23% placebo, 5 studies, 732 participants, NNT 5.0 (3.7 to 7.4)), ketoprofen over 6 to 12 weeks (63% ketoprofen, 48% placebo, 4 studies, 2573 participants, NNT 6.9 (5.4 to 9.3)), and topical diclofenac preparations over 6 to 12 weeks (60% diclofenac, 50% placebo, 4 studies, 2343 participants, NNT 9.8 (7.1 to 16)). In postherpetic neuralgia, topical high‐concentration capsaicin had moderate‐quality evidence of limited efficacy (33% capsaicin, 24% placebo, 2 studies, 571 participants, NNT 11 (6.1 to 62)).

We judged evidence of efficacy for other therapies as low or very low quality. Limited evidence of efficacy, potentially subject to publication bias, existed for topical preparations of ibuprofen gels and creams, unspecified diclofenac formulations and diclofenac gel other than Emulgel, indomethacin, and ketoprofen plaster in acute pain conditions, and for salicylate rubefacients for chronic pain conditions. Evidence for other interventions (other topical NSAIDs, topical salicylate in acute pain conditions, low concentration capsaicin, lidocaine, clonidine for neuropathic pain, and herbal remedies for any condition) was very low quality and typically limited to single studies or comparisons with sparse data.

We assessed the evidence on withdrawals as moderate or very low quality, because of small numbers of events. In chronic pain conditions lack of efficacy withdrawals were lower with topical diclofenac (6%) than placebo (9%) (11 studies, 3455 participants, number needed to treat to prevent (NNTp) 26, moderate‐quality evidence), and topical salicylate (2% vs 7% for placebo) (5 studies, 501 participants, NNTp 21, very low‐quality evidence). Adverse event withdrawals were higher with topical capsaicin low‐concentration (15%) than placebo (3%) (4 studies, 477 participants, NNH 8, very low‐quality evidence), topical salicylate (5% vs 1% for placebo) (7 studies, 735 participants, NNH 26, very low‐quality evidence), and topical diclofenac (5% vs 4% for placebo) (12 studies, 3552 participants, NNH 51, very low‐quality evidence).

In acute pain, systemic or local adverse event rates with topical NSAIDs (4.3%) were no greater than with topical placebo (4.6%) (42 studies, 6740 participants, high quality evidence). In chronic pain local adverse events with topical capsaicin low concentration (63%) were higher than topical placebo (5 studies, 557 participants, number needed to treat for harm (NNH) 2.6), high quality evidence. Moderate‐quality evidence indicated more local adverse events than placebo in chronic pain conditions with topical diclofenac (NNH 16) and local pain with topical capsaicin high‐concentration (NNH 16). There was moderate‐quality evidence of no additional local adverse events with topical ketoprofen over topical placebo in chronic pain. Serious adverse events were rare (very low‐quality evidence).

GRADE assessments of moderate or low quality in some of the reviews were considered by us to be very low because of small numbers of participants and events.

Authors' conclusions

There is good evidence that some formulations of topical diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains, with low (good) NNT values. There is a strong message that the exact formulation used is critically important in acute conditions, and that might also apply to other pain conditions. In chronic musculoskeletal conditions with assessments over 6 to 12 weeks, topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis, as did topical high‐concentration capsaicin in postherpetic neuralgia. Though NNTs were higher, this still indicates that a small proportion of people had good pain relief.

Use of GRADE in Cochrane Reviews with small numbers of participants and events requires attention.

Author(s)

Sheena Derry, Philip J Wiffen, Eija A Kalso, Rae Frances Bell, Dominic Aldington, Tudor Phillips, Helen Gaskell, R Andrew Moore

Abstract

Plain language summary

Do painkillers rubbed on the skin really work?

Bottom line

Diclofenac Emulgel, ketoprofen gel, piroxicam gel, and diclofenac plaster work reasonably well for strains and sprains. For hand and knee osteoarthritis, the nonsteroidal anti‐inflammatory drugs (NSAIDs) topical diclofenac and topical ketoprofen rubbed on the skin for at least 6 to 12 weeks help reduce pain by at least half in a modest number of people. For postherpetic neuralgia (pain following shingles), topical high‐concentration capsaicin (derived from chili peppers) can reduce pain by at least half in a small number of people.

Background

Painkillers rubbed onto the skin are called topical (local) painkillers (analgesics). There has been considerable debate over whether, how, and in what painful condition, they work.

Study characteristics

We looked for systematic reviews examining topical painkillers in the Cochrane Database of Systematic Reviews (the Cochrane Library) published up to February 2017. Reviews assessed treatment of short‐term (acute, less than three months) or long‐term (chronic, more than three months) pain conditions. We examined how well the topical painkillers worked, any harm they caused, and whether people dropped out of the studies. We also looked at the quality of the evidence.

Key results

Most reviews assessed the effects of a topical painkiller with a topical placebo. A topical placebo is the same as the active material, except that it has no painkiller in it. Using a placebo cancels out the effects that rubbing might have for some of these topical analgesics.

For strains and sprains, several topical NSAID painkillers rubbed on the skin help reduce pain by at least half over about a week in around 1 in 2 to 1 in 5 people. These are diclofenac Emulgel, ketoprofen gel, piroxicam gel, diclofenac Flector plaster, and diclofenac other plaster. How the drugs are made up is important in determining how well they work.

For hand and knee osteoarthritis the NSAID painkillers topical diclofenac and topical ketoprofen rubbed on the skin help reduce pain by at least half over at least 6 to 12 weeks in around 1 in 5 to 1 in 10 people. For postherpetic neuralgia, a single application of topical high‐concentration capsaicin can reduce pain by at least half in around 1 in 12 people for 8 to 12 weeks.

There is no good evidence to support any other topical painkiller in any other painful condition.

Topical low‐concentration capsaicin caused local side events (such as itching or rash) in 4 in 10 people, and side effects caused withdrawal in 1 in 12 people. Side effects and withdrawal because of side effects were otherwise uncommon or not different from those with a topical placebo. Serious side effects were uncommon.

Quality of the evidence

The quality of the evidence ranged from high to very low. The main reason for evidence being very low quality was the small number of participants in some studies, which make it impossible (or unsafe) to estimate benefit or harm.

Author(s)

Sheena Derry, Philip J Wiffen, Eija A Kalso, Rae Frances Bell, Dominic Aldington, Tudor Phillips, Helen Gaskell, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with pain

The major implication for people with pain is the knowledge that there is a body of reliable evidence about the efficacy of topical analgesics in different types of acute and chronic pain. Not every person will achieve good pain relief even with the most effective drugs, and analgesic failure is to be expected with particular drugs in particular people. Failure to achieve good pain relief should not be acceptable because it is likely that failure with any one drug could be reversed with another.

For clinicians

The major implication for clinicians is the knowledge that there is a body of reliable evidence about a number of topical analgesics in acute and chronic pain. Drug and formulation matter, so choice of therapy should usually be driven by the evidence: topical diclofenac and ketoprofen gel for strains and sprains, and to an extent in knee and hand osteoarthritis. Topical capsaicin high‐concentration may be of limited use in some people with postherpetic neuralgia.

Topical salicylate, low‐concentration capsaicin, clonidine, and lidocaine are not well supported by evidence, or much evidence of effect. There may be circumstances when an experienced clinician may still choose to use them, because the evidence does not exclude beneficial effects in a small percentage of people.

For policy makers

The issue is not which topical analgesic product, but achieving success ‐ good pain relief is the goal of treatment. Surveys over a long period have shown that acute and chronic pain are poorly treated, and that many people experience moderate or severe pain despite being on treatment. Pain treatment is often part of a complex of interactions between the person with pain, their pain condition, and desired outcome; the overview helps by presenting evidence from which rational choices and decisions can be made.

For funders

The important message is that some topical analgesics can produce very good pain relief for some people with acute or chronic pain. The issue is not which topical analgesic product works best, but achieving success for individual people with pain. Good pain relief is the goal of treatment. Surveys over a long period have shown that acute and chronic pain are poorly treated, and that many people experience moderate or severe pain despite being on treatment. Pain treatment is often part of a complex of interactions between the person with pain, their pain condition, and desired outcome; the overview helps by presenting evidence from which rational choices and decisions can be made, especially about the place of particular products in care pathways.

Implications for research 

General

The individual reviews and this overview have highlighted the lack of good evidence for many topical analgesics. Most of the studies and the participants included in them did not contribute to any reliable assessment of efficacy or harm. That is a waste, and the ethics of research of that sort is hard to justify.

Most topical analgesics are inexpensive, and have not had the detailed examination in large, properly‐conducted randomised trials that would be expected of modern medicines. And yet they offer good levels of pain relief for at least some people with acute and chronic pain, with a general absence of systemic adverse events in this overview, but also in studies designed to examine rare but serious harm.

Design

While there appears to be general consensus over design of studies, many of the individual studies in the individual reviews fail to meet reasonable standards. Much of that reflects the age of the studies and the standards of reporting extant at the time of publication. Others are more fundamental, such as having an adequate duration of studies investigating chronic pain; while efficacy may be established relatively early (four to six weeks), longer duration allows for assessment of tolerability.

As much as studies are needed to examine efficacy compared with placebo, or a commonly used active comparator, study designs to examine the pragmatic value of topical analgesics might be of especial value in chronic pain conditions. An example of such a trial design has been published (Moore 2010c).

Measurement (endpoints)

People with acute and chronic pain want an outcome of treatment that is equivalent to 'no worse than mild pain'. There is no reason why current pain trial methods could not report this as an outcome.

Other

Many of the improvements in understanding acute pain have been derived from individual participant‐level analyses. These can only come from close co‐operation with the pharmaceutical industry, which overwhelmingly funds the studies and 'owns' the data. Industry has a responsibility to perform more useful analyses than just those required for regulatory purposes. The main implication for research is methodological, and that is driven by data analysis at the level of the individual participant.

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