Topical NSAIDs for acute pain in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To review the evidence from controlled trials on the efficacy and safety of topically applied NSAIDs in acute pain (mainly strains and sprains, but excluding postsurgical pain where topical NSAIDs are not used). Topical NSAIDs will be compared with topical placebos, with differences between individual NSAIDs investigated by indirect comparison, since few, if any, studies examine two topical preparations head to head (Mason 2004a). In addition, any topical NSAID will be compared with any oral NSAID.
Background
Topical nonsteroidal anti‐inflammatory drugs (NSAIDs) for pain relief remain one of the more controversial subjects in analgesic practice. In some parts of the world they have been available for many years, are widely available without prescription, widely advertised, used extensively, and evidence for their use is considered adequate. In other parts of the world they are regarded as little more than placebo, with any apparent effect attributed to the process of rubbing. In other places their use is almost unknown. In England almost three million prescriptions for topical NSAIDs were dispensed in 2006 (PACT 2006).
There is good evidence for the efficacy of oral NSAIDs in acute and chronic musculoskeletal pain (Moore 1998a; Mason 2004a; Mason 2004b). In the US the Food and Drug Administration licensed topical nonsteroidal products in 2007, and it is expected that in England the National Institute for Clinical Excellence (NICE) will recommend topical therapies as first line treatment in its guidelines for osteoarthritis in 2008. A review of topical analgesics covers not only clinical trials, but also studies investigating the underlying science to explain biological plausibility (Bandolier 2005).
For a topical formulation to be effective, it must first penetrate the skin. Only when the drug has entered the lower layers of the skin can it be absorbed by blood and transported to the site of action, or penetrate deeper into areas where inflammation occurs. Individual drugs have different degrees of penetration. A balance between lipid and aqueous solubility is needed to optimise penetration, and use of prodrug esters has been suggested as a way of enhancing permeability. Formulation is also crucial to good skin penetration. Experiments with artificial membranes or human epidermis suggest that creams are generally less effective than gels or sprays, but newer formulations such as microemulsions may have greater potential.
Once the drug has reached the site of action, it must be present at a sufficiently high concentration to inhibit cox enzymes and produce pain relief. It is probable that topical NSAIDs exert their action both by local reduction of symptoms arising from periarticular structures, and by systemic delivery to intracapsular structures. Tissue levels of NSAIDs applied topically certainly reach levels high enough to inhibit cyclooxygenase‐2 (Bandolier 2005). Plasma concentrations found after topical administration, however, are only a fraction (usually much less than 5%) of the levels found in plasma following oral administration. Topical application can potentially limit systemic adverse events by increasing local effects, and minimizing systemic concentrations of the drug. We know that upper gastrointestinal bleeding is low with chronic use of topical NSAIDs (Evans 1995), but have no certain knowledge of lower effects on heart failure, or renal failure, both of which are associated with oral NSAID use.
New versions of topical NSAIDs are becoming available, with more and better trials being performed. An updated review of evidence for their efficacy is needed for commissioners (purchasers of healthcare), prescribers and consumers to make informed choices about their use. Many trials of newer preparations have yet to be published, and are not yet available. Contact with pharmaceutical companies to attempt to have access to these new trials will be an important part of searching.
This is one of a series of reviews being conducted on topical analgesics, including NSAIDs in chronic pain (Derry 2008a), topical rubefacients (Matthews 2008) and topical capsaicin (Derry 2008b).
Objectives
To review the evidence from controlled trials on the efficacy and safety of topically applied NSAIDs in acute pain (mainly strains and sprains, but excluding postsurgical pain where topical NSAIDs are not used). Topical NSAIDs will be compared with topical placebos, with differences between individual NSAIDs investigated by indirect comparison, since few, if any, studies examine two topical preparations head to head (Mason 2004a). In addition, any topical NSAID will be compared with any oral NSAID.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled double blind trials comparing topical NSAIDs with placebo or other active treatment for acute pain, with at least ten patients per treatment arm and outcomes close to seven days (minimum three days). Trials published only as abstracts or studying experimentally induced pain will be excluded.
Types of participants
Adult patients (16 years or more) with acute pain of at least moderate intensity resulting from strains, sprains or sports injuries.
Types of interventions
Included studies will have at least one arm using a topical NSAID, and a comparator arm using placebo or other active treatment. The topical NSAID should be applied at least once daily. Salicylate and benzydamine are no longer classified as topical NSAIDs and will not be included in this review.
Types of outcome measures
Information will be sought on patient characteristics: age, sex, and condition to be treated.
Primary outcomes
The primary outcome will be "clinical success", defined as a 50% reduction in pain, or 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 (Moore 1998a). The following hierarchy of outcomes, in order of preference, will be used to extract data for the primary outcome:
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patient reported reduction in pain of at least 50%;
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patient reported global assessment of treatment;
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pain on movement;
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pain on rest or spontaneous pain;
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undefined "improvement".
Only patient reported outcomes will be used. Physician or investigator reported outcomes of efficacy will not be used.
Secondary outcomes
Secondary outcomes sought will be:
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numbers of patients with adverse events: local and systemic;
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numbers of withdrawals: all cause, lack of efficacy, and adverse events.
We anticipate that outcomes will be reported after different durations of treatment, and will extract data reported as close to seven days as possible, with a minimum of three days. Where outcomes are reported after longer durations of treatment these will also be extracted. We also anticipate that reporting of adverse events will vary between trials with regard to the terminology used, method of ascertainment, and categories that are reported (e.g. occurring in at least 5% of patients or where there is a statistically significant difference between treatment groups). Care will be taken to identify these details.
Search methods for identification of studies
The following databases will be searched:
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MEDLINE (via Ovid)
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EMBASE (via Ovid)
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Cochrane CENTRAL
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Oxford Pain Relief Database (Jadad 1996a)
The MEDLINE search strategy can be seen in Appendix 1. This strategy will be revised appropriately for other databases.
Reference lists of review articles and included studies will be searched.
Manufacturers have previously been asked for details of unpublished studies, and new manufacturers or UK distributors will also be asked about unpublished studies as they are identified.
There will be no language restriction.
Data collection and analysis
Review authors will not be blinded to the authors' names and institutions, journal of publication, or study results at this or any stage of the review. Two review authors will independently select the studies for inclusion, assess methodological quality, and extract data. Disagreements will be resolved through discussion.
Selection of studies
Titles and abstracts of studies identified by the searches will be reviewed on screen to eliminate those that clearly do not satisfy inclusion criteria. Full reports of the remaining studies will be obtained to determine inclusion in the review. Crossover trials will be considered only if data from the first treatment period is reported separately. Studies in oral, ocular or buccal diseases will be excluded.
Assessment of methodological quality
Included studies will be assessed for quality using a five‐point scale (Jadad 1996b) that considers randomisation, blinding, and study withdrawals and dropouts. Trial validity will be assessed using a 16‐point scale (Smith 2000).
Data extraction
Information on patients, interventions, and outcomes from the original reports will be abstracted into a standard data extraction form. Authors will not be contacted for further information.
Data analysis
Intention to treat analyses will be performed. Homogeneity will be examined visually using L'Abbe plots (L'Abbe 1987).
Where appropriate, data for each dichotomous outcome will be pooled and used to calculate numbers‐needed‐to‐treat‐to‐benefit (NNTs) with 95% confidence intervals (CI) (Cook 1995). Relative benefit and relative risk estimates with 95% CIs will be calculated using the fixed‐effect model (Morris 1995). A statistically significant benefit of topical NSAID over control is assumed when the lower limit of the 95% CI of the relative benefit is greater than one. A statistically significant benefit of control over active treatment is assumed when the upper limit of the 95% CI is less than one. Number‐needed‐to‐treat‐to‐harm (NNH) and relative risk will be calculated for these outcomes in the same way as for NNTs and relative benefit.
Statistically significant differences between NNTs for different topical NSAIDs will be tested using the z test (Tramer 1997), where there is sufficient data to do so, and where the clinical trials are sufficiently similar in types of patient, outcome, and duration to make such comparisons sensible.
Sensitivity analyses for the primary outcome for topical agent versus placebo are planned for:
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high versus low quality (< 3 versus 3 or more) and validity (< 9 versus 9 or more) scores;
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study size (< 40 versus 40 or more);
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outcome (undefined "improvement" versus others);
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differences between individual NSAIDs;
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time of assessment of primary outcome.
Trials comparing topical NSAIDs against an active comparator will also be examined, although it is thought unlikely that there will be a common comparator.
At least 200 patients must be available in any of these different contexts before information is pooled (Moore 1998b).
