CMAJ • March 1, 2005; 172 (5). doi:10.1503/cmaj.1041679.
© 2005 CMA Media Inc. or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
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Correspondance

Is topical treatment of osteoarthritis site-specific?

Arthur A.M. Bookman* and J.Z. Shainhouse{dagger}

Division of Rheumatology, University Health Network, Western Division, University of Toronto, Toronto, Ont.;* Dimethaid Health Care Ltd., Markham, Ont.{dagger}

As Vivian McAlister notes, the study by Hui and associates1 demonstrated some systemic absorption of diclofenac after topical application. However, the plasma level was only 11.8 (standard deviation [SD] 4.2) ng/mL, approximately 125 times below the level seen after ingestion of a 50-mg tablet of an oral formulation.2

This finding is consistent with the site-specific action of topical NSAIDs, which can achieve an analgesic effect much greater than that expected on the basis of observed serum levels.3 For example, according to Vaile and Davis,3 "topically applied versus orally administered drug[s] generally show very low relative concentrations [in the plasma] ... unlikely to explain efficacy." Similarly, in studies of patients scheduled for knee surgery, tissue levels of topically applied NSAIDs were much greater than blood levels and were similar to tissue levels achieved with oral therapy.4 After multiple applications of topical diclofenac for up to 84 days,5 the mean plasma level of the drug was still only 8.95 (SD 9.17) ng/mL.6 Early experiments in rats7 demonstrated an effect of oral diclofenac at 0.3 mg/kg — an amount that became the basis for oral dose-ranging trials in humans — yet some 30 years later, there is still no recognized pharmacokinetic correlation between clinical effect and blood levels. Intuitively, however, it is difficult to conceive that an oral dose producing the low systemic levels seen after topical application would have any clinical effect.

A more recently published study8 demonstrating the clinical equivalence of this topical diclofenac solution and oral diclofenac puts the magnitude of its analgesic effect into perspective. The observed improvement in pain scores with topical diclofenac cannot be accounted for by the miniscule blood levels of diclofenac and could be achieved only by local accumulation of a therapeutic concentration at the pain site.

McAlister also asks about the concomitant use of low-dose ASA. When we eliminated the 43 patients who used ASA (up to 325 mg/day) the p values were even more convincing.

Our data do show improvements in pain scores in both control groups (vehicle control and placebo).9 This placebo effect may very well represent a true response,10 and we agree that establishing efficacy warrants a traditional superiority trial comparing active drug with placebo.5,9 In standard medical practice, however, we would be inclined to follow the thinking of Hróbjartsson and Gøtzsche10 that "outside the setting of clinical trials, there is no justification for the use of placebos."

Footnotes

Competing interests: Dr. Bookman has received compensastion from Dimethaid Health Care Inc. for his participation in a clinical trial and has received speaker fees on 2 occasions. Dr. Shainhouse is a paid employee of Dimethaid and has been granted stock options in the company.


References

  1. Hui X, Hewitt PG, Poblete N, Maibach HI, Shainhouse JZ, Wester RC. In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers. Pharm Res 1998;15(10):1589-95. [CrossRef][Medline]
  2. Voltaren product monograph. In: Compendium of pharmaceuticals and specialties. Ottawa: Canadian Pharmacists Association; 2004. p. 2203-4.
  3. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. A review of the literature. Drugs 1998;56(5):783-99.[CrossRef][Medline]
  4. Rolf C, Engstrom B, Beauchard C, Jacobs LD, Le Libroux A. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology (Oxford) 1999; 38:564-7.
  5. Roth SA, Shainhouse JZ. Safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med 2004;164:2017-23.[Abstract/Free Full Text]
  6. Pennsaid product monograph. In: Compendium of pharmaceuticals and specialties. Ottawa: Canadian Pharmacists Association; 2004. p. 1503-6.
  7. Krupp PJ, Menasse-Gdynia R, Sallmann A, Wilhelmi G, Ziel R, Jaques R. Sodium (o-((2,6-dichlorophenyl)-amino)-phenyl)-acetate (GP 45 840), a new non-steroidal anti-inflammatory agent. Experientia 1973;29:450-2.[CrossRef][Medline]
  8. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (Pennsaid®) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheum 2004; 31:2002-12.[Abstract/Free Full Text]
  9. Bookman AAM, Williams KSA, Shainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ 2004; 171 (4):333-8. [Abstract/Free Full Text]
  10. Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001; 344:1594-602.[Abstract/Free Full Text]




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