Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials
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《英国医生杂志》
1 Academic Rheumatology, University of Nottingham, City Hospital, Nottingham NG5 1PB, 2 Rheumatology Unit, City Hospital
Correspondence to: W Zhang weiya.zhang@nottingham.ac.uk
Abstract
Osteoarthritis is the most common form of arthritis and the major cause of disability in elderly people.1 2 It represents a major disease burden for patients, health services, and society.3 Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain in musculoskeletal tissues, but their use comes at the cost of toxicity, with a 2-4% annual incidence of serious gastrointestinal ulcer and complications—four times higher than in non-users.4-9 NSAIDs have been applied topically for decades. This route possibly reduces gastrointestinal adverse reactions by maximising local delivery and minimising systemic toxicity.10 Some experimental evidence supports this, but at large joints such as the knee, bloodborne delivery may be the predominant mechanism for deep tissues.11 Pain associated with osteoarthritis may be periarticular in origin rather than intracapsular, and topical application may act through effects on peripheral and central sensitisation.12 Irrespective of the mechanism, topical NSAIDs are popular with health professionals and with patients as over the counter medicines. Several randomised controlled trials of short duration (less than four weeks) have been undertaken in both periarticular lesions and osteoarthritis.13-26 A systematic review in 1998 confirmed that topical NSAIDs were superior to placebo over two weeks in the treatment of chronic pain, including pain due to osteoarthritis and tendinitis.27 We did a meta-analysis to determine the benefit of NSAIDs in treating osteoarthritis beyond two weeks.
Methods
We identified 133 citations, of which 77 remained after omission of duplicate articles. Overall, there were 18 potentially relevant randomised controlled trials (16 in English and two in German). Five were further excluded because either the participants did not exclusively have osteoarthritis or the comparison was between topical NSAIDs and oral NSAIDs compared with oral NSAIDs. Our inclusion criteria were met by 13 trials, representing 1983 patients (fig 1 and table 1). All trials, except for one with unknown sponsorship, were sponsored or partially sponsored with study drugs and placebo by pharmaceutical companies.18 All were stated as randomised controlled trials, but there were no details on method of randomisation. The withdrawal rate was 1% to 23%. A funnel plot showed noticeable asymmetry in the 11 placebo controlled trials (fig 2).
Fig 1 Selection of randomised controlled trials
Table 1 Characteristics of randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs (NSAIDs) with placebo or oral NSAIDs in patients with osteoarthritis
Fig 2 Funnel plot of randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs with placebo (asymmetry P=0.04)
Efficacy
Reduction in pain
Topical NSAIDs were superior to placebo in the first two weeks of treatment but not the following two weeks (fig 3 and table 2). Topical NSAIDs were less effective than oral NSAIDs numerically at any week and statistically in the first week (see table 2).
Fig 3 Effect sizes (95% confidence intervals) in pain relief between topical non-steroidal anti-inflammatory drugs and placebo
Table 2 Pooled effect sizes for pain relief and improvements in function and stiffness in randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs (NSAIDs) with placebo or oral NSAIDs
Improvements in function and stiffness
The effect size for improvement in function also showed superiority of topical NSAIDs over placebo in the first two weeks but not in weeks 3 and 4 (see table 2). A statistically significant effect size for improvement in stiffness was seen at one week but not at two weeks.
Clinical response rate
The clinical response rate ratio was statistically significant in the first but not fourth week (table 3). No difference was found between topical NSAIDs and oral NSAIDs.
Table 3 Clinical response rate ratio and numbers needed to treat with 95% confidence intervals
Adverse events
Topical NSAIDs had no more side effects than placebo. Compared with oral NSAIDs, fewer patients taking topical NSAIDs had any adverse events, withdrawals due to side effects, and gastrointestinal side effects, but significantly more patients had local side effects such as rash, itch, and burning(table 4).
Table 4 Pooled rate ratio (95% confidence intervals) of side effects
Sensitivity analysis
Sensitivity analyses showed that although baseline pain score influenced the statistical inference only, the type of topical NSAID produced significantly different effect sizes. Other factors did not affect the results (table 5).
Table 5 Sensitivity analysis of effect size (95% confidence interval) for reduction in pain between topical non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, according to quality of studies, site of osteoarthritis, and pain scores at baseline
Discussion
Felson DT. Epidemiology of hip and knee osteoartritis. Epidemiol Rev 1988;10: 1-28.
Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 2001;60: 91-7.
Yelin E. The earnings, income, and assets of persons aged 51-61 with and without musculoskeletal conditions. J Rheumatol 1997;24: 2024-30.
Wynne HA, Campell M. Pharmacoeconomics of nonsteroidal anti-inflammatory drugs (NSAIDs). Pharmacoeconomics 1994;3: 107-23.
Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95: 1681-90.
Gutthann SP, Garcia Rodriguez LA, Raiford DS. Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997;8: 18-24.
Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: 241-9.
Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective—1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol 1998;51(suppl): 8-16.
Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325: 624-7.
Anon. Trolamine salycylate cream in osteoarthritis of the knee. JAMA 1982;247: 1311-3.
Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions—a review of the literature. Drugs 1998;56: 783-99.
Doherty M, Jones A. Topical NSAIDs. In: Brandt K, Doherty M, Lohmander S, eds. Osteoarthritis. 2nd ed. Oxford: Oxford University Press, 2003: 291-5.
Akermark C, Forsskahl B. Topical indomethacin in overuse injuries in athletes: a randomised double-blind study comparing Elimetacin with oral indomethacin and placebo. Int J Sports Med 1990;11: 393-6.
Diebschlag W, Nocker W, Bullingham R. A double-blind study of the efficacy of ketorolac tromethamine gel in the treatment of ankle sprain, in comparison to placebo and etofenamate. J Clin Pharmacol 1990;30: 82-9.
Hosie GAC, Rapier C. The topical NSAID, felbinac, versus oral ibuprofen: a comparison of efficacy in the treatment of acute lower back injury. Br J Clin Res 1993;4: 5-17.
Morrison W. A multicentre, randomised, double-blind, double-dummy trial to compare the use of topical Traxam gel with oral ibuprofen in the treatment of acute neck sprain. Clinical trial report. Wayne, NJ: Lederle Laboratories, 1993.
Vanderstraeten G, Schuermans P. Study on the effect of etofenamate 10% cream in comparison with an oral NSAID in strains and sprains due to sports injuries. Acta Belgica-Medica Physica 1990;13: 139-41.
Dreiser RL, Tisne-Camus M. DHEP plasters as a topical treatment of knee osteoarthritis—a double-blind placebo-controlled study. Drugs Exp Clin Res 1993;19: 117-23.
Eberhardt R ZTHR. . . Fortschr Med 1995;113: 446-50.
Grace D, Rogers J, Skeith K, Anderson K. Topical diclofenac versus placebo: a double blind, randomized clinical trial in patients with osteoarthritis of the knee. J Rheumatol 1999;26: 2659-63.
Koenen NJ, Haag RF, Bias P, Rose P. Percutaneous therapy of activated osteoarthritis of the knee—comparison between DMSO and diclofenac. Munch Med Wochenschr 1996;138: 534-8.
Rothacker DQ, Lee I, Littlejohn III TW. Effectiveness of a single topical application of 10% trolamine salicylate cream in the symptomatic treatment of osteoarthritis. J Clin Rheumatol 1998;4: 6-12.
Rovensky J, Micekova D, Gubzova Z, Fimmers R, Lenhard G, Vogtle-Junkert U, et al. Treatment of knee osteoarthritis with a topical non-steroidal antiinflammatory drug. Results of a randomized, double-blind, placebo-controlled study on the efficacy and safety of a 5% ibuprofen cream. Drugs Exp Clin Res 2001;27: 209-21.
Sandelin J, Harilainen A, Crone H, Hamberg P, Forsskahl B, Tamelander G. Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel. Scand J Rheumatol 1997;26: 287-92.
Waikakul S, Penkitti P, Soparat K, Boonsanong W. Topical analgesics for knee arthrosis: a parallel study of ketoprofen gel and diclofenac emulgel. J Med Assoc Thailand 1997;80: 593-7.
Zacher J, Burger KJ, Farber L, Grave M, Abberger H, Bertsch K. Topical diclofenac versus oral ibuprofen: a double blind, randomized clinical trial to demonstrate efficacy and tolerability in patients with activated osteoarthritis of the finger joints (Heberden and/or Bouchard arthritis). Aktuel Rheumatol 2001;26: 7-14.
Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topical applied non-steroidal anti-inflammatory drugs. BMJ 1998;316: 333-8.
Li Wan Po A, Zhang W. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ 1997;315: 1565-71.
Hedges LV. Fitting continues models to effect size data. J Edu Stat 1982;7: 245-70.
Rothman KJ. Modern epidemiology. Boston: Little, Brown, 1986: 177-233.
Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;320: 452-4.
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomised clinical trials. Stat Med 1991;10: 1665-77.
Egger M, Smith JD, Schneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315: 629-34.
Algozzine GJ, Pharm D, Gerald H, Doering PL, Araujo OE, Akin KC. Trolamine salicylate cream in osteoarthritis of the knee. JAMA 1982;247: 1311-3.
Bruhlmann P, Michel BA. Topical diclofenac patch in patients with knee osteoarthritis: a randomized, double-blind, controlled clinical trial. Clin Exp Rheumatol 2003;21: 193-8.
Dickson D J. A double-blind evaluation of topical piroxicam gel with oral ibuprofen in osteoarthritis of the knee. Curr Ther Res 1991;49: 199-207.
Ottillinger B, Gomor B, Michel BA, Pavelka K, Beck W, Elsasser U. Efficacy and safety of eltenac gel in the treatment of knee osteoarthritis. Osteoarthritis Cartilage 2001;9: 272-80.
Roth SH. A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis. Int J Tiss React 1995;17: 129-32.
Rothacher D, Difigilo C, Lee I. A clinical trial of topical 10% trolamine salicylate in osteoarthritis. Curr Ther Res 1994;55: 584-97.
Shackel NA, Day RO, Kellet B, Books PM. Copper-salicylate gel for pain relief in osteoarthritis: a randomized controlled trial. Med J Aust 1997;167: 134-6.
Walker-Bone K, Javaid K, Arden N, Cooper C. Medical management of osteoarthritis. BMJ 2000;321: 936-40.
Scott DL. Guidelines for the diagnosis, investigation and management of osteoarthritis of the hip and knee. Report of the Joint Working Group of the British Society for Rheumatology and the Research Unit of the Royal College of Physician. J R Coll Physicians Lond 1993;27: 391-6.
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, 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;62: 1145-55.
American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43: 1905-15.
Egger M, Zellweger-Zahner T, Schneider M, Junker, Lengeler C, Antes G. Language bias in randomised controlled trials published in English and German. Lancet 1997;350: 326-9.(Jinying Lin, visiting sch)
Correspondence to: W Zhang weiya.zhang@nottingham.ac.uk
Abstract
Osteoarthritis is the most common form of arthritis and the major cause of disability in elderly people.1 2 It represents a major disease burden for patients, health services, and society.3 Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain in musculoskeletal tissues, but their use comes at the cost of toxicity, with a 2-4% annual incidence of serious gastrointestinal ulcer and complications—four times higher than in non-users.4-9 NSAIDs have been applied topically for decades. This route possibly reduces gastrointestinal adverse reactions by maximising local delivery and minimising systemic toxicity.10 Some experimental evidence supports this, but at large joints such as the knee, bloodborne delivery may be the predominant mechanism for deep tissues.11 Pain associated with osteoarthritis may be periarticular in origin rather than intracapsular, and topical application may act through effects on peripheral and central sensitisation.12 Irrespective of the mechanism, topical NSAIDs are popular with health professionals and with patients as over the counter medicines. Several randomised controlled trials of short duration (less than four weeks) have been undertaken in both periarticular lesions and osteoarthritis.13-26 A systematic review in 1998 confirmed that topical NSAIDs were superior to placebo over two weeks in the treatment of chronic pain, including pain due to osteoarthritis and tendinitis.27 We did a meta-analysis to determine the benefit of NSAIDs in treating osteoarthritis beyond two weeks.
Methods
We identified 133 citations, of which 77 remained after omission of duplicate articles. Overall, there were 18 potentially relevant randomised controlled trials (16 in English and two in German). Five were further excluded because either the participants did not exclusively have osteoarthritis or the comparison was between topical NSAIDs and oral NSAIDs compared with oral NSAIDs. Our inclusion criteria were met by 13 trials, representing 1983 patients (fig 1 and table 1). All trials, except for one with unknown sponsorship, were sponsored or partially sponsored with study drugs and placebo by pharmaceutical companies.18 All were stated as randomised controlled trials, but there were no details on method of randomisation. The withdrawal rate was 1% to 23%. A funnel plot showed noticeable asymmetry in the 11 placebo controlled trials (fig 2).
Fig 1 Selection of randomised controlled trials
Table 1 Characteristics of randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs (NSAIDs) with placebo or oral NSAIDs in patients with osteoarthritis
Fig 2 Funnel plot of randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs with placebo (asymmetry P=0.04)
Efficacy
Reduction in pain
Topical NSAIDs were superior to placebo in the first two weeks of treatment but not the following two weeks (fig 3 and table 2). Topical NSAIDs were less effective than oral NSAIDs numerically at any week and statistically in the first week (see table 2).
Fig 3 Effect sizes (95% confidence intervals) in pain relief between topical non-steroidal anti-inflammatory drugs and placebo
Table 2 Pooled effect sizes for pain relief and improvements in function and stiffness in randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs (NSAIDs) with placebo or oral NSAIDs
Improvements in function and stiffness
The effect size for improvement in function also showed superiority of topical NSAIDs over placebo in the first two weeks but not in weeks 3 and 4 (see table 2). A statistically significant effect size for improvement in stiffness was seen at one week but not at two weeks.
Clinical response rate
The clinical response rate ratio was statistically significant in the first but not fourth week (table 3). No difference was found between topical NSAIDs and oral NSAIDs.
Table 3 Clinical response rate ratio and numbers needed to treat with 95% confidence intervals
Adverse events
Topical NSAIDs had no more side effects than placebo. Compared with oral NSAIDs, fewer patients taking topical NSAIDs had any adverse events, withdrawals due to side effects, and gastrointestinal side effects, but significantly more patients had local side effects such as rash, itch, and burning(table 4).
Table 4 Pooled rate ratio (95% confidence intervals) of side effects
Sensitivity analysis
Sensitivity analyses showed that although baseline pain score influenced the statistical inference only, the type of topical NSAID produced significantly different effect sizes. Other factors did not affect the results (table 5).
Table 5 Sensitivity analysis of effect size (95% confidence interval) for reduction in pain between topical non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, according to quality of studies, site of osteoarthritis, and pain scores at baseline
Discussion
Felson DT. Epidemiology of hip and knee osteoartritis. Epidemiol Rev 1988;10: 1-28.
Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 2001;60: 91-7.
Yelin E. The earnings, income, and assets of persons aged 51-61 with and without musculoskeletal conditions. J Rheumatol 1997;24: 2024-30.
Wynne HA, Campell M. Pharmacoeconomics of nonsteroidal anti-inflammatory drugs (NSAIDs). Pharmacoeconomics 1994;3: 107-23.
Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95: 1681-90.
Gutthann SP, Garcia Rodriguez LA, Raiford DS. Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997;8: 18-24.
Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: 241-9.
Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective—1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol 1998;51(suppl): 8-16.
Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325: 624-7.
Anon. Trolamine salycylate cream in osteoarthritis of the knee. JAMA 1982;247: 1311-3.
Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions—a review of the literature. Drugs 1998;56: 783-99.
Doherty M, Jones A. Topical NSAIDs. In: Brandt K, Doherty M, Lohmander S, eds. Osteoarthritis. 2nd ed. Oxford: Oxford University Press, 2003: 291-5.
Akermark C, Forsskahl B. Topical indomethacin in overuse injuries in athletes: a randomised double-blind study comparing Elimetacin with oral indomethacin and placebo. Int J Sports Med 1990;11: 393-6.
Diebschlag W, Nocker W, Bullingham R. A double-blind study of the efficacy of ketorolac tromethamine gel in the treatment of ankle sprain, in comparison to placebo and etofenamate. J Clin Pharmacol 1990;30: 82-9.
Hosie GAC, Rapier C. The topical NSAID, felbinac, versus oral ibuprofen: a comparison of efficacy in the treatment of acute lower back injury. Br J Clin Res 1993;4: 5-17.
Morrison W. A multicentre, randomised, double-blind, double-dummy trial to compare the use of topical Traxam gel with oral ibuprofen in the treatment of acute neck sprain. Clinical trial report. Wayne, NJ: Lederle Laboratories, 1993.
Vanderstraeten G, Schuermans P. Study on the effect of etofenamate 10% cream in comparison with an oral NSAID in strains and sprains due to sports injuries. Acta Belgica-Medica Physica 1990;13: 139-41.
Dreiser RL, Tisne-Camus M. DHEP plasters as a topical treatment of knee osteoarthritis—a double-blind placebo-controlled study. Drugs Exp Clin Res 1993;19: 117-23.
Eberhardt R ZTHR. . . Fortschr Med 1995;113: 446-50.
Grace D, Rogers J, Skeith K, Anderson K. Topical diclofenac versus placebo: a double blind, randomized clinical trial in patients with osteoarthritis of the knee. J Rheumatol 1999;26: 2659-63.
Koenen NJ, Haag RF, Bias P, Rose P. Percutaneous therapy of activated osteoarthritis of the knee—comparison between DMSO and diclofenac. Munch Med Wochenschr 1996;138: 534-8.
Rothacker DQ, Lee I, Littlejohn III TW. Effectiveness of a single topical application of 10% trolamine salicylate cream in the symptomatic treatment of osteoarthritis. J Clin Rheumatol 1998;4: 6-12.
Rovensky J, Micekova D, Gubzova Z, Fimmers R, Lenhard G, Vogtle-Junkert U, et al. Treatment of knee osteoarthritis with a topical non-steroidal antiinflammatory drug. Results of a randomized, double-blind, placebo-controlled study on the efficacy and safety of a 5% ibuprofen cream. Drugs Exp Clin Res 2001;27: 209-21.
Sandelin J, Harilainen A, Crone H, Hamberg P, Forsskahl B, Tamelander G. Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel. Scand J Rheumatol 1997;26: 287-92.
Waikakul S, Penkitti P, Soparat K, Boonsanong W. Topical analgesics for knee arthrosis: a parallel study of ketoprofen gel and diclofenac emulgel. J Med Assoc Thailand 1997;80: 593-7.
Zacher J, Burger KJ, Farber L, Grave M, Abberger H, Bertsch K. Topical diclofenac versus oral ibuprofen: a double blind, randomized clinical trial to demonstrate efficacy and tolerability in patients with activated osteoarthritis of the finger joints (Heberden and/or Bouchard arthritis). Aktuel Rheumatol 2001;26: 7-14.
Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topical applied non-steroidal anti-inflammatory drugs. BMJ 1998;316: 333-8.
Li Wan Po A, Zhang W. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ 1997;315: 1565-71.
Hedges LV. Fitting continues models to effect size data. J Edu Stat 1982;7: 245-70.
Rothman KJ. Modern epidemiology. Boston: Little, Brown, 1986: 177-233.
Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;320: 452-4.
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomised clinical trials. Stat Med 1991;10: 1665-77.
Egger M, Smith JD, Schneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315: 629-34.
Algozzine GJ, Pharm D, Gerald H, Doering PL, Araujo OE, Akin KC. Trolamine salicylate cream in osteoarthritis of the knee. JAMA 1982;247: 1311-3.
Bruhlmann P, Michel BA. Topical diclofenac patch in patients with knee osteoarthritis: a randomized, double-blind, controlled clinical trial. Clin Exp Rheumatol 2003;21: 193-8.
Dickson D J. A double-blind evaluation of topical piroxicam gel with oral ibuprofen in osteoarthritis of the knee. Curr Ther Res 1991;49: 199-207.
Ottillinger B, Gomor B, Michel BA, Pavelka K, Beck W, Elsasser U. Efficacy and safety of eltenac gel in the treatment of knee osteoarthritis. Osteoarthritis Cartilage 2001;9: 272-80.
Roth SH. A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis. Int J Tiss React 1995;17: 129-32.
Rothacher D, Difigilo C, Lee I. A clinical trial of topical 10% trolamine salicylate in osteoarthritis. Curr Ther Res 1994;55: 584-97.
Shackel NA, Day RO, Kellet B, Books PM. Copper-salicylate gel for pain relief in osteoarthritis: a randomized controlled trial. Med J Aust 1997;167: 134-6.
Walker-Bone K, Javaid K, Arden N, Cooper C. Medical management of osteoarthritis. BMJ 2000;321: 936-40.
Scott DL. Guidelines for the diagnosis, investigation and management of osteoarthritis of the hip and knee. Report of the Joint Working Group of the British Society for Rheumatology and the Research Unit of the Royal College of Physician. J R Coll Physicians Lond 1993;27: 391-6.
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, 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;62: 1145-55.
American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43: 1905-15.
Egger M, Zellweger-Zahner T, Schneider M, Junker, Lengeler C, Antes G. Language bias in randomised controlled trials published in English and German. Lancet 1997;350: 326-9.(Jinying Lin, visiting sch)