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Topical preparations for chronic disorders of the knee: a review
The Knee 7 Ž2000. 207᎐210
Review article
Topical preparations for chronic disorders of the knee: a review Tessa Whittona , Robert W. Johnsonb,U b
a Royal United Hospital, Combe Park, Bath, BA1 3NG, UK Sir Humphry Da¨ y Department of Anaesthesia, Bristol Royal Infirmary, Bristol, BS2 8HW, UK
Received 30 June 2000; received in revised form 31 August 2000; accepted 14 September 2000
1. Introduction There are a large number of topical applications available for the treatment of acute and chronic musculo-skeletal conditions: non-steroidal anti-inflammatory drugs ŽNSAIDs., rubifacients Žsubstances ‘heating to redness’ the area to which applied topically but without known pharmacological action on nerve conduction or inflammatory processes. and more recently, capsaicin. They take the form of gels, creams, ointments, transdermal patches and sprays. This review will consider their usefulness in the treatment of pain arising from chronic arthritic and soft tissue conditions of the knee, in terms of their effectiveness and safety profile.
2. NSAIDs Such drugs inhibit cyclo-oxygenase, an enzyme converting arachidonic acid to various types of prostaglandins. Prostaglandins are produced in response to tissue trauma and mediate components of the peripheral inflammatory response. Prostaglandins also sensitise peripheral and central nociceptors in association with other mediators including histamine and bradykinin. These drugs have activity at many sites and have gastropathic, antihaemostatic and neprotoxic effects. They may also cause cognitive and hepatic dysfunction. Anaphylaxis may occur and asthmatic attacks may be induced in susceptible patients. Newer drugs may reduce gastrointestinal side effects. U
Corresponding author. Tel.: q44-117-928-2766; fax: q44-117928-4964.
2.1. Efficacy NSAIDs are widely used in the UK: 5% of the NHS total prescriptions are for NSAIDs Žpredominantly oral. ᎏ this accounts for 20᎐24 million prescriptions per year w1x. A quantitative systematic review of topically applied NSAIDs was published in the British Medical Journal in 1998 w1x. It reviewed 86 trials involving over 10 000 patients, for both acute and chronic conditions. The chronic conditions studied were single joint arthropathies and rheumatic disorders. Of 12 high quality randomised, controlled trials comparing a topical NSAID with placebo, seven out of the 12 showed superiority of the NSAID. The relative benefit of all 12 studies was 2.0 Ž95% confidence interval 1.5᎐2.7., with number needed to treat ŽNNT. of 3.1 Ž2.7᎐3.8.. This is a similar NNT to that of oral analgesics in moderate to severe pain Žfrom any cause. w2x. The percentage of patients achieving a successful outcome with a topical NSAID was 30᎐90%, compared to 5᎐60% with placebo. All placebo controls in trials using a topical gel or cream were rubbed in; any effect of the topical drug was therefore not due to rubbing. Two studies in this review compared a topical NSAID with an oral NSAID: neither showed a significant benefit of the oral over the topical preparation w3,4x. No high quality trial has yet compared a topical NSAID with the oral form of the same drug w5x. We found a number of studies which looked at the effectiveness of topical NSAIDs in the treatment of chronic knee conditions and further studies involving other joints. Felbinac gel has been compared to an
0968-0160r00r$ - see front matter 䊚 2000 Elsevier Science B.V. All rights reserved. PII: S 0 9 6 8 - 0 1 6 0 Ž 0 0 . 0 0 0 7 1 - 5
208
T. Whitton, R.W. Johnson r The Knee 7 (2000) 207᎐210
oral NSAID in two double-blind, double-dummy studies involving large numbers of patients w6,7x and found to be as effective as the oral drug to which it was compared Žfenbufen and ibuprofen, respectively.. A randomised, double-blind, placebo-controlled study found that copper-salicylate gel was not superior to placebo in relieving pain of osteoarthritis of the knee and hip w8x. Another randomised, double-blind study compared eltenac gel with oral diclofenac and placebo and found the gel to be as effective as diclofenac and statistically more effective than placebo in those patients with severe osteoarthritis of the knee w9x.
may reflect a problem with the vehicle rather than the active component of these preparations. Other adverse reactions, such as bronchospasm and renal impairment, which limit the use of oral NSAIDs have been described with topical preparations w25᎐27x. Patients at higher risk of adverse effects may have been excluded. A postmarketing surveillance study of one topical preparation showed a 1.5% incidence of adverse effects, mainly cutaneous, with an incidence of gastro-intestinal effects of 0.1%, none of which were deemed serious w28x. These figures from clinical practice are similar to those seen in controlled trials of felbinac w29x.
2.2. Safety Although there is evidence that topical NSAIDs are more effective than placebo and as effective as an oral NSAID, there is still resistance to their prescription w10,11x. The cost of topical preparations initially seems high. What then is their advantage over oral NSAIDs if they are as effective but cost more? The use of topical preparations of NSAIDs is associated with a much lower incidence of gastro-intestinal adverse effects than that associated with the oral form, indeed this is one factor which has prompted their development. With chronic use of oral NSAIDs Žmore than 2 months’ use., one in 2000 users will die from gastro-intestinal complications who would not have done had they not been taking a NSAID w12x. This accounts for approximately 2000 deaths in the UK per year. For each patient taking a NSAID, the annual cost of adverse effects has been calculated as £48 w13x. It appears that the low incidence of systemic side effects seen with topical NSAIDs is related to the low plasma concentrations of drug seen with this administration route w14,15x: plasma concentrations of 1᎐10% of those of oral preparations have been demonstrated in both humans and animals w16᎐18x. A review of the pharmacology of topical NSAIDs w19x found evidence that substantial soft tissue concentrations associated with low plasma concentrations can be achieved with local application w20᎐22x but concluded that evidence for significant synovial fluid concentrations was scanty. A more recent study on topical ketoprofen has shown good intra-articular penetration associated with low plasma levels w23x. Large variations in concentrations have been found in several studies: this may be due to differences in application techniques and factors such as skin thickness and integrity w24x. Fixed dose patches may allow more standardised dosage. The incidence of local skin reactions has been calculated as 3.6%, no higher than that seen with placebo w1x, and appears to vary with the product used. The incidence of skin reactions to placebo gels
3. Capsaicin 3.1. Mode of action Capsaicin is a naturally occurring irritant alkaloid, found in chilli peppers. The substance has a direct stimulatory action on both C and A␦ nociceptive fibres in primary afferent nerves. It acts upon vanilloid receptors and repeated application to the skin results in a depletion of the neurotransmitter substance P from sensory C-fibres both peripherally and centrally, resulting in inhibition of local pain w30x. Endogenous neuropeptides such as substance P have been implicated in the pathogenesis of arthritic pain w31,32x, with elevation of substance P levels found in the plasma and synovial tissue of patients with osteoarthritis w33x. Its application is associated with a mild to moderate burning sensation, usually transient, which may limit its use in some patients. Because of this burning, blinding during trials may be limited. A beneficial effect is most unlikely until the substance has been applied 3᎐4 times daily for 2 weeks or more. It is possible that a vanilloid analogue will be developed which lacks the initial irritant effects. 3.2. Efficacy One review found an odds ratio Žratio of number receiving benefit from active medication compared with placebo. of 4.36 Ž95% CI 2.77, 6.88. from the pooled results of three randomised, double-blind, placebo-controlled trials of varying sizes w34x. One study of patients with osteo- and rheumatoid arthritis of the knees showed a significant reduction in pain scores in patients treated with 0.025% capsaicin for 4 weeks compared with placebo w35x. Another study of similar size and design confirmed this result, demonstrating a significant reduction in pain after 4 weeks of treatment with 0.025% capsaicin compared to placebo w36x. This study also found the burning associ-
T. Whitton, R.W. Johnson r The Knee 7 (2000) 207᎐210
ated with the use of capsaicin decreased with time, with only 7% of patients experiencing it at 12 weeks. Another placebo-controlled trial found a highly statistically significant reduction in articular tenderness in patients with osteoarthritis of the hands after 4 weeks treatment with 0.075% capsaicin w37x. Both 0.025% and 0.075% capsaicin creams are available in the UK as 45-g tubes. If the cream is used four times per day, personal experimentation has shown us that a tube will last between 3 and 4 weeks, at a cost of approximately £15 per tube.
4. Rubifacients We found no randomised, controlled trials on the use of rubifacient creams, ointments or sprays, although there is much anecdotal evidence for their efficacy. This may be due to a beneficial effect of rubbing the affected area or counterirritation activating gating mechanisms within the spinal cord.
5. Conclusion In summary, a body of evidence appears to be growing supporting the efficacy of topical NSAIDs in the treatment of pain from chronic arthritic conditions, together with evidence of an impressive lack of serious gastro-intestinal side effects, a factor which may offset their higher cost. More high quality studies are needed to consolidate these findings and to clarify patient selection criteria. The evidence for efficacy of capsaicin is still limited at present, although the results from the few studies that there are is encouraging. Again, more studies are needed. We cannot comment on conventional rubefacients as there is no scientific evidence to commend their use. It would seem appropriate to offer patients a trial period of topical analgesic therapy with these agents, sequentially if the first fails despite compliance, in view of their safety, relative economy and reasonable efficacy. References w1x Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied nonsteroidal anti-inflammatory drugs. Br Med J 1998;316: 333᎐338. w2x McQuay HJ, Moore RA, Justins D. Treating acute pain in hospital. Br Med J 1997;314:1531᎐1535. w3x Browning RC, Johson K. Reducing the dose of oral NSAIDs by use of feldene gel: an open study in elderly patients with osteoarthritis. Adv Ther 1994;11:198᎐206. w4x Golden EL. A double-blind comparison of orally ingested aspirin and a topically applied salicylate cream in the relief of rheumatic pain. Cur Ther Res 1978;4:524᎐529.
209
w5x Gotzsche PC. Non-steroidal anti-inflammatory drugs. Br Med J 2000;320:1058᎐1061. w6x Tsuyama N, Kurokawa T, Nihei T, Nagano A, Tachibana N, Hanaoka K. Clinical evaluation of L-141 topical agent on osteoarthrosis deformans of the knees. Clin Med 1985; 1:697᎐729. w7x Dieppe PA. The topical NSAID felbinac versus oral ibuprofen: a comparison of efficacy in the treatment of mild to moderate osteoarthritis of the knee. Clinical trial report, Lederle Laboratories, 1993. w8x Shackel NA, Day RO, Kellett B, Brooks PM. Copper-salicylate gel for pain relief in osteoarthritis: a randomised controlled trial. MJA 1997;167:134᎐136. w9x Sandelin J, Harilainen A, Crone H, Hamberg P, Forsskahl B, Tamelander G. Local NSAID gel Želtinac . in the treatment of osteoarthritis of the knee. Scand J Rheumatol 1997;26: 287᎐292. w10x Topical non-steroidal anti-inflammatory drugs: an update. MeReC Bulletin 1997;8:29᎐32. w11x Duerden M et al. Safety, efficacy and therapeutic role of NSAIDs must be clarified wletterx. Br Med J 1998;317:280. w12x Tramer M, Moore RA, Reynolds DJM, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000;85:169᎐182. w13x Moore RA, Phillips CJ. Cost of NSAID adverse effects to the UK National Health Service. J Med Econ 1999;2:45᎐55. w14x Evans JMM, McMahon A, McGilchrist M, White G, Murray F, McDevitt D et al. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case᎐control study. Br Med J 1995;311:22᎐26. w15x Wynne HA, Rawlins MD. Are systemic levels of non-steroidal anti-inflammatory drugs relevant to acute upper gastrointestinal haemorrhage? Eur J Clin Pharmacol 1993;44:309᎐313. w16x Rabinowitz RL, Feldman ES, Weinberger A et al. Comparative tissue absorption of oral C-aspirin and topical triethanolamine C-salicylate in human and canine knee joints. J Clin Pharmacol 1982;22:42᎐48. w17x Taburet AM, Singlas RC, Thomas F et al. Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers. J Clin Pharm Ther 1996; 20:101᎐107. w18x Radermacher J, Jentsch D, Scholl MA et al. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol 1991;31:537᎐541. w19x Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. Drugs 1998;56:783᎐799. w20x Dominkus M, Nicolakos M, Kotz R et al. Comparison of tissue and plasma levels of ibuprofen after oral and topical administration. Arzneimittel Forschung 1996;46:1138᎐1143. w21x Bauer H, Waldorf-Bolten E, Bolten W. The pharmacokinetics, pharmacodynamics and comparative efficacy of flurbiprofen local action transcutaneous ŽLAT. wabstract x. Clin Rheumatol 1994;13:356. w22x Frostick SP, Varley G, Smith C. The absorption of flurbiprofen from a topical preparation in patients undergoing an arthroscopy wabstract x. Clin Rheumatol 1994;13:356. w23x Rolf C, Engstrom B, Beauchard C, Jacobs LD, Le Liboux A. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology 1999;38: 564᎐567. w24x Grahame R. The NSAID patch. Eur J Rheumatol Inflamm 1994;14:1᎐2.
210
T. Whitton, R.W. Johnson r The Knee 7 (2000) 207᎐210
w25x Sitenga GL, Ing EB, Van Dellen RG et al. Asthma caused by topical application of ketorolac. Ophthalmology 1996;103: 890᎐892. w26x O’Callaghan CA, Andrews PA, Ogg CS. Renal disease and use of topical non-steroidal anti-inflammatory drugs. Br Med J 1994;308:110᎐111. w27x Fernando AHN, Thomas S, Temple RM. Renal failure after topical use of NSAIDs wletterx. Br Med J 1994;308:533. w28x Newbery R, Shuttleworth P, Rapier C. A multicentre post marketing surveillance study to evaluate the safety and efficacy of felbinac 3% gel in the treatment of musculoskeletal disorders in general practice. Eur J Clin Res 1992;3:139᎐150. w29x Hosie G, Bird H. The topical NSAID felbinac versus oral NSAIDs: a critical review. Eur J Rheumatol Inflamm 1994;14:21᎐28. w30x Fitzgerald M. Capsaicin and sensory neurons ᎏ a review. Pain 1983;15:109᎐130. w31x Badalamente MA, Cherney SB. Periosteal and vascular in-
w32x w33x w34x w35x w36x w37x
nervation of the human patella in degenerative joint disease. Semin Arthritis Rheum Suppl 2 1989;18:61᎐66. Zimmermann M. Pain mechanisms and mediators in osteoarthritis. Semin Arthritis Rheum Suppl 2 1989;18:22᎐29. Marshall KW, Chiu B, Inman RD. Substance P and arthritis: analysis of plasma and synovial fluid levels. Arthritis Rheum 1990;33:87᎐90. Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. A meta-analysis. Eur J Clin Pharmacol 1994;46:517᎐522. Deal CL et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 1991;13:383᎐393. Altman RD et al. Capsaicin cream 0.025% as monotherapy for osteoarthritis: a double-blind study. Semin Arthritis Rheum Suppl 3 1994;23:25᎐33. McCarthy GM, McCarty DL. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 1992;19:604᎐607.
Review article
Topical preparations for chronic disorders of the knee: a review Tessa Whittona , Robert W. Johnsonb,U b
a Royal United Hospital, Combe Park, Bath, BA1 3NG, UK Sir Humphry Da¨ y Department of Anaesthesia, Bristol Royal Infirmary, Bristol, BS2 8HW, UK
Received 30 June 2000; received in revised form 31 August 2000; accepted 14 September 2000
1. Introduction There are a large number of topical applications available for the treatment of acute and chronic musculo-skeletal conditions: non-steroidal anti-inflammatory drugs ŽNSAIDs., rubifacients Žsubstances ‘heating to redness’ the area to which applied topically but without known pharmacological action on nerve conduction or inflammatory processes. and more recently, capsaicin. They take the form of gels, creams, ointments, transdermal patches and sprays. This review will consider their usefulness in the treatment of pain arising from chronic arthritic and soft tissue conditions of the knee, in terms of their effectiveness and safety profile.
2. NSAIDs Such drugs inhibit cyclo-oxygenase, an enzyme converting arachidonic acid to various types of prostaglandins. Prostaglandins are produced in response to tissue trauma and mediate components of the peripheral inflammatory response. Prostaglandins also sensitise peripheral and central nociceptors in association with other mediators including histamine and bradykinin. These drugs have activity at many sites and have gastropathic, antihaemostatic and neprotoxic effects. They may also cause cognitive and hepatic dysfunction. Anaphylaxis may occur and asthmatic attacks may be induced in susceptible patients. Newer drugs may reduce gastrointestinal side effects. U
Corresponding author. Tel.: q44-117-928-2766; fax: q44-117928-4964.
2.1. Efficacy NSAIDs are widely used in the UK: 5% of the NHS total prescriptions are for NSAIDs Žpredominantly oral. ᎏ this accounts for 20᎐24 million prescriptions per year w1x. A quantitative systematic review of topically applied NSAIDs was published in the British Medical Journal in 1998 w1x. It reviewed 86 trials involving over 10 000 patients, for both acute and chronic conditions. The chronic conditions studied were single joint arthropathies and rheumatic disorders. Of 12 high quality randomised, controlled trials comparing a topical NSAID with placebo, seven out of the 12 showed superiority of the NSAID. The relative benefit of all 12 studies was 2.0 Ž95% confidence interval 1.5᎐2.7., with number needed to treat ŽNNT. of 3.1 Ž2.7᎐3.8.. This is a similar NNT to that of oral analgesics in moderate to severe pain Žfrom any cause. w2x. The percentage of patients achieving a successful outcome with a topical NSAID was 30᎐90%, compared to 5᎐60% with placebo. All placebo controls in trials using a topical gel or cream were rubbed in; any effect of the topical drug was therefore not due to rubbing. Two studies in this review compared a topical NSAID with an oral NSAID: neither showed a significant benefit of the oral over the topical preparation w3,4x. No high quality trial has yet compared a topical NSAID with the oral form of the same drug w5x. We found a number of studies which looked at the effectiveness of topical NSAIDs in the treatment of chronic knee conditions and further studies involving other joints. Felbinac gel has been compared to an
0968-0160r00r$ - see front matter 䊚 2000 Elsevier Science B.V. All rights reserved. PII: S 0 9 6 8 - 0 1 6 0 Ž 0 0 . 0 0 0 7 1 - 5
208
T. Whitton, R.W. Johnson r The Knee 7 (2000) 207᎐210
oral NSAID in two double-blind, double-dummy studies involving large numbers of patients w6,7x and found to be as effective as the oral drug to which it was compared Žfenbufen and ibuprofen, respectively.. A randomised, double-blind, placebo-controlled study found that copper-salicylate gel was not superior to placebo in relieving pain of osteoarthritis of the knee and hip w8x. Another randomised, double-blind study compared eltenac gel with oral diclofenac and placebo and found the gel to be as effective as diclofenac and statistically more effective than placebo in those patients with severe osteoarthritis of the knee w9x.
may reflect a problem with the vehicle rather than the active component of these preparations. Other adverse reactions, such as bronchospasm and renal impairment, which limit the use of oral NSAIDs have been described with topical preparations w25᎐27x. Patients at higher risk of adverse effects may have been excluded. A postmarketing surveillance study of one topical preparation showed a 1.5% incidence of adverse effects, mainly cutaneous, with an incidence of gastro-intestinal effects of 0.1%, none of which were deemed serious w28x. These figures from clinical practice are similar to those seen in controlled trials of felbinac w29x.
2.2. Safety Although there is evidence that topical NSAIDs are more effective than placebo and as effective as an oral NSAID, there is still resistance to their prescription w10,11x. The cost of topical preparations initially seems high. What then is their advantage over oral NSAIDs if they are as effective but cost more? The use of topical preparations of NSAIDs is associated with a much lower incidence of gastro-intestinal adverse effects than that associated with the oral form, indeed this is one factor which has prompted their development. With chronic use of oral NSAIDs Žmore than 2 months’ use., one in 2000 users will die from gastro-intestinal complications who would not have done had they not been taking a NSAID w12x. This accounts for approximately 2000 deaths in the UK per year. For each patient taking a NSAID, the annual cost of adverse effects has been calculated as £48 w13x. It appears that the low incidence of systemic side effects seen with topical NSAIDs is related to the low plasma concentrations of drug seen with this administration route w14,15x: plasma concentrations of 1᎐10% of those of oral preparations have been demonstrated in both humans and animals w16᎐18x. A review of the pharmacology of topical NSAIDs w19x found evidence that substantial soft tissue concentrations associated with low plasma concentrations can be achieved with local application w20᎐22x but concluded that evidence for significant synovial fluid concentrations was scanty. A more recent study on topical ketoprofen has shown good intra-articular penetration associated with low plasma levels w23x. Large variations in concentrations have been found in several studies: this may be due to differences in application techniques and factors such as skin thickness and integrity w24x. Fixed dose patches may allow more standardised dosage. The incidence of local skin reactions has been calculated as 3.6%, no higher than that seen with placebo w1x, and appears to vary with the product used. The incidence of skin reactions to placebo gels
3. Capsaicin 3.1. Mode of action Capsaicin is a naturally occurring irritant alkaloid, found in chilli peppers. The substance has a direct stimulatory action on both C and A␦ nociceptive fibres in primary afferent nerves. It acts upon vanilloid receptors and repeated application to the skin results in a depletion of the neurotransmitter substance P from sensory C-fibres both peripherally and centrally, resulting in inhibition of local pain w30x. Endogenous neuropeptides such as substance P have been implicated in the pathogenesis of arthritic pain w31,32x, with elevation of substance P levels found in the plasma and synovial tissue of patients with osteoarthritis w33x. Its application is associated with a mild to moderate burning sensation, usually transient, which may limit its use in some patients. Because of this burning, blinding during trials may be limited. A beneficial effect is most unlikely until the substance has been applied 3᎐4 times daily for 2 weeks or more. It is possible that a vanilloid analogue will be developed which lacks the initial irritant effects. 3.2. Efficacy One review found an odds ratio Žratio of number receiving benefit from active medication compared with placebo. of 4.36 Ž95% CI 2.77, 6.88. from the pooled results of three randomised, double-blind, placebo-controlled trials of varying sizes w34x. One study of patients with osteo- and rheumatoid arthritis of the knees showed a significant reduction in pain scores in patients treated with 0.025% capsaicin for 4 weeks compared with placebo w35x. Another study of similar size and design confirmed this result, demonstrating a significant reduction in pain after 4 weeks of treatment with 0.025% capsaicin compared to placebo w36x. This study also found the burning associ-
T. Whitton, R.W. Johnson r The Knee 7 (2000) 207᎐210
ated with the use of capsaicin decreased with time, with only 7% of patients experiencing it at 12 weeks. Another placebo-controlled trial found a highly statistically significant reduction in articular tenderness in patients with osteoarthritis of the hands after 4 weeks treatment with 0.075% capsaicin w37x. Both 0.025% and 0.075% capsaicin creams are available in the UK as 45-g tubes. If the cream is used four times per day, personal experimentation has shown us that a tube will last between 3 and 4 weeks, at a cost of approximately £15 per tube.
4. Rubifacients We found no randomised, controlled trials on the use of rubifacient creams, ointments or sprays, although there is much anecdotal evidence for their efficacy. This may be due to a beneficial effect of rubbing the affected area or counterirritation activating gating mechanisms within the spinal cord.
5. Conclusion In summary, a body of evidence appears to be growing supporting the efficacy of topical NSAIDs in the treatment of pain from chronic arthritic conditions, together with evidence of an impressive lack of serious gastro-intestinal side effects, a factor which may offset their higher cost. More high quality studies are needed to consolidate these findings and to clarify patient selection criteria. The evidence for efficacy of capsaicin is still limited at present, although the results from the few studies that there are is encouraging. Again, more studies are needed. We cannot comment on conventional rubefacients as there is no scientific evidence to commend their use. It would seem appropriate to offer patients a trial period of topical analgesic therapy with these agents, sequentially if the first fails despite compliance, in view of their safety, relative economy and reasonable efficacy. References w1x Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied nonsteroidal anti-inflammatory drugs. Br Med J 1998;316: 333᎐338. w2x McQuay HJ, Moore RA, Justins D. Treating acute pain in hospital. Br Med J 1997;314:1531᎐1535. w3x Browning RC, Johson K. Reducing the dose of oral NSAIDs by use of feldene gel: an open study in elderly patients with osteoarthritis. Adv Ther 1994;11:198᎐206. w4x Golden EL. A double-blind comparison of orally ingested aspirin and a topically applied salicylate cream in the relief of rheumatic pain. Cur Ther Res 1978;4:524᎐529.
209
w5x Gotzsche PC. Non-steroidal anti-inflammatory drugs. Br Med J 2000;320:1058᎐1061. w6x Tsuyama N, Kurokawa T, Nihei T, Nagano A, Tachibana N, Hanaoka K. Clinical evaluation of L-141 topical agent on osteoarthrosis deformans of the knees. Clin Med 1985; 1:697᎐729. w7x Dieppe PA. The topical NSAID felbinac versus oral ibuprofen: a comparison of efficacy in the treatment of mild to moderate osteoarthritis of the knee. Clinical trial report, Lederle Laboratories, 1993. w8x Shackel NA, Day RO, Kellett B, Brooks PM. Copper-salicylate gel for pain relief in osteoarthritis: a randomised controlled trial. MJA 1997;167:134᎐136. w9x Sandelin J, Harilainen A, Crone H, Hamberg P, Forsskahl B, Tamelander G. Local NSAID gel Želtinac . in the treatment of osteoarthritis of the knee. Scand J Rheumatol 1997;26: 287᎐292. w10x Topical non-steroidal anti-inflammatory drugs: an update. MeReC Bulletin 1997;8:29᎐32. w11x Duerden M et al. Safety, efficacy and therapeutic role of NSAIDs must be clarified wletterx. Br Med J 1998;317:280. w12x Tramer M, Moore RA, Reynolds DJM, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000;85:169᎐182. w13x Moore RA, Phillips CJ. Cost of NSAID adverse effects to the UK National Health Service. J Med Econ 1999;2:45᎐55. w14x Evans JMM, McMahon A, McGilchrist M, White G, Murray F, McDevitt D et al. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case᎐control study. Br Med J 1995;311:22᎐26. w15x Wynne HA, Rawlins MD. Are systemic levels of non-steroidal anti-inflammatory drugs relevant to acute upper gastrointestinal haemorrhage? Eur J Clin Pharmacol 1993;44:309᎐313. w16x Rabinowitz RL, Feldman ES, Weinberger A et al. Comparative tissue absorption of oral C-aspirin and topical triethanolamine C-salicylate in human and canine knee joints. J Clin Pharmacol 1982;22:42᎐48. w17x Taburet AM, Singlas RC, Thomas F et al. Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers. J Clin Pharm Ther 1996; 20:101᎐107. w18x Radermacher J, Jentsch D, Scholl MA et al. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol 1991;31:537᎐541. w19x Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. Drugs 1998;56:783᎐799. w20x Dominkus M, Nicolakos M, Kotz R et al. Comparison of tissue and plasma levels of ibuprofen after oral and topical administration. Arzneimittel Forschung 1996;46:1138᎐1143. w21x Bauer H, Waldorf-Bolten E, Bolten W. The pharmacokinetics, pharmacodynamics and comparative efficacy of flurbiprofen local action transcutaneous ŽLAT. wabstract x. Clin Rheumatol 1994;13:356. w22x Frostick SP, Varley G, Smith C. The absorption of flurbiprofen from a topical preparation in patients undergoing an arthroscopy wabstract x. Clin Rheumatol 1994;13:356. w23x Rolf C, Engstrom B, Beauchard C, Jacobs LD, Le Liboux A. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology 1999;38: 564᎐567. w24x Grahame R. The NSAID patch. Eur J Rheumatol Inflamm 1994;14:1᎐2.
210
T. Whitton, R.W. Johnson r The Knee 7 (2000) 207᎐210
w25x Sitenga GL, Ing EB, Van Dellen RG et al. Asthma caused by topical application of ketorolac. Ophthalmology 1996;103: 890᎐892. w26x O’Callaghan CA, Andrews PA, Ogg CS. Renal disease and use of topical non-steroidal anti-inflammatory drugs. Br Med J 1994;308:110᎐111. w27x Fernando AHN, Thomas S, Temple RM. Renal failure after topical use of NSAIDs wletterx. Br Med J 1994;308:533. w28x Newbery R, Shuttleworth P, Rapier C. A multicentre post marketing surveillance study to evaluate the safety and efficacy of felbinac 3% gel in the treatment of musculoskeletal disorders in general practice. Eur J Clin Res 1992;3:139᎐150. w29x Hosie G, Bird H. The topical NSAID felbinac versus oral NSAIDs: a critical review. Eur J Rheumatol Inflamm 1994;14:21᎐28. w30x Fitzgerald M. Capsaicin and sensory neurons ᎏ a review. Pain 1983;15:109᎐130. w31x Badalamente MA, Cherney SB. Periosteal and vascular in-
w32x w33x w34x w35x w36x w37x
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