R. ANDREW MOORE, MA, DPhil, DSc,

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Director of Research,
Pain Research, Nuffield Department of Anaesthetics,
University of Oxford, The Churchill,
Oxford OX3 7LJ, United Kingdom
Address reprint requests to Dr. Moore. E-mail: andrew.moore@pru.ox.ac.uk

Until publication of the large randomized comparison of topical with oral diclofenac in this issue of The Journal¹, the title of this editorial would have been written as a question rather than a statement. Although circumstantial evidence existed, proof was lacking. This trial fulfils criteria of quality, validity, and size, and, together with supporting evidence, proves topical nonsteroidal antiinflammatory drug (NSAID) efficacy.

THE TRIAL

The study is properly randomized, with concealment of allocation, and properly blinded using a double-dummy technique, so bias is highly unlikely. It was designed and conducted accorded to OARSI recommendations^2,3, and as a formal equivalence study. It used outcomes specified by OMERACT (Outcome Measures in Rheumatology Clinical Trials)⁴, lasted for 12 weeks, and, crucially, directly compared topical diclofenac with 150 mg oral diclofenac. There was no massage, so any beneficial result with topical diclofenac could not have been due to rubbing. It was large, randomizing 622 patients, much bigger than oral NSAIDtrials in the pre-coxib era^5,6.

Topical and oral diclofenac produced equivalent improvements in pain, physical function, and patient global assessment of 36–44% and 42–49%, respectively: a little more with oral than topical diclofenac, but rarely significantly so. The number of responders was 66% and 71%.

Equivalent effect came with different adverse events. Topical diclofenac had more skin-related problems, like dry skin, pruritus, and rash, usually mild, and resolving on withdrawal. Oral diclofenac had more gastrointestinal adverse events (48% vs 35% for topical diclofenac). These were classified as severe in 10% of patients taking oral diclofenac, compared with 2.6% with topical. Laboratory adverse events were also worse with oral diclofenac, including liver enzyme elevations, creatinine clearance, and hemoglobin changes. The magnitude of the difference was often quite large, with abnormal hemoglobin, for instance, in 10% of subjects taking oral diclofenac compared with 2% on topical.

Overall, 28% of patients discontinued oral diclofenac because of adverse events (25%) or lack of efficacy (3%). With topical diclofenac the overall numbers were similar (30%), with 21% discontinuing because of adverse events and 9% because of lack of efficacy.

SCIENTIFIC BUTTRESSES

To be effective, topical NSAID have to penetrate the skin, and either enter the circulation or additionally be absorbed into underlying tissue to inhibit cyclooxygenases.

Depending on the molecule and delivery system, NSAID dermal penetration can be extensive. A comprehensive review⁷ indicated that a balance between lipid and aqueous solubility was needed to optimize permeation. An in vitro-based index of topical antiinflammatory activity combined dermal penetration with cyclooxygenase inhibitory effect⁸. It indicated that ketoprofen, ketorolac, and diclofenac had acceptable efficiency for external use.

Plasma concentrations after topical NSAID are low^9-12, much lower than after oral. For instance, after 400 mg oral ibuprofen, peak plasma concentrations of 30–60 µg/ml occur within 1 hour¹³. Maximum concentrations after topical were less (mostly much less) than 2 µg/ml. With topical diclofenac or ketoprofen, plasma concentrations were generally under 100 ng/ml. Topical application produces plasma concentrations 5% or less than the maximum oral concentration.

Synovial fluid concentrations are similar after topical and oral administration^9-12,14. Tissue concentrations can be very high after topical administration^9,10,12, with concentrations of tens of µg/g, and perhaps one or 2 orders of magnitude higher than in plasma or synovial fluid.

CLINICAL BUTTRESSES

Systematic reviews of randomized trials in acute and chronic pain have shown topical analgesics to be effective: NSAID^11,15-17, rubefacients¹⁸, and capsaicin¹⁹. Trials were randomized and double-blind, but were short, generally no longer than 4 weeks, and samples were small.

Evidence on rubefacients and capsaicin was limited (Table 1). These agents were statistically better than placebo, but clinically unimpressive. The rubefacient result was compromised because 3 trials with adequate quality and validity scores had no statistically significant effect¹⁸. With capsaicin, 37% of patients benefited, but local adverse events affected almost half¹⁹.

Table 1. Systematic reviews of trials of topical analgesics.

A review of topical NSAID in acute and chronic conditions¹⁵ included salicylates. Updated without salicylates¹⁶, topical NSAID were effective in strains and sprains over one week with an overall number needed to treat (NNT) of 3.8 (3.8 to 4.4) compared with placebo in 26 trials with 2853 patients; local and systemic adverse events were no different from placebo. Ketoprofen was significantly better than other topical NSAID.

An updated systematic review of topical NSAID in chronic musculoskeletal¹⁷ pain produced an overall NNT of 4.6 (3.8 to 5.9) compared with placebo for all NSAID. This analysis included 14 trials with 1502 patients in placebo comparisons, and produced similar results for 5 trials in knee osteoarthritis (OA) as in other musculoskeletal conditions. Only 3 trials compared topical with oral NSAID in patients with OA of the knee or finger joints, where the oral NSAID was 1200 mg ibuprofen or 100 mg diclofenac daily. In these trials with 764 patients there was no statistically significant difference between routes of administration¹⁹.

COMMENT

What we have is a pyramid of evidence. The lowest layer is of laboratory and pharmacokinetic studies supporting skin penetration of NSAID and uptake into blood and high levels in underlying tissue. The middle layer is from systematic reviews of small, less valid short trials that demonstrate better efficacy than placebo, and probably equal efficacy with oral NSAID. The pinnacle is this new trial¹, demonstrating equivalence of topical and oral diclofenac in a large, valid, high quality trial.

Equivalent effect comes with fewer severe gastric adverse events, and lower rates of abnormal hemoglobin, a possible marker for lower bowel blood loss. The challenge now for topical NSAID is to confirm safety and economic benefit, and define the patients for whom they are the best choice.

REFERENCES

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3. Altman R, Brandt K, Hochberg M, Moskowitz R. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996;4:217-43. [MEDLINE]

4. Bellamy N, Kean WF, Buchanan WW, Gerecz-Simon E, Campbell J. Double blind randomized controlled trial of sodium meclofenamate (Meclomem) and diclofenac sodium (Voltaren): Post validation reapplication of the WOMAC Osteoarthritis Index. J Rheumatol 1992;19:153-9. [MEDLINE]

5. Towheed T, Shea B, Wells G, Hochberg M. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip. Cochrane Library (May 21, 1999). Cochrane Database Syst Rev 2000;CD000517.

6. Watson MC, Brookes ST, Kirwan JR, Faulkner A. Non-aspirin, non-steroidal anti-inflammatory drugs (NSAIDS) for osteoarthritis of the knee. Cochrane Library (May 21, 1999). Cochrane Database Syst Rev 2000;CD000142.

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9. Dominkus M, Nicolakis M, Kotz R, Wilkinson FE, Kaiser RR, Chlud K. Comparison of topical and plasma levels of ibuprofen after oral and topical administration. Arzneimittelforschung 1996;46:1138-43. [MEDLINE]

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11. Heynemann CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic disease. Drugs 2000;60:555-74. [MEDLINE]

12. Osterwalder A, Reiner V, Reiner G, Lualdi P. Tissue absorption and distribution of ketoprofen after patch application in subjects undergoing knee arthroscopy or endoscopic carpal ligament release. Arzneimittelforschung 2002;52:822-7. [MEDLINE]

13. Davies NM. Clinical pharmacokinetics of ibuprofen. Clin Pharmacokinet 1998;34:101-54. [MEDLINE]

14. Radermacher J, Jentsch D, Scholl MA, Lustinetz T, Frölich JC. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol 1991;31:537-41. [MEDLINE]

15. Moore RA, Carroll D, Wiffen PJ, Tramèr M, McQuay HJ. Quantitative systematic review of topically-applied non-steroidal anti-inflammatory drugs. BMJ 1998;316:333-8. [MEDLINE]

16. Mason L, Moore RA, Edwards JE, Derry S, McQuay HJ. Topical NSAIDs for acute pain: a meta-analysis. BMC Family Practice 2004;5:10. [Internet. Cited July 6, 2004.] Available from: www.biomedcentral.com/1471-2296/5/10/abstract. [MEDLINE]

17. Mason L, Moore RA, Edwards JE, Derry S, McQuay HJ. Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis. BMC Musculoskelet Disord 2004. Internet. [Cited August 27, 2004] Available from: www.biomedcentral.com/1471-2474/5/28.

18. Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ 2004;328:995-8. [MEDLINE]

19. Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 2004;328:991-4. [MEDLINE]