Topical NSAIDS for chronic musculoskeletal 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 chronic musculoskeletal pain. Topical NSAIDs will be compared with topical placebo, and different drugs compared indirectly because few, if any, trials test two topical preparations head to head (Mason 2004b). In addition, any topical NSAID will be compared directly with any oral NSAID.
Background
Topical 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 in 2006, the most commonly prescribed topical NSAIDs were ibuprofen (1.3 million prescriptions dispensed), diclofenac (700,000 prescriptions), ketoprofen (300,000 prescriptions) and piroxicam (200,000 prescriptions). The most common formulation was gel (PACT 2006).
There is good evidence for the efficacy of topical NSAIDs in acute and chronic musculoskeletal pain (Moore 1998, 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 examining 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, 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. 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 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, 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 acute pain (Massey 2008), topical rubefacients (Matthews 2008) and topical capsaicin (Derry 2008).
Objectives
To review the evidence from controlled trials on the efficacy and safety of topically applied NSAIDs in chronic musculoskeletal pain. Topical NSAIDs will be compared with topical placebo, and different drugs compared indirectly because few, if any, trials test two topical preparations head to head (Mason 2004b). In addition, any topical NSAID will be compared directly 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 chronic pain, with at least ten patients per treatment arm and duration of at least two weeks. Trials published only as abstracts or studying experimentally induced pain will be excluded.
Types of participants
Adult patients (16 years or more) with chronic (at least three months' duration) pain of at least moderate intensity resulting from any cause.
Types of interventions
Included studies will have at least one arm using a topical NSAID, and a comparator arm using placebo or an active analgesic intervention such as an oral NSAID. Topical NSAIDs 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 1998). 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, and particularly serious gastrointestinal problems;
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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 fourteen days as possible, with a minimum of seven 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 the 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. Study 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 active treatment 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 the number 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 use 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.
It is planned to combine data for all topical agents versus placebo for analysis of the primary outcome of clinical success, with sensitivity analyses for:
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differences between individual NSAIDs, irrespective of formulation;
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duration of study (four weeks or less versus more than four weeks);
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outcome (undefined "improvement" versus others);
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high versus low quality (two versus three or more) and validity (eight or less versus nine or more) scores;
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study size (39 or less versus 40 or more).
For secondary outcomes relating to adverse events and withdrawals, data for all topical agents versus placebo will be combined, with sensitivity analysis for:
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differences between individual NSAIDs;
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time of assessment of secondary outcome.
Trials comparing topical NSAIDs against an active comparator (topical or other route) will also be examined, although it is thought unlikely that there will be a common comparator. Particular attention will be paid to trials comparing topical and other (e.g. oral) routes of application of the same drug.
At least 200 participants must be available in any of these different contexts before information will be pooled (Moore 1998b).
