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Topical NSAIDs for chronic musculoskeletal pain

 

Clinical bottom line

Topical NSAIDs were clearly better than placebo in chronic musculoskeletal pain, with an NNT of 4.4 (3.6 to 5.6) in the best trials. Studies were generally of short duration, and no single preparation could be shown to be better than another. No study showed oral NSAID to be better than topical NSAID.

Local adverse events, systemic adverse events, or withdrawals due to an adverse event were rare, and no different between topical NSAID and placebo.


Background

The utility of topical NSAIDs has been questioned. This systematic review updated a previous review by accepting only higher quality trials (randomised, double blind), omitting salicylates, and adding newer trials.

References


L Mason et al. Topical NSAIDs for chronic musculoskeletal pain. BMC Musculoskeletal Disorders 2004 5:28 (http://www.biomedcentral.com/1471-2474/5/28)


J Lin et al. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ 2004 329: 324-330.


Systematic review by Mason et al

The review sought studies in four electronic databases, reviews, and by writing to all companies worldwide marketing topical NSAIDs.

Patients were generally over 40 years old, predominantly with musculoskeletal disorders, and with baseline pain of moderate to severe intensity.

Results

Placebo controlled trials

Fourteen trials with information from 1,502 patients were analysed for efficacy. Topical NSAIDs as a class were significantly better than placebo (Table 1), with an NNT of 4.6 (3.8 to 5.9). There were 10 studies with higher quality and validity scores that minimised bias, and these also had an NNT of 4.4 (Table 1).

Table 1: Main results for topical NSAIDs in strains and sprains

Number of
Success/total
Trial characteristic
Trials
Patients
Treatment
Placebo
RB
(95% CI)
NNT
(95% CI)
Efficacy
All trials
14
1502
371/771
193/731
1.9 (1.7 to 2.2)
4.6 (3.8 to 5.9)
Validity score 9 or more and quality score 3 or more
10
1197
247/622
98/575
2.4 (2.0 to 3.0)
4.4 (3.6 to 5.6)
Condition
knee osteoarthritis
5
567
127/307
58/260
2.0 (1.6 to 2.6)
5.3 (3.8 to 8.6)
other musculoskeletal
9
935
244/464
135/471
1.9 (1.6 to 2.2)
4.2 (3.3 to 5.6)
Adverse events
Type of adverse event
trials
patients
event with treatment
event with placebo
RR (95% CI)
 
Placebo controlled trials
Local adverse events
15
1734
53/949
48/785
1.0 (0.7 to 1.4)
Systemic adverse events
16
1838
33/1002
14/836
1.7 (0.96 to 2.85)
Withdrawals because of adverse events
10
1225
10/697
7/528
0.9 (0.4 to 2.1)
Active controlled trials: topical vs oral
Type of adverse event
trials
patients
event with topical
event with oral
RR (95% CI)
Local adverse events
2
443
19/243
4/118
3.0 (1.1 to 8.5)
Systemic adverse events
3
764
82/408
87/356
0.83 (0.6 to 1.1)
Withdrawals because of adverse events
3
764
19/408
24/356
0.7 (0.4 to 1.3)

Eighteen placebo controlled trials (2,032 patients) provided some information on adverse events (Table 1). There was no statistically significant difference between topical NSAID and topical placebo for the number of patients experiencing local adverse events (6%), systemic adverse events (3%), or the number withdrawing due to an adverse event (1%). With topical NSAID or topical placebo, local adverse events were usually described as rash, itching or stinging, and were predominantly mild.

Trials with oral NSAIDs

Three trials, with 764 patients, compared a topical NSAID with an oral NSAID (diclofenac 100 mg daily in one trial and ibuprofen 1,200 mg daily in two). Overall rates of treatment success were similar for topical NSAID (37%) and oral NSAID (37%), with no statistically significant difference (relative benefit 1,1; 0.9 to 1.3).

Adverse events

Eight of the active controlled trials (1,461 patients) provided some information on adverse events (Table 2). In two active controlled trials comparing topical with oral NSAID, local adverse events occurred more frequently (8%) with topical than with oral NSAID (3%). Systemic adverse events and adverse event withdrawals did not differ between topical and oral NSAID.

Another view of of the same topic (Lin et al)

Another review of topical NSAIDs in musculoskeletal pain in the BMJ (Lin et al) was published in 2004. It concluded that there was no evidence of superior efficacy beyond two weeks of use. It is worth looking at how this conclusion was reached.

  1. Four studies included in the meta-analysis used topical salicylates, which are not now classified as NSAIDs.
  2. Outcomes are converted to effect sizes for reporting. This gives an overall smoothed out average result but can allow different outcomes to be pooled, and pooling means where there is probably a skewed distribution can be a problem.
  3. Clinical response is defined as at least moderate or excellent or 50% reduction in pain or improvement in symptoms. After removing trials that used salicylates, for comparisons against placebo only one trial provides data for analysis at one week, one trial at two weeks, and no trials at three or four weeks. Similarly for comparison of topical vs oral NSAID, only one trial provides data at four weeks, and shows no difference between topical and oral preparations for this outcome.
  4. One paper (Ottillinger) appears as three trials in one of the figures. It is actually three doses of eltenac (0.1, 0.3, 1.0%) vs placebo. it is not sensible to treat the individual arms of the trial as separate comparable trials.
  5. Eltenac, even the highest dose does not show significant benefit over placebo, at two trials that used it.
  6. Eltenac had no effect at one week, two weeks, three weeks or four weeks. Eltenac is the only topical NSAID tested beyond two weeks in the review.
  7. In August 2004 a large (248 patient) randomised trial of topical diclofenac and placebo for four weeks in patients with osteoarthritis of the knee was published [1]. Statistical benefit over placebo was found for pain, physical function, stiffness, pain on walking, and global assessment.
  8. Other large and long duration studiews showing long-term efficacy of topical NSAIDs in osteoarthritis are due to be published in 2004.

Comment

Topical NSAIDs were clearly better than placebo in chronic musculoskeletal pain. There was a limitation of study duration, which was generally of two weeks or so. There was insufficient information on different topical NSAID preparations to tell whether any one topical NSAID was better than another.

In limited studies topical NSAIDs were no different from standard doses of oral NSAID. Topical NSAIDs were not associated with any higher rate of adverse events, either local or systemic.

There is limited information about topical NSAID use in osteoarthritis. Any conclusion that they work only for two weeks is a difficult one. It is the case that studies in the reviews were limited to two weeks, and those of longer duration were in salicylates, or topical preparations that don't work at any time. At least one new four week study has shown efficacy, and several others will be published in late 2005 onwards. Perhaps worth revisiting then.

Reference:

  1. AA Bookman et al. Effect of topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. Canadian Medical Association Journal 2004 171: 333-338.