Topical NSAIDs for acute pain: a meta-analysis

Relevant studies were sought regardless of publication language, type, date or status. Studies included in the previous review were examined for inclusion in this updated version, according to our inclusion criteria. The Cochrane Library, MEDLINE and PreMedline, EMBASE and PubMed were used to find relevant studies published since the last review, for the years 1996 to April 2003. Reference lists of retrieved articles were also searched. The search strategy included "application: topical" together with "cream", "gel" etc, together with generic names of NSAIDs, and proprietary preparations of topical treatment in which the principal active ingredient was an NSAID [6, 7] (see Additional file 1: search strategy). Twenty pharmaceutical companies in the UK, 66 in Europe, and two in North America, known to manufacture topical NSAIDs, were sent letters asking if they could supply papers.

We identified reports of randomised, double-blind, active or placebo-controlled trials in which treatments were administered to adult patients with acute pain resulting from any strains, sprains or sports injuries. Excluded conditions were oral, ocular or buccal diseases. Application of treatment had to be at least once daily. At least ten patients had to be randomised to a treatment group. Outcomes closest to seven days were extracted.

Trial quality was assessed using a validated three-item scale with a maximum quality score of five [8]. Included studies had to score at least two points, one for randomisation and one for blinding. A sixteen-point scale was used to assess trial validity [9].

Quality and validity assessments were made independently by at least two reviewers. Extracted outcomes were verified by one other reviewer. Disputes were settled by discussion between all reviewers.

We defined our own outcome of clinical success, representing approximately a 50% reduction in pain [1]. This was either the number of patients with a "good" or "excellent" global assessment of treatment, or "none" or "slight" pain on rest or movement (or comparable wording) measured on a categorical scale. A hierarchy of outcomes was used to extract efficacy information, shown below in order of preference:

1) number of patients with a 50% or more reduction in pain

2) patient reported global assessment of treatment

3) pain on movement

4) pain on rest or spontaneous pain

5) physician or investigator global assessment of treatment

In addition, the number of patients showing undefined "improvement" was also accepted.

Secondary outcomes were extracted from included papers that reported them. These were the number of patients (i) reporting one or more local adverse event (itching, stinging, rash), (ii) reporting one or more systemic adverse event (iii) withdrawing from trials due to adverse events.

The number of patients randomised into each treatment group (intention to treat) was used in the efficacy analysis. Information was pooled for the number of patients in each trial achieving at least 50% pain relief, or similar measure, for both topical NSAID and control. These were used to calculate NNT with a 95% confidence interval (CI) [10]. Relative benefit and relative risk estimates with 95% CIs were calculated using the fixed effects model [11]. A statistically significant benefit of topical NSAID over control was assumed when the lower limit of the 95% CI of the relative benefit was greater than one. A statistically significant benefit of control over active treatment was assumed when the upper limit of the 95% CI was less than one. Number-needed-to-harm (NNH) and relative risk were calculated for these outcomes in the same way as for NNTs and relative benefit. Homogeneity of trials was assessed visually [12‐14]. All calculations were performed using Microsoft Excel X for the Macintosh and RevMan 4.2. In sensitivity analyses the z test was used [15]. QUOROM guidelines were followed [16].

Our prior intention was to perform sensitivity analyses on pooled outcomes using the z test in terms of quality score (less than 2 versus 3 or more), validity score (less than 8 versus 9 or more), size (less than 40 patients per group versus 40 or more, the median in a previous meta-analysis [1]), outcome type (higher versus lower preference outcomes), and particular NSAID used. At least three studies had to be available in any of these different contexts before information was pooled.

Ten out of the 20 UK companies, and two out of 66 European companies that we contacted replied to our request for studies. However, only three companies supplied us with useful material; either published studies or bibliographies. One company supplied material that was unpublished at the time of writing [17].

We identified 89 potential papers from our searches. Fifty-three were excluded (see Additional file 2: studies excluded from the review, Additional file 3: QUOROM flow diagram). Of the original 89, 64 papers were in the previous review, of which we excluded 30; four placebo and 15 active controlled trials used salicylates, four placebo controlled trials used benzydamine, two were single blind, and one each had inappropriate randomisation, did not state dose or duration of treatment, had no useable data, used mixed pain conditions including some chronic conditions, or had an inappropriate add-on design. There were 25 potential papers not in the previous review. Of these, 23 were excluded because they were not randomised (9), had no useable data (4), were not double blind (3), were experimental (2), or for other reasons (5).

Thirty-six trials met the selection criteria; 34 from the previous review and two new ones. Twenty-four trials [17‐40] had only placebo controls, eight [41‐48] only active controls, and four [49‐52] had both placebo and active controls. Of the 12 active controlled trials, nine compared one topical NSAID with a different topical NSAID, and three [44, 48, 49] used oral NSAID controls. Details of all included studies with outcomes and quality and validity scores are in Additional files 4 (Outcome details of placebo-controlled trials) and 5 (Outcome details of active-controlled trials). Information about patients was limited, though age ranges were given. Patients had mainly sports injuries, soft tissue injuries, or sprains and strains.

Quality scores were high, with 24/28 placebo controlled and 11/12 active controlled trials scoring 3 or more points out of a maximum of 5. Validity scores were also high, with 25/28 placebo controlled and 10/12 active controlled trials scoring 9 or more out of a maximum of 16 (see Additional files 4 and 5).

Three trials, with 433 patients, compared a topical NSAID with an oral NSAID (indomethacin 75 mg daily in one trial and ibuprofen 1,200 mg daily in two). One trial [44] compared different topical and oral NSAIDs (felbinac foam with oral ibuporofen), while the other two compared the same topical and oral NSAID, ibuprofen in one [48] and indomethacin in the other [49]. Overall rates of treatment success were similar for topical NSAID (57%) and oral NSAID (62%), with no statistically significant difference (relative benefit 0.9; 0.8 to 1.1).

The other nine trials compared one topical preparation with another (see Additional file 5), For only topical piroxicam 0.5% compared with topical indomethacin 1% was there at least three trials (with 716 patients). Piroxicam was significantly more effective than indomethacin, with improvement in 52% on piroxicam and 39% on indomethacin. The relative benefit was 1.3 (1.1 to 1.5) and the NNT for piroxicam compared with indomethacin was 8 (5 to 20). Local adverse events were less common with piroxicam (2%) than with indomethacin (10%). The relative risk for an adverse event with piroxicam was 0.2 (0.1 to 0.5) compared with indomethacin, and the number needed to prevent one local adverse event was 14 (9 to 26).