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Safety and Efficacy of Topical Diclofenac Sodium Gel for Knee Osteoarthritis in Elderly and Younger Patients

Pooled Data from Three Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicentre Trials

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Abstract

Background: NSAIDs used for the treatment of osteoarthritis (OA) have dose-related risks for gastrointestinal, cardiovascular and renal adverse events (AEs), particularly in elderly patients. Topical NSAIDs reduce systemic NSAID exposure and may mitigate these risks.

Objective: To evaluate the safety and efficacy of topical diclofenac sodium 1% gel (DSG) versus vehicle in patients aged 25–64 or ≥65 years who have been diagnosed with knee OA.

Study Design: Pooled data from three 12-week, randomized, double-blind, parallel-group, multicentre trials.

Setting: US primary care, internal medicine, orthopaedic and rheumatology practices.

Patients: Aged ≥25 years with mild to moderate (Kellgren-Lawrence grade 1–3) knee OA.

Intervention: After a 1-week analgesic washout, patients applied 4 g of DSG or vehicle four times daily to one knee. Rescue paracetamol (acetaminophen) up to 4 g/day was allowed.

Main Outcome Measure: Key efficacy outcomes common to the three trials were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (0–20) and physical function (0–68) subscales, global rating of disease (GRD; 100-mm visual analogue scale [VAS]) and pain on movement (POM; 100-mm VAS). ANOVA was used to compare efficacy outcome differences (DSG vs vehicle) by age (25–64 or ≥65 years). A flare design was used that defined a subset of patients who experienced increased pain during the washout period (modified efficacy subpopulation [MES]).

Results: The MES included both patients aged 25–64 (n=602) and ≥65 (n = 374) years. Patients in each age group applied >90% of scheduled doses. Among patients aged 25–64 years, the improvement from baseline to week 12 (least squares mean [standard error]) was greater for DSG versus vehicle for WOMAC pain (−5.8 [0.3] vs −4.7 [0.3], p = 0.007), WOMAC physical function (−17.9 [0.9] vs −14.2 [0.9], p = 0.002), GRD (−29.5 [1.6] vs −23.8 [1.6], p = 0.01) and POM (−37.3 [1.8] vs −29.0 [1.8], p <0.001). Among patients aged ≥65 years, the improvements from baseline for most efficacy outcome scores were significantly greater with DSG versus vehicle: WOMAC pain (−5.3 [0.3] vs −4.1 [0.4], p = 0.02), WOMAC physical function (−15.5 [1.1] vs −11.0 [1.1], p = 0.004) and POM (−33.7 [2.2] vs −26.4 [2.2], p = 0.02). The efficacy of DSG did not differ significantly between patients aged 25–64 years and ≥65 years: WOMAC pain (p = 0.85), WOMAC physical function (p = 0.70), GRD (p = 0.86) and POM (p = 0.81). The incidence of any AE was greater with DSG than with vehicle among patients aged 25–64 years (56.6% vs 50.8%) and ≥65 years (55.8% vs 43.9%). Treatment-related application site dermatitis was more common with DSG compared with vehicle in both younger (4.0% vs 0.7%, respectively) and older (5.8% vs 0.4%, respectively) patients and was the main reason for the difference in treatment-related AEs between the DSG and vehicle groups. Gastrointestinal AEs were infrequent among patients treated with DSG and similar to incidence rates with vehicle in both age groups.

Conclusions: DSG was effective and generally well tolerated in adults regardless of age. These data support the topical application of DSG for relief of OA knee pain in elderly and younger patients.

Clinicaltrials.gov registration numbers NCT00171626, NCT00171678, NCT00426621.

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References

  1. Dawson J, Linsell L, Zondervan K, et al. Impact of persistent hip or knee pain on overall health status in elderly people: a longitudinal population study. Arthritis Rheum 2005 Jun 15; 53(3): 368–74

    Article  PubMed  Google Scholar 

  2. Dawson J, Linsell L, Zondervan K, et al. Epidemiology of hip and knee pain and its impact on overall health status in older adults. Rheumatology (Oxford) 2004 Apr; 43(4): 497–504

    Article  CAS  Google Scholar 

  3. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998 May; 41(5): 778–99

    Article  PubMed  CAS  Google Scholar 

  4. Oliveria SA, Felson DT, Reed JI, et al. Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum 1995 Aug; 38(8): 1134–41

    Article  PubMed  CAS  Google Scholar 

  5. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol 2006 Feb; 20(1): 3–25

    Article  PubMed  Google Scholar 

  6. Van Saase JLCM, van Romunde LKJ, Cats A, et al. Epidemiology of osteoarthritis: Zoetermeer survey: comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 1989; 48: 271–80

    Article  PubMed  Google Scholar 

  7. Dillon CF, Rasch EK, Gu Q, et al. Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Survey 1991–94. J Rheumatol 2006 Nov; 33(11): 2271–9

    PubMed  Google Scholar 

  8. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health 1994 Mar; 84(3): 351–8

    Article  PubMed  CAS  Google Scholar 

  9. McKenna MT, Michaud CM, Murray CJ, et al. Assessing the burden of disease in the United States using disability-adjusted life years. Am J Prev Med 2005 Jun; 28(5): 415–23

    Article  PubMed  Google Scholar 

  10. American College of Rheumatology. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000 Sep; 43(9): 1905–15

    Article  Google Scholar 

  11. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th ed. Glenview (IL): American Pain Society, 2003

    Google Scholar 

  12. Jordan KM, Arden NK, Doherty M, et al. EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003 Dec; 62(12): 1145–55

    Article  PubMed  CAS  Google Scholar 

  13. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 2007 Sep; 15(9): 981–1000

    Article  PubMed  CAS  Google Scholar 

  14. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008; 16(2): 137–62

    Article  PubMed  CAS  Google Scholar 

  15. Evans JM, McMahon AD, McGilchrist MM, et al. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case-control study. BMJ 1995 Jul 1; 311(6996): 22–6

    Article  PubMed  CAS  Google Scholar 

  16. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of non-steroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991 Nov 15; 115(10): 787–96

    PubMed  CAS  Google Scholar 

  17. Caldwell B, Aldington S, Weatherall M, et al. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med 2006 Mar; 99(3): 132–40

    Article  PubMed  CAS  Google Scholar 

  18. Hermann M, Ruschitzka F. Cardiovascular risk of cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs. Ann Med 2007; 39(1): 18–27

    Article  PubMed  CAS  Google Scholar 

  19. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004 Dec 4–10; 364(9450): 2021–9

    Article  PubMed  CAS  Google Scholar 

  20. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006 Jun 3; 332(7553): 1302–8

    Article  PubMed  CAS  Google Scholar 

  21. Motsko SP, Rascati KL, Busti AJ, et al. Temporal relationship between use of NSAIDs, including selective COX-2 inhibitors, and cardiovascular risk. Drug Saf 2006; 29(7): 621–32

    Article  PubMed  CAS  Google Scholar 

  22. Barkin RL, Buvanendran A. Focus on the COX-1 and COX-2 agents: renal events of nonsteroidal and anti-inflammatory drugs — NSAIDs. Am J Ther 2004 Mar–Apr; 11(2): 124–9

    Article  PubMed  Google Scholar 

  23. Evans JM, McGregor E, McMahon AD, et al. Nonsteroidal anti-inflammatory drugs and hospitalization for acute renal failure. Q J Med 1995 Aug; 88(8): 551–7

    CAS  Google Scholar 

  24. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005 Jun 11; 330(7504): 1366

    Article  PubMed  CAS  Google Scholar 

  25. Osteoarthritis: the care and management of osteoarthritis in adults. London: National Collaborating Centre for Chronic Conditions, 2008 Feb. Report no.: NICE clinical guideline 59

  26. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009 Aug; 57(8): 1331–46

    Article  Google Scholar 

  27. Kienzler J, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol New Drugs 2010 Jan; 50: 50–61

    Article  CAS  Google Scholar 

  28. Altman RD, Dreiser RL, Fisher CL, et al. Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. J Rheumatol 2009 Sep; 36(9): 1991–9

    Article  PubMed  Google Scholar 

  29. Baraf HS, Gold M, Clark MB, et al. Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: a randomized controlled trial. Phys Sportsmed 2010; 38(2): 19–28

    Article  PubMed  Google Scholar 

  30. Barthel HR, Haselwood D, Longley 3rd S, et al. Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum 2009 Dec; 39(3): 203–12

    Article  PubMed  CAS  Google Scholar 

  31. Pham T, Van Der Heijde D, Lassere M, et al. Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol 2003 Jul; 30(7): 1648–54

    PubMed  Google Scholar 

  32. Bross IDJ. How to use ridit analysis. Biometrics 1958 Jun 15; 14: 18–38

    Article  Google Scholar 

  33. Zhang W, Doherty M, Leeb BF, et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007; 66(3): 377–88

    Article  PubMed  CAS  Google Scholar 

  34. Altman R, Brandt K, Hochberg M, et al. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society — results from a workshop. Osteoarthritis Cartilage 1996 Dec; 4(4): 217–43

    Article  PubMed  CAS  Google Scholar 

  35. Bjordal JM, Ljunggren AE, Klovning A, et al. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ 2004; 329(7478): 1317–22

    Article  PubMed  CAS  Google Scholar 

  36. Simon LS, Grierson LM, Naseer Z, et al. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain 2009 Apr 18; 143(3): 238–45

    Article  PubMed  CAS  Google Scholar 

  37. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskelet Disord 2005; 6: 44

    Article  PubMed  Google Scholar 

  38. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial [see comment]. Arch Intern Med 2004 Oct 11; 164(18): 2017–23

    Article  PubMed  CAS  Google Scholar 

  39. Baraf HSB, Gloth FM, Gold MS, et al. Efficacy of diclofenac sodium topical gel 1% in knee osteoarthritis of Kellgren-Lawrence grades 1, 2, or 3 severity [abstract]. J Gen Intern Med 2009; 24(S1): S68

    Google Scholar 

  40. Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 2006 Mar; 119(3): 255–66

    Article  PubMed  CAS  Google Scholar 

  41. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004 Aug 21–27; 364(9435): 665–74

    Article  PubMed  CAS  Google Scholar 

  42. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000 Sep 13; 284(10): 1247–55

    Article  PubMed  CAS  Google Scholar 

  43. Peniston JH, Gold MS, Clark MB, et al. An open-label long-term safety trial of diclofenac sodium 1% gel in patients with osteoarthritis of the knee. American Osteopathic Association 2009 Osteopathic Medical Conference & Exposition; 2009 Nov 1–5; New Orleans (LA)

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Acknowledgements

Novartis Consumer Health, Inc., Parsippany, NJ, USA funded the clinical trials. Endo Pharmaceuticals Inc., Chadds Ford, PA, USA funded this post hoc pooled analysis and the editorial support provided by Complete Healthcare Communications, Inc., Chadds Ford, PA, USA.

Herbert S.B. Baraf has received consulting fees from Novartis. F. Michael Gloth has received consulting fees and participated in speakers’ bureaus for Novartis. H. Richard Barthel has nothing to disclose. Morris S. Gold is an employee of Novartis Consumer Health, Inc., Parsippany, NJ, USA, the clinical trial sponsor. Roy D. Altman has received research grants from Novartis Consumer Health, Inc., Endo Pharmaceuticals, Inc. and Ferring Pharmaceuticals, Inc. (Parsippany, NJ, USA); consulting fees from Novartis Consumer Health, Inc., Ferring Pharmaceuticals, Inc. and Rottapharm (Monza, Italy); and participated in speakers’ bureaus for Ferring Pharmaceuticals, Inc. and Forest Laboratories, Inc. (New York, NY, USA).

Jeffrey Coleman, MA, Kris Schuler, MS, and Robert Gatley, MD, of Complete Healthcare Communications, Inc., Chadds Ford, PA, USA, provided editorial support for this manuscript (literature search, document retrieval, data verification, writing and proofing).

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Authors and Affiliations

  1. Center for Rheumatology and Bone Research, a division of the Arthritis and Rheumatism Associates, Wheaton, Maryland, USA

    Herbert S. B. Baraf

  2. Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    F. Michael Gloth

  3. Private Practice (Rheumatology), Santa Barbara, California, USA

    H. Richard Barthel

  4. Novartis Consumer Health, Inc., Parsippany, New Jersey, USA

    Morris S. Gold

  5. David Geffen School of Medicine, University of California, Los Angeles, California, USA

    Roy D. Altman

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Baraf, H.S.B., Gloth, F.M., Barthel, H.R. et al. Safety and Efficacy of Topical Diclofenac Sodium Gel for Knee Osteoarthritis in Elderly and Younger Patients. Drugs Aging 28, 27–40 (2011). https://doi.org/10.2165/11584880-000000000-00000

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