Topical NSAIDs for acute musculoskeletal pain in adults

Sheena Derry, R Andrew Moore, Helen Gaskell, Mairead McIntyre, Philip J Wiffen, Sheena Derry, R Andrew Moore, Helen Gaskell, Mairead McIntyre, Philip J Wiffen

Abstract

Background: Use of topical NSAIDs to treat acute musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of 'Topical NSAIDs for acute pain in adults' originally published in Issue 6, 2010.

Objectives: To determine the efficacy and safety of topically applied NSAIDs in acute musculoskeletal pain in adults.

Search methods: We searched the Cochrane Register of Studies Online, MEDLINE, and EMBASE to February 2015. We sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers websites. For the earlier review, we also searched our own in-house database and contacted manufacturers.

Selection criteria: We included randomised, double-blind, active or placebo (inert carrier)-controlled trials in which treatments were administered to adults with acute pain resulting from strains, sprains or sports or overuse-type injuries (twisted ankle, for instance). There had to be at least 10 participants in each treatment arm, with application of treatment at least once daily.

Data collection and analysis: Two review authors independently assessed studies for inclusion, and extracted data. We used numbers of participants achieving each outcome to calculate the risk ratio and numbers needed to treat for an additional beneficial outcome (NNT) or additional harmful outcome (NNH) compared with placebo or other active treatment. We reported 95% confidence intervals (CI). We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs.

Main results: For this update we added 14 new included studies (3489 participants), and excluded four studies. We also identified 20 additional reports of completed or ongoing studies that have not been published in full. The earlier review included 47 studies.This update included 61 studies. Most compared topical NSAIDs in the form of a gel, spray, or cream with a similar topical placebo; 5311 participants were treated with a topical NSAID, 3470 with placebo, and 220 with an oral NSAID. This was a 63% increase in the number of included participants over the previous version of this review. We also identified a number of studies in clinical trial registries with unavailable results amounting to about 5900 participants for efficacy and 5300 for adverse events.Formulations of topical diclofenac, ibuprofen, ketoprofen, piroxicam, and indomethacin demonstrated significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebo (moderate or high quality data). Benzydamine did not. Three drug and formulation combinations had NNTs for clinical success below 4. For diclofenac, the Emulgel® formulation had the lowest NNT of 1.8 (95% CI 1.5 to 2.1) in two studies using at least 50% pain intensity reduction as the outcome. Diclofenac plasters other than Flector® also had a low NNT of 3.2 (2.6 to 4.2) based on good or excellent responses in some studies. Ketoprofen gel had an NNT of 2.5 (2.0 to 3.4), from five studies in the 1980s, some with less well defined outcomes. Ibuprofen gel had an NNT of 3.9 (2.7 to 6.7) from two studies with outcomes of marked improvement or complete remission. All other drug and formulation combinations had NNT values above 4, indicating lesser efficacy.There were insufficient data to compare reliably individual topical NSAIDs with each other or the same oral NSAID.Local skin reactions were generally mild and transient, and did not differ from placebo (high quality data). There were very few systemic adverse events (high quality data) or withdrawals due to adverse events (low quality data).

Authors' conclusions: Topical NSAIDs provided good levels of pain relief in acute conditions such as sprains, strains and overuse injuries, probably similar to that provided by oral NSAIDs. Gel formulations of diclofenac (as Emugel®), ibuprofen, and ketoprofen, and some diclofenac patches, provided the best effects. Adverse events were usually minimal.Since the last version of this review, the new included studies have provided additional information. In particular, information on topical diclofenac is greatly expanded. The present review supports the previous review in concluding that topical NSAIDs are effective in providing pain relief, and goes further to demonstrate that certain formulations, mainly gel formulations of diclofenac, ibuprofen, and ketoprofen, provide the best results. Large amounts of unpublished data have been identified, and this could influence results in updates of this review.

Conflict of interest statement

SD has no conflicts relating to this review or any similar product.

RAM has no conflicts relating to this review or any similar product.

PW has no conflicts relating to this review or any similar product.

HG has no conflicts relating to this review or any similar product.

MM has no conflicts relating to this review or any similar product.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
4
4
Forest plot of comparison: 2 Individual NSAID versus placebo, outcome: 2.1 Clinical success.
5
5
L'Abbé plot of clinical success in studies of topical diclofenac versus topical placebo. The size of the symbol is proportional to the size of the study (inset scale). Dark blue: Emulgel; light blue: spray/gel; red: Flector; pink: other patch or plaster.
6
6
L'Abbé plot of clinical success in studies of topical ketoprofen versus topical placebo. The size of the symbol is proportional to the size of the study (inset scale). Light blue: ketoprofen gel; pink: ketoprofen plaster.
1.1. Analysis
1.1. Analysis
Comparison 1 Individual NSAID versus placebo, Outcome 1 Clinical success.
1.2. Analysis
1.2. Analysis
Comparison 1 Individual NSAID versus placebo, Outcome 2 Local adverse events.
2.1. Analysis
2.1. Analysis
Comparison 2 Diclofenac versus placebo (effect of formulation), Outcome 1 Clinical success.
3.1. Analysis
3.1. Analysis
Comparison 3 Ibuprofen versus placebo (effect of formulation), Outcome 1 Clinical success.
4.1. Analysis
4.1. Analysis
Comparison 4 Ketoprofen versus placebo, Outcome 1 Clinical success.
5.1. Analysis
5.1. Analysis
Comparison 5 All topical NSAIDs versus placebo, Outcome 1 Local adverse events.
5.2. Analysis
5.2. Analysis
Comparison 5 All topical NSAIDs versus placebo, Outcome 2 Systemic adverse events.
5.3. Analysis
5.3. Analysis
Comparison 5 All topical NSAIDs versus placebo, Outcome 3 Adverse event withdrawals.
6.1. Analysis
6.1. Analysis
Comparison 6 Topical NSAID versus active comparator, Outcome 1 Clinical success ‐ topical piroxicam vs topical indomethacin.
6.2. Analysis
6.2. Analysis
Comparison 6 Topical NSAID versus active comparator, Outcome 2 Local adverse events ‐ topical piroxicam vs topical indomethacin.

References

References to studies included in this review Airaksinen 1993 {published data only}

    1. Airaksinen O, Venäläinen J, Pietiläinen T. Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries. International Journal of Clinical Pharmacology, Therapy and Toxicology 1993;31(11):561‐3.
Ăkermark 1990 {published data only}
    1. Ăkermark C, Forsskåhl B. Topical indomethacin in overuse injuries in athletes. A randomized double blind study comparing Elmetacin® with oral indomethacin and placebo. International Journal of Sports Medicine 1990;11(5):393‐6.
Aoki 1984 {published data only}
    1. Aoki T, Numajiri M, Yamamoto M. A well controlled comparative study of piroxicam gel, indomethacin gel and placebo gel in the treatment of trauma. Japanese Pharmacology and Therapeutics 1984;12(12):101‐17.
Auclair 1989 {published data only}
    1. Auclair J, Georges M, Grapton X, Gryp L, D'Hooghe M, Meisser RG, et al. A double‐blind controlled multi‐center study of percutaneous niflumic acid gel and placebo in the treatment of Achilles heel tendinitis. Current Therapeutic Research 1989;46(4):782‐8.
Billigmann 1996 {published data only}
    1. Billigmann PW. Treatment of ankle distortion with ibuprofen gel [Therapie von Sprunggelenks‐distosionen mit ibuprofen‐mikrogel]. Therapiewoche 1996;46(21):1187‐92.
Campbell 1994 {published data only}
    1. Campbell J, Dunn T. Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains. Journal of Accident and Emergency Medicine 1994;11(3):178‐82.
Chatterjee 1977 {published data only}
    1. Chatterjee DS. A double‐blind clinical study with benzydamine 3% cream on soft tissue injuries in an occupational health centre. Journal of International Medical Research 1977;5(6):450‐8.
Costantino 2011 {published data only}
    1. Costantino C, Kwarecki J, Samokhin AV, Mautone G, Rovati S. Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double‐blind, parallel‐group, placebo‐controlled, multicentre, phase III trial. Clinical Drug Investigation 2011;31(1):15‐26. [DOI: 10.2165/11585890-000000000-00000]
Coudreuse 2010 {published data only}
    1. Coudreuse JM, Vathaire F. Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double‐blind, placebo‐controlled, clinical study. Current Medical Research and Opinion 2010;26(9):2221‐8. [DOI: 10.1185/03007995.2010.508020]
Curioni 1985 {published data only}
    1. Curioni BG, Domenica F, Daolio P, Spignoli G. Evaluation of ibuproxam gel in traumatology [Valutazione dell'efficacia terapeutica di ibudros gel in traumatologia]. Clinica Europea 1985;24(3):456‐60.
Diebshlag 1990 {published data only}
    1. Diebschlag W, Nocker W, Bullingham R. A double‐blind study of the efficacy of topical ketorolac tromethamine gel in the treatment of ankle sprain, in comparison to placebo and etofenamate. Journal of Clinical Pharmacology 1990;30(1):82‐9.
Dreiser 1988 {published data only}
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Dreiser 1989 {published data only}
    1. Dreiser RL. Clinical trial ‐ Fatsum gel FG‐6. Supplied by Menarini 1989.
Dreiser 1990 {published data only}
    1. Dreiser RE, Charlot J, Lopez A, Ditisheim A. Clinical evaluation of niflumic acid gel in the treatment of uncomplicated ankle sprains. Current Medical Research and Opinion 1990;12(2):93‐9.
Dreiser 1994 {published data only}
    1. Dreiser RL, Roche R, Sahb R, Thomas F, Leutenegger E. Flurbiprofen local action transcutaneous (LAT tm): clinical evaluation in the treatment of acute ankle sprains. European Journal of Rheumatology and Inflammation 1994;14(4):9‐13.
Fioravanti 1999 {published data only}
    1. Fioravanti A, Cicero MR, Nerucci F, Manopulo R, Marcolongo R. Double‐blind controlled clinical study of the efficacy and tolerability of diclofenac‐N‐(2‐hydroxyethyl)‐pyrrolidine lecithin gel compared with diclofenac‐N‐(2‐hydroxyethyl)‐pyrrolidine gel in patients with peri and extraarticular inflammatory diseases. Drugs under Experimental and Clinical Research 1999;25(5):235‐40.
Fujimaki 1985 {published data only}
    1. Fujimaki E, et al. Clinical evaluation of piroxicam gel versus indomethacin gel and placebo in the treatment of muscle pain: a double‐blind, multicenter study. Japanese Pharmacology and Therapeutics 1985;12(12):119‐37.
Gallacchi 1990 {published data only}
    1. Gallacchi G, Mautone G, Lauldi P. Topical treatment with diclofenac hydroxyethylpyrrilidine (Flector gel 1%). Clinical Trials Journal 1990;27(1):58‐64.
González de Vega 2013 {published data only}
    1. González de Vega C, Speed C, Wolfarth B, González J. Traumeel vs. diclofenac for reducing pain and improving ankle mobility after acute ankle sprain: a multicentre, randomised, blinded, controlled and non‐inferiority trial. International Journal of Clinical Practice 2013;67(10):979‐89. [DOI: 10.1111/ijcp.12219]
Governali 1995 {published data only}
    1. Governali E, Casalini D. A controlled clinical study on ketoprofen gel 5% versus ketoprofen ointment 1% in patients with post‐traumatic lesions [Ricerda clinica controllata tra ketoprofene gel 5% e ketoprofene crema 1% in pazienti con postumi di lesioni traumatiche]. Riabilitazione 1995;28(1):61‐9.
Gualdi 1987 {published data only}
    1. Gualdi A, Bonollo L, Martini A, Forgione A. Non‐steroidal anti‐inflammatory drugs for topical therapy in traumatology: a double‐blind study with flunoxaprofen and ketoprofen [Antinflammatori no steroidi per uso topico in traumatologia: studio clinico con flunoxaprofene e chetoprofene]. Riforma Medica 1987;102(10):401‐4.
Haig 1986 {published data only}
    1. Haig G. Portable thermogram technique for topically applied benzydamine cream in acute soft‐tissue injuries. Internation Journal of Tissue Reactions 1986;8(2):145‐7.
Hoffmann 2012 {published data only}
    1. Hoffmann P, Kopačka P, Gugliotta B, Rovati S. Efficacy and tolerability of DHEP‐heparin plaster in reducing pain in mild‐to‐moderate muscle contusions: a double‐blind, randomized trial. Current Medical Research and Opinion 2012;28(8):1313‐21. [DOI: 10.1185/03007995.2012.709182]
Hofman 2000 {published data only}
    1. Hofman J, Nasswetter G, Cayetti LM. Lysine clonixinate gel in soft tissue injuries. Controlled randomized prospective double‐blind clinical trial with diclofenac [Clonixinato de lisina gel en lesiones de tejidos blandos ensayo clinico prospectivo doble ciego al azar controlado con diclofenac]. Prensa Medica Argentina 2000;87(5):513‐20.
Hosie 1993 {published data only}
    1. Hosie GAC. The topical NSAID, felbinac, versus oral ibuprofen: a comparison of efficacy in the treatment of acute lower back injury. British Journal of Clinical Research 1993;4:5‐17.
Jenoure 1997 {published data only}
    1. Jenoure PJ, Rostan A, Gremion G, Meier JL, Grossen R, Bielinki R, et al. Multicentre, double‐blind, controlled clinical study on the efficacy of diclofenac epolamine Tissugel plaster in patients with epicondylitis [Studio multicentrico controllato in doppio cieco su diclofenac Tissugel plaster in pazienti con epicondilite]. Medicina Dello Sport 1977;50(3):285‐92.
Joussellin 2003 {published data only}
    1. Joussellin E. Flector Tissugel for the treatment of painful ankle sprains [Flector Tissugel dans le traitement des entorses douloureuses de la cheville]. Journal de Traumatologie du Sport 2003;20:1S5‐9.
    1. Lionberger DR, Joussellin E, Lanzarotti A, Yanchick J, Magelli M. Diclofenac epolamine topical patch relieves pain associated with ankle sprain. Journal of Pain Research 2011;4:47‐53. [DOI: 10.2147/JPR.S15380]
    1. Lionberger DR, Joussellin E, Yanchick J, Magelli M, Lanzarotti A. Pooled analysis of clinical trial data evaluating the safety and effectiveness of diclofenac epolamine topical patch 1.3% for the treatment of acute ankle sprain. Open Access Journal of Sports Medicine 2011;2:75‐84. [DOI: 10.2147/OAJSM.S17048]
Julien 1989 {published data only}
    1. Julien D. Clinical trial ‐ Fastum gel FG‐8. Supplied by Menarini 1989.
Klainguti 2010 {published data only}
    1. Klainguti A, Forgacs A, Berkes I, Castellacci E. A plaster containing DHEP and heparin for mild to moderate contusions and sprains with haematoma: a double‐blind randomized study. Current Medical Research and Opinion 2010;26(9):2243‐51. [DOI: 10.1185/03007995.2010.508022]
Kockelbergh 1985 {published data only}
    1. Kockelbergh M, Verspeelt P, Caloine R, Dermaux F. Local anti inflammatory treatment with a ketoprofen gel: current clinical findings. Journal Belge de Medecine Physique et de Rehabilitation 1985;8(4):205‐13.
Kuehl 2011 {published data only}
    1. Kuehl K, Carr W, Yanchick J, Magelli M, Rovati S. Analgesic efficacy and safety of the diclofenac epolamine topical patch 1.3% (DETP) in minor soft tissue injury. International Journal of Sports Medicine 2011;32(8):635‐43. [DOI: 10.1055/s-0031-1275359]
Li 2013 {published data only}
    1. Li C, Frangione V, Rovati S, Zheng Q. Diclofenac epolamine medicated plaster in the treatment of minor soft tissue injuries: a multicenter randomized controlled trial. Current Medical Research and Opinion 2013;29(9):1137‐46. [DOI: 10.1185/03007995.2013.816669]
Linde 1985 {published data only}
    1. Linde F, Hvass I, Jürgensen U, Madsen F. Treatment of sprained ankles with 5% benzydamine creme. A double‐blind study [Ankelforstuvninger behandlet med benzydamin 5% creme]. Ugeskrift for Laeger 1985;148(1):12‐3.
Machen 2002 {published data only}
    1. Machen J, Whitefield M. Efficacy of a proprietary ibuprofen gel in soft tissue injuries: a randomised, double blind placebo controlled study. International Journal of Clinical Practice 2002;56(2):102‐6.
Mahler 2003 {published data only}
    1. Mahler P, Mahler F, Duruz H, Ramazzina M, Liguori V, Mautone G. Double‐blind, randomized, controlled study on the efficacy and safety of a novel diclofenac epolamine gel formulated with lecithin for the treatment of sprains, strains and contusions. Drugs under Experimental and Clinical Research 2003;29(1):45‐52.
Mazières 2005a {published data only}
    1. Mazières B, Rouanet S, Velicy J, Scarsi C, Reiner V. Topical ketoprofen patch (100 mg) for the treatment of ankle sprain: a randomized, double‐blind, placebo‐controlled study. American Journal of Sports Medicine 2005;33(4):515‐23. [DOI: 10.1177/0363546504268135]
Mazières 2005b {published data only}
    1. Mazières B, Rouanet S, Guillon Y, Scarsi C, Reiner V. Topical ketoprofen patch in the treatment of tendinitis: a randomized, double blind, placebo controlled study. Journal of Rheumatology 2005;32(8):1563‐70.
McLatchie 1989 {published data only}
    1. McLatchie GR, McDonald M, Lawrence GF, Rogmans D, Lisai P, Hibberd M. Soft tissue trauma: a randomised controlled trial of the topical application of felbinac, a new NSAID. British Journal of Clinical Practice 1989;43(8):277‐80.
Morris 1991 {published data only}
    1. Morris WD, Scott HV, Peters WA, Ketelbey JW. Felbinac topical gel for acute soft tissue sports injuries. New Zealand Journal of Sports Medicine 1991;19:45‐7.
NCT01255423 {unpublished data only}
    1. Novartis (Sponsors). A randomized, double‐blind, multi‐center, placebo‐controlled, parallel group study to evaluate the efficacy and safety of diclofenac sodium topical gel (DSG) 1% applied 4 times daily in subjects with acute ankle sprain. (accessed 3 February 2015) 2012. [CTG: NCT01255423]
NCT01272934 {unpublished data only}
    1. Novartis (Sponsors). A randomized, double‐blind, multi‐center, placebo‐controlled, parallel group study to evaluate the efficacy and safety of diclofenac sodium topical gel (DSG) 1% applied four times daily in subjects with acute ankle sprain. (accessed 3 February 2015) 2013. [CTG: NCT01272934]
NCT01272947 {unpublished data only}
    1. Novartis (Sponsors). A randomized, double‐blind, multi‐center, placebo‐controlled, parallel group study to evaluate the efficacy and safety of diclofenac sodium topical gel (DSG) 1% applied four times daily in subjects with acute blunt soft tissue injuries/contusions of the limbs. (accessed 3 February 2015) 2012. [CTG: NCT01272947]
    1. Pallay R, Pabst H, Giannetti B, Burnett I, Monnet J. Diclofenac sodium topical gel (DSG) 1% for acute soft tissue injuries/contusions of the limbs. 2013 Annual Assembly of the American Academy of Physical Medicine and Rehabilitation. National Harbor, MD United States, 2013; Vol. 5 (9 Suppl 1):S204.
Noret 1987 {published data only}
    1. Noret A, Roty V, Allington N, Hauters P, Zuinen C, Poels R. Ketoprofen gel as topical treatment for sport injuries. Acta Therapeutica 1987;13:367‐78.
Parrini 1992 {published data only}
    1. Parrini M, Cabitza P, Arrigo A, Vanasia M. Efficacy and tolerability of ketoprofen lysine salt foam for topical use in the treatment of traumatic pathologies of the locomotor apparatus [Efficacia e tollerabilita del ketoprofene sale di lisina schiuma per uso topico nel trattamento di alcune patologie traumatiche dell'apparato locomotore]. La Clinica Terapeutica 1992;141(9):199‐204.
Picchio 1981 {published data only}
    1. Picchio AA, Volta S, Longoni A. Controlled clinical trial of ibuprofen for topical use in sport injuries [Studio clinico controllato sull'impiego dell'ibuprofen per uso topico in traumatologica sportiva]. Medicina dello Sport 1981;34:403‐6.
Predel 2004 {published data only}
    1. Mueller EA, Kirch W, Reiter S. Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo‐controlled trial. Expert Opinion on Pharmacotherapy 2010;11(4):493‐8. [DOI: 10.1517/14656560903535898]
    1. Predel HG, Koll R, Pabst H, Dieter R, Gallacchi G, Giannetti B, et al. Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study. British Journal of Sports Medicine 2004;38(3):318‐23. [DOI: 10.1136/bjsm.2003.005017]
Predel 2012 {published data only}
    1. Predel HG, Hamelsky S, Gold M, Giannetti B. Efficacy and safety of diclofenac diethylamine 2.32% gel in acute ankle sprain. Medicine and Science in Sports and Exercise 2012;44(9):1629‐36. [DOI: 10.1249/MSS.0b013e318257ed41]
Predel 2013a {published data only}
    1. Predel HG, Giannetti B, Seigfried B, Novellini R, Menke G. A randomized, double‐blind, placebo‐controlled multicentre study to evaluate the efficacy and safety of diclofenac 4% spray gel in the treatment of acute uncomplicated ankle sprain. Journal of International Medical Research 2013;41(4):1187‐202. [DOI: 10.1177/0300060513487639]
Predel 2013b {published data only}
    1. Predel HG, Giannetti B, Pabst H, Schaefer A, Hug AM, Burnett I. Efficacy and safety of diclofenac diethylamine 1.16% gel in acute neck pain: a randomized, double‐blind, placebo‐controlled study. BMC Musculoskeletal Disorders 2013;14:250. [DOI: 10.1186/1471-2474-14-250]
Ramesh 1983 {published data only}
    1. Ramesh N, Steuber U. Ibuprofen in a cream vehicle for accidental and sport injuries [Dolgit creme bei unfall‐ und sportverletzungen]. Therapiewoche 1983;33:4563‐70.
Rowbotham 2003 {published data only}
    1. Rowbotham M, Galer B, Block J, Backonja M. Flector Tissugel: efficacy and safety in minor sport injuries. A vs controlled clinical trial. Journal of Sports Traumatology 2003;20:IS15‐IS20.
Russell 1991 {published data only}
    1. Russell AL. Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double‐blind study comparing efficacy and safety. Clinical and Investigative Medicine 1991;14(1):35‐43.
Saillant 1998 {published data only}
    1. Lionberger DR, Joussellin E, Yanchick J, Magelli M, Lanzarotti A. Pooled analysis of clinical trial data evaluating the safety and effectiveness of diclofenac epolamine topical patch 1.3% for the treatment of acute ankle sprain. Open Access Journal of Sports Medicine 2011;2:75‐84. [DOI: 10.2147/OAJSM.S17048]
    1. Saillant G. Study comparing the efficacy and tolerance of Flector Tissugel® to that of a placebo in the treatment of benign ankle sprains [Étude comparant l’efficacité et la tolérance de FlectorTissugel® à celles d’un placebo dans le traitement des entorses bénignes de la cheville]. Medicine du Sport 1998;72:1‐5.
Sanguinetti 1989 {published data only}
    1. Sanguinetti C. Treatment of soft tissue injury with BPAA gel. Results of an Italian multicenter study vs. placebo [Trattemento con BPAA gel dei traumi dei tessuti moli]. Clinica Terapeutica 1989;130(5):255‐258.
Sinniger 1981 {published data only}
    1. Sinniger M, Blanchard P. Controlled clinical trial with Fentiazac cream in sport microtraumatology. Journal of International Medical Research 1981;9(4):300‐2.
Spacca 2005 {published data only}
    1. Spacca G, Cacchio A, Forg?cs A, Monteforte P, Rovetta G. Analgesic efficacy of a lecithin‐vehiculated diclofenac epolamine gel in shoulder periarthritis and lateral epicondylitis: a placebo‐controlled, multicenter, randomized, double‐blind clinical trial. Drugs under Experimental and Clinical Research 2005;31(4):147‐54.
Sugioka 1984 {published data only}
    1. Sugioka Y. Multicenter clinical evaluation of piroxicam gel vs. indomethacin gel in the treatment of non‐traumatic diseases of tendon or muscle. Japanese Pharmacology and Therapeutics 1984;12:139‐53.
Thorling 1990 {published data only}
    1. Thorling J, Linden B, Berg R, Sandahl A. A double blind comparison of naproxen gel and placebo in the treatment of soft tissue injuries. Current Medical Research and Opinion 1990;12:242‐8.
Tonutti 1994 {published data only}
    1. Tonutti A. The use of ketoprofen gel 5% (orudis gel) in traumatology: controlled double‐blind study vs etofenamate [Utilizzazione del ketoprofene gel 5% (orudis gel) nella pratica traumatologica: studio in doppio cieco controllato verso etofenamato]. Ortopedia e Traumatologia Oggi 1994;14(3):119‐25.
Vecchiet 1991 {published data only}
    1. Vecchiet L, Colozzi A. Effects of meclofenamic acid in the treatment of lesions deriving from minor traumatology. Clinical Journal of Pain 1991;7 Suppl 1:S54‐9.
Whitefield 2002 {published data only}
    1. Whitefield M, O'Kane CJA, Anderson S. Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomised, double blind study. Journal of Clinical Pharmacy and Therapeutics 2002;27(6):409‐17.
References to studies excluded from this review Ambrus 1987 {published data only}
    1. Ambrus P, Böhmer D. Mobilat ointment in acute sprains [Mobilat Salbe bei akuten Distorsionen]. Fortschritte der Medizin 1987;105(13):259‐62.
Anon 1993 {unpublished data only}
    1. Anon. Comparative clinical efficacy of Oruvail, piroxicam and diclofenac gels in soft tissue injury. Unpublished.
Ascherl 1982 {published data only}
    1. Ascherl R, Schlemmer H, Blumel G, Lechner F. The effectiveness of etofenamate in minor sports injuries of the knee and ankle joint. A double blind study [Die Wirksamkeit der Etofenamat in kleineren Sportverletzungen am Knie und Sprunggelenk. Eine Doppelblind‐Studie]. Fortschritte der Medizin 1982;100(37):1729‐34.
Bagliani 1976 {published data only}
    1. Bagliani A, Montalbetti L. Topical treatment of thrombophlebitis with feprazone and benzydamine. Controlled clinical study [Il trattamento topico di tromboflebite con feprazone e benzidamina. Studio clinico controllato]. Minerva Medica 1976;67(14):880‐4.
Baracchi 1982 {published data only}
    1. Baracchi G, Messina Denaro S, Piscini S. Experience of the topical use of isobutylfenylproprionic acid (Ibuprofen) in traumatic inflammation. A double‐blind comparison with placebo [Esperienza sull'impiego topico dell'acido isobutil‐fenil‐propionico (ibuprofen) nella flogosi traumatica. Confronto a doppia cecita con placebo]. Gazzetta Medica Italiana 1982;141(12):691‐4.
Böhmer 1995 {published data only}
    1. Böhmer D, Ambrus P. Treatment of muscular injuries with diclofenac‐diethylammonium emugel [Behandlung von muskelverletzungen mit diclofenac‐diethylammonium emugel]. Sportverletzung Sportschaden 1995;9:94‐5.
Burnham 1998 {published data only}
    1. Burnham R, Gregg R, Healy P, Steadward R. The effectiveness of topical diclofenac for lateral epicondylitis. Clinical Journal of Sport Medicine 1998;8(2):78‐81.
Cesarone 2008 {published data only}
    1. Cesarone MR, Belcaro G, Pellegrini L, Ledda A, Vinciguerra G, Ricci A, et al. Treatment of ankle sprain in patients with vascular diseases of the lower limbs. Minerva Cardioangiologica 2008;56 (5 Suppl):39‐46.
Coulibaly 2009 {published data only}
    1. Coulibaly SK, Courau S, Staiger C. The sprained ankle: comparative study of a comfreyroot extract ointment versus a diclofenac gel [Entorses de la cheville: étude comparative entre un extrait à base de racines de consoude et le diclofénac]. Phytothérpie 2009;7:147‐9. [DOI: 10.1007/s10298-009-0383-x]
Diebschlag 1985 {published data only}
    1. Diebschlag W. Benzydamine cream in post‐traumatic oedema. International Journal of Tissue Reactions 1985;7(3):219‐23.
Diebschlag 1986 {published data only}
    1. Diebschlag W. Diclofenac in blunt traumatic ankle joint swelling. Volumetric monitoring in a placebo controlled double blind trial [Diclofenac in stumpfen traumatischen Sprunggelenk Schwellung. Volumetrische Überwachung in einer Placebo‐kontrollierten Doppelblind‐Studie]. Fortschritte der Medizin 1986;104(21):437‐40.
Diebschlag 1992 {published data only}
    1. Diebschlag W, Nocker W, Lehmacher W. Treatment of acute sprains of the ankle joint. A comparison of the effectiveness and tolerance of two gel preparations containing indomethacin [Die Behandlung der akuten Verstauchungen des Sprunggelenks. Ein Vergleich der Wirksamkeit und Verträglichkeit von zwei Gel‐Zubereitungen mit Indometacin]. Fortschritte der Medizin 1992;110(6):64‐72.
Fantato 1971 {published data only}
    1. Fantato S, Gregorio M. Clinical evaluation of topical benzydamine in traumatology. Arzneimittel‐Forschung 1971;21(10):1530‐5.
Galer 2000 {published data only}
    1. Galer BS, Rowbotham M, Perander J, Devers A, Friedman E. Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial. Journal of Pain and Symptom Management 2000;19(4):287‐94.
Hallmeier 1986 {published data only}
    1. Hallmeier B, Michelbach B. Etofenamate under tape bandages ‐ a controlled study [Etofenamat unter tape‐verbänden]. Medizinische Welt 1986;37(43):1344‐8.
Hallmeier 1988 {published data only}
    1. Hallmeier B. Efficacy and tolerance of etofenamate and diclofenac in acute sports injuries [Wirksamkeit und Verträglichkeit von Etofenamat und Diclofenac bei akuten Sportverletzungen]. Rheuma 1988;8:183‐6.
Kaneko 1999 {published data only}
    1. Kaneko M, Shimojo H, Saito H, Onuma Y, Yamashita K. Clinical evaluation of felbinac patch (SELSPOT) on post‐traumatic disease: clinical comparative study versus commercially available patch. Japanese Pharmacology and Therapeutics 1999;27:75‐85.
Kockelbergh 1985b {published data only}
    1. Kockelbergh M, Verspeelt P, Caloine R, Dermaux F. Local anti‐inflammatory treatment with a ketoprofen gel: current clinical findings [Traitement anti‐inflammatoire local par un gel de kétoprofène: données cliniques récentes]. Journal Belge de Medecine Physique et de Rehabilitation 1985;8(4):205‐13 (study 2).
Kuwabara 2013 {published data only}
    1. Kuwabara Y, Hamamoto H, Hikake S, Miwa Y. A randomized, multi‐center, double‐blind, placebo‐controlled phase II/III trial to evaluate the eftopical patch in the treatment of pain. Journal of Pain. 2013; Vol. 14 (4 Suppl 1):S73.
Lee 1991 {published data only}
    1. Lee EH, Lee PY, Ngai AT, Chiu EH. Treatment of acute soft tissue trauma with a topical non‐steroidal anti‐inflammatory drug (biphenylacetic acid 3% gel). Singapore Medical Journal 1991;32(4):238‐41.
Link 1996 {published data only}
    1. Link R, Balint G, Pavlik G, Otto J, Krause W. Topical treatment of soft tissue rheumatism and athletic injuries. Effectiveness and tolerance of a new ketoprofen gel [Topische Behandlung von Weichteil‐Rheumatismus und Sportverletzungen. Wirksamkeit und Verträglichkeit eines neuen Ketoprofen Gel]. Fortschritte der Medizin 1996;114(25):311‐4.
May 2007 {published data only}
    1. May JJ, Lovell G, Hopkins WG. Effectiveness of 1% diclofenac gel in the treatment of wrist extensor tenosynovitis in long distance kayakers. Journal of Science and Medicine in Sport 2007;10(1):59‐65.
Oakland 1993 {published data only}
    1. Oakland C, Rapier C. A comparison of the efficacy of the topical NSAID felbinac and ultrasound in the treatment of acute ankle injuries. British Journal of Clinical Research 1993;4:89‐96.
Odaglia 1987 {unpublished data only}
    1. Odaglia G, Sereni G. Sports minor traumatology: results of a double‐blind controlled clinical study ketoprofen (fastum gel 2.5%) versus placebo. Menarini unpublished data.
Picardi 1993 {published data only}
    1. Picardi E, Iasio R. Efficacy of percutaneous anti‐inflammatory drugs (NSAIDs) in swimmers and waterpolo players [Efficacia dei farmaci antinfiammatori (FANS) per via percutanea in atleti di nuoto e pallanuoto]. Clinica Terapeutica 1993;143(6):507‐9.
Taboada 1992 {published data only}
    1. Taboada A. Controlled trial of piroxicam gel associated with ultrasound in acute disturbances of the locomotive system [Experienca controlada con gel de piroxicam asociado a ultrasonidos en afecciones agudas del aparato locomotor]. Prensa Medica Argentina 1992;79(10):630‐2.
Vanderstraeten 1990 {published data only}
    1. 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(3):139‐41.
Vinciguerra 2008 {published data only}
    1. Vinciguerra G, Belcaro G, Cesarone MR, Errichi BM, Renzo A, Errichi S, et al. Management of uncomplicated ankle sprains with topical or oral ketoprofen treatment. A registry study. Minerva Cardioangiologica 2008;56 (5 Suppl):47‐53.
Von Klug 1977 {published data only}
    1. Klug H. Experience with a locally applied anti‐inflammatory drug [Erfahrungen mit einem local anwendbaren antirheumatikum]. Arzneimittel‐Forschung/Drug Research 1977;27:1350‐4.
References to studies awaiting assessment NCT00351104 {published data only}
    1. Endo Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled, parallel group phase III study of the efficacy, tolerability and safety of ketoprofen topical patch, 20% (KTP) in the treatment of pain associated with grade 1 or grade 2 ankle sprain or strain. (accessed 3 February 2015) 2008. [CTG: NCT00351104]
NCT00352625 {unpublished data only}
    1. Endo Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled, parallel group phase III study of the efficacy, tolerability and safety of ketoprofen topical patch, 20% (KTP) in the treatment of pain associated with tendonitis or bursitis of the shoulder, elbow or knee. (accessed 3 February 2015) 2008. [CTG: NCT00352625]
NCT00426985 {unpublished data only}
    1. Endo Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled, parallel group phase iii study of the efficacy, tolerability and safety of ketoprofen topical patch, 20% (KTP) in the treatment of pain associated with tendonitis or bursitis of the shoulder, elbow or knee. (accessed 3 February 2015) 2008. [CTG: NCT00426985]
NCT00640705 {unpublished data only}
    1. Cerimon Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled study of the efficacy and safety of a diclofenac sodium patch for the topical treatment of pain due to mild to moderate ankle sprain. (accessed 3 February 2015) 2008. [CTG: NCT00640705]
NCT00640939 {unpublished data only}
    1. Cerimon Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled study of the efficacy and safety of a diclofenac sodium patch for the topical treatment of pain due to mild to moderate tendonitis or bursitis. (accessed 3 February 2015) 2008. [CTG: NCT00640939]
NCT00680472 {unpublished data only}
    1. Hisamitsu Pharmaceutical Co, Inc (Sponsors). A randomized, multicenter, double‐blind, placebo‐controlled, two‐week study to assess the efficacy and safety of HKT‐500 in subjects with acute shoulder pain. (accessed 3 February 2015) 2015. [CTG: NCT00680472]
NCT00680784 {unpublished data only}
    1. Hisamitsu Pharmaceutical Co, Inc (Sponsors). A randomized, multicenter, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of HKT‐500 in the treatment of pain associated with Grade I or Grade II ankle sprain. (accessed 3 February 2015) 2015. [CTG: NCT00680784]
NCT00765700 {unpublished data only}
    1. Ekman E, Skrepnik S, Jones M, Lawson K, Schupp J. Efficacy and safety of ketoprofen 10% cream in acute soft tissue injuries (phase 3 study tdlp‐110‐001). Proceedings of the 13th World Congress on Pain 2010 Aug 29 – Sept 2; Montreal, Canada.
    1. Imprimis Pharmaceuticals, Inc (Sponsors). A randomized, multicenter, double‐blind, placebo‐controlled, parallel‐group, phase 3 study to assess the efficacy and safety of Ketotransdel™ (Ketoprofen topical cream 10%) in the treatment of pain associated with mild to moderate acute soft tissue injury. (accessed 3 February 2015) 2013. [CTG: NCT00765700]
NCT00869063 {unpublished data only}
    1. Cerimon Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled study of the efficacy and safety of a diclofenac sodium patch for the topical treatment of acute pain due to mild to moderate wrist sprain, strain or contusion. (accessed 3 February 2015) 2010. [CTG: NCT00869063]
NCT00869180 {unpublished data only}
    1. Cerimon Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled study of the efficacy and safety of a diclofenac sodium patch for the topical treatment of acute pain due to mild to moderate ankle sprain. (accessed 3 February 2015) 2010. [CTG: NCT00869180]
NCT00931866 {unpublished data only}
    1. Cerimon Pharmaceuticals (Sponsors). A randomized, double‐blind, placebo‐controlled study of the efficacy and safety of a diclofenac sodium patch for the topical treatment of acute pain due to mild to moderate soft tissue injuries. (accessed 3 February 2015) 2010. [CTG: NCT00931866]
NCT01874626 {unpublished data only}
    1. Strategic Science & Technologies, LLC (Sponsors). A randomized, double‐blind, placebo‐controlled, multi‐dose, pivotal study to determine the efficacy and safety of SST 0225, a topical ibuprofen cream, in the treatment of pain associated with acute ankle sprain. (accessed 3 February 2015) 2014. [CTG: NCT01874626]
NCT01957215 {unpublished data only}
    1. GlaxoSmithKline (Sponsors). A clinical study to assess the efficacy of pain relief of topical indomethacin patch over placebo in ankle sprain patients. (accessed 3 February 2015) 2015. [CTG: NCT01957215]
NCT02324270 {unpublished data only}
    1. Actavis Inc (Sponsors). Randomized, double‐blind, multiple‐center, placebo‐controlled study comparing the safety and efficacy of generic diclofenac epolamine to Flector® patch in the treatment of acute pain due to minor ankle sprain. (accessed 3 February 2015) 2014. [CTG: NCT02324270]
Sarzi‐Puttini 2014 {published data only}
    1. Sarzi‐Puttini P, Atzeni F, Damiani C, Casale R, Barbagallo M, Cazzola M. A double‐blind, randomised, parallel group, active controlled, multicentre study to assess the therapeutic non‐inferiority of SKP‐021, a 0.3% ketoprofen patch, versus diclofenac sodium patch in patients with acute inflammatory musculoskeletal injuries. Proceeding of the Annual European Congress of Rheumatology of the European League Against Rheumatism, EULAR 2014 June 11‐14; Paris, France. 2014:73.
References to ongoing studies NCT01945034 {unpublished data only}
    1. Pfizer (Sponsors). Placebo‐controlled, double‐blind evaluation of the efficacy and safety of ibuprofen 5% topical gel for the treatment of ankle sprain. (accessed 3 February 2015) 2014. [CTG: NCT01945034]
NCT02100670 {unpublished data only}
    1. GlaxoSmithKline (Sponsors). A clinical study to assess the efficacy and onset of pain relief of topical MFC51123 diclofenac‐menthol gel versus controls in ankle sprain. (accessed 3 February 2015) 2014. [: NCT02100670]
NCT02290821 {unpublished data only}
    1. Novartis (Sponsors). A randomized, double‐blind, placebo‐controlled, parallel group study to evaluate the efficacy and safety of diclofenac sodium topical gel (DSG) 1% applied four times daily in subjects with acute blunt soft tissue injuries/contusions of the limbs. (accessed 3 February 2015) 2015. [CTG: NCT02290821]
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