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AINE tópicos para el dolor musculoesquelético agudo en adultos

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References

Airaksinen 1993 {published data only}

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. CENTRAL

Ăkermark 1990 {published data only}

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. CENTRAL

Aoki 1984 {published data only}

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. CENTRAL

Auclair 1989 {published data only}

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. CENTRAL

Billigmann 1996 {published data only}

Billigmann PW. Treatment of ankle distortion with ibuprofen gel [Therapie von Sprunggelenks‐distosionen mit ibuprofen‐mikrogel]. Therapiewoche 1996;46(21):1187‐92. CENTRAL

Campbell 1994 {published data only}

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. CENTRAL

Chatterjee 1977 {published data only}

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. CENTRAL

Costantino 2011 {published data only}

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]CENTRAL

Coudreuse 2010 {published data only}

Coudreuse JM, de 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]CENTRAL

Curioni 1985 {published data only}

Curioni BG, Di 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. CENTRAL

Diebshlag 1990 {published data only}

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. CENTRAL

Dreiser 1988 {published data only}

Dreiser RL. Clinical trial of efficacy and tolerability of topical ibuprofen in the treatment of tendinitis. Le Journal International De Médecine 1988;119:15‐31. CENTRAL

Dreiser 1989 {published data only}

Dreiser RL. Clinical trial ‐ Fatsum gel FG‐6. Supplied by Menarini1989. CENTRAL

Dreiser 1990 {published data only}

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. CENTRAL

Dreiser 1994 {published data only}

Dreiser RL, Roche R, de 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. CENTRAL

Fioravanti 1999 {published data only}

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. CENTRAL

Fujimaki 1985 {published data only}

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. CENTRAL

Gallacchi 1990 {published data only}

Gallacchi G, Mautone G, Lauldi P. Topical treatment with diclofenac hydroxyethylpyrrilidine (Flector gel 1%). Clinical Trials Journal 1990;27(1):58‐64. CENTRAL

González de Vega 2013 {published data only}

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]CENTRAL

Governali 1995 {published data only}

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. CENTRAL

Gualdi 1987 {published data only}

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. CENTRAL

Haig 1986 {published data only}

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. CENTRAL

Hoffmann 2012 {published data only}

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]CENTRAL

Hofman 2000 {published data only}

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. CENTRAL

Hosie 1993 {published data only}

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. CENTRAL

Jenoure 1997 {published data only}

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. CENTRAL

Joussellin 2003 {published data only}

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. CENTRAL
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]CENTRAL
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]CENTRAL

Julien 1989 {published data only}

Julien D. Clinical trial ‐ Fastum gel FG‐8. Supplied by Menarini1989. CENTRAL

Klainguti 2010 {published data only}

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]CENTRAL

Kockelbergh 1985 {published data only}

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. CENTRAL

Kuehl 2011 {published data only}

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]CENTRAL

Li 2013 {published data only}

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]CENTRAL

Linde 1985 {published data only}

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. CENTRAL

Machen 2002 {published data only}

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. CENTRAL

Mahler 2003 {published data only}

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. CENTRAL

Mazières 2005a {published data only}

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]CENTRAL

Mazières 2005b {published data only}

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. CENTRAL

McLatchie 1989 {published data only}

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. CENTRAL

Morris 1991 {published data only}

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. CENTRAL

NCT01255423 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT01255423 (accessed 3 February 2015)2012. [CTG: NCT01255423]CENTRAL

NCT01272934 {unpublished data only}

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. clinicaltrials.gov/ct2/show/results/NCT01272934 (accessed 3 February 2015)2013. [CTG: NCT01272934]CENTRAL

NCT01272947 {unpublished data only}

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. clinicaltrials.gov/ct2/show/results/NCT01272947 (accessed 3 February 2015)2012. [CTG: NCT01272947]CENTRAL
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. CENTRAL

Noret 1987 {published data only}

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. CENTRAL

Parrini 1992 {published data only}

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. CENTRAL

Picchio 1981 {published data only}

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. CENTRAL

Predel 2004 {published data only}

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]CENTRAL
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]CENTRAL

Predel 2012 {published data only}

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]CENTRAL

Predel 2013a {published data only}

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]CENTRAL

Predel 2013b {published data only}

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]CENTRAL

Ramesh 1983 {published data only}

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. CENTRAL

Rowbotham 2003 {published data only}

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. CENTRAL

Russell 1991 {published data only}

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. CENTRAL

Saillant 1998 {published data only}

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]CENTRAL
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. CENTRAL

Sanguinetti 1989 {published data only}

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. CENTRAL

Sinniger 1981 {published data only}

Sinniger M, Blanchard P. Controlled clinical trial with Fentiazac cream in sport microtraumatology. Journal of International Medical Research 1981;9(4):300‐2. CENTRAL

Spacca 2005 {published data only}

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. CENTRAL

Sugioka 1984 {published data only}

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. CENTRAL

Thorling 1990 {published data only}

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. CENTRAL

Tonutti 1994 {published data only}

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. CENTRAL

Vecchiet 1991 {published data only}

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. CENTRAL

Whitefield 2002 {published data only}

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. CENTRAL

Ambrus 1987 {published data only}

Ambrus P, Böhmer D. Mobilat ointment in acute sprains [Mobilat Salbe bei akuten Distorsionen]. Fortschritte der Medizin 1987;105(13):259‐62. CENTRAL

Anon 1993 {unpublished data only}

Anon. Comparative clinical efficacy of Oruvail, piroxicam and diclofenac gels in soft tissue injury. Unpublished. CENTRAL

Ascherl 1982 {published data only}

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. CENTRAL

Bagliani 1976 {published data only}

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. CENTRAL

Baracchi 1982 {published data only}

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. CENTRAL

Böhmer 1995 {published data only}

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. CENTRAL

Burnham 1998 {published data only}

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. CENTRAL

Cesarone 2008 {published data only}

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. CENTRAL

Coulibaly 2009 {published data only}

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]CENTRAL

Diebschlag 1985 {published data only}

Diebschlag W. Benzydamine cream in post‐traumatic oedema. International Journal of Tissue Reactions 1985;7(3):219‐23. CENTRAL

Diebschlag 1986 {published data only}

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. CENTRAL

Diebschlag 1992 {published data only}

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. CENTRAL

Fantato 1971 {published data only}

Fantato S, De Gregorio M. Clinical evaluation of topical benzydamine in traumatology. Arzneimittel‐Forschung 1971;21(10):1530‐5. CENTRAL

Galer 2000 {published data only}

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. CENTRAL

Hallmeier 1986 {published data only}

Hallmeier B, Michelbach B. Etofenamate under tape bandages ‐ a controlled study [Etofenamat unter tape‐verbänden]. Medizinische Welt 1986;37(43):1344‐8. CENTRAL

Hallmeier 1988 {published data only}

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. CENTRAL

Kaneko 1999 {published data only}

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. CENTRAL

Kockelbergh 1985b {published data only}

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). CENTRAL

Kuwabara 2013 {published data only}

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. CENTRAL

Lee 1991 {published data only}

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. CENTRAL

Link 1996 {published data only}

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. CENTRAL

May 2007 {published data only}

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. CENTRAL

Oakland 1993 {published data only}

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. CENTRAL

Odaglia 1987 {unpublished data only}

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. CENTRAL

Picardi 1993 {published data only}

Picardi E, De 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. CENTRAL

Taboada 1992 {published data only}

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. CENTRAL

Vanderstraeten 1990 {published data only}

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. CENTRAL

Vinciguerra 2008 {published data only}

Vinciguerra G, Belcaro G, Cesarone MR, Errichi BM, Di 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. CENTRAL

Von Klug 1977 {published data only}

Von Klug H. Experience with a locally applied anti‐inflammatory drug [Erfahrungen mit einem local anwendbaren antirheumatikum]. Arzneimittel‐Forschung/Drug Research 1977;27:1350‐4. CENTRAL

NCT00351104 {published data only}

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. clinicaltrials.gov/ct2/show/NCT00351104 (accessed 3 February 2015)2008. [CTG: NCT00351104]CENTRAL

NCT00352625 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00352625 (accessed 3 February 2015)2008. [CTG: NCT00352625]CENTRAL

NCT00426985 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00426985 (accessed 3 February 2015)2008. [CTG: NCT00426985]CENTRAL

NCT00640705 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00640705 (accessed 3 February 2015)2008. [CTG: NCT00640705]CENTRAL

NCT00640939 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00640939 (accessed 3 February 2015)2008. [CTG: NCT00640939]CENTRAL

NCT00680472 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00680472 (accessed 3 February 2015)2015. [CTG: NCT00680472]CENTRAL

NCT00680784 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00680784 (accessed 3 February 2015)2015. [CTG: NCT00680784]CENTRAL

NCT00765700 {unpublished data only}

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. CENTRAL
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. clinicaltrials.gov/ct2/show/NCT00765700 (accessed 3 February 2015)2013. [CTG: NCT00765700]CENTRAL

NCT00869063 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00869063 (accessed 3 February 2015)2010. [CTG: NCT00869063]CENTRAL

NCT00869180 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00869180 (accessed 3 February 2015)2010. [CTG: NCT00869180]CENTRAL

NCT00931866 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT00931866 (accessed 3 February 2015)2010. [CTG: NCT00931866]CENTRAL

NCT01874626 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT01874626 (accessed 3 February 2015)2014. [CTG: NCT01874626]CENTRAL

NCT01957215 {unpublished data only}

GlaxoSmithKline (Sponsors). A clinical study to assess the efficacy of pain relief of topical indomethacin patch over placebo in ankle sprain patients. clinicaltrials.gov/ct2/show/NCT01957215 (accessed 3 February 2015)2015. [CTG: NCT01957215]CENTRAL

NCT02324270 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT02324270 (accessed 3 February 2015)2014. [CTG: NCT02324270]CENTRAL

Sarzi‐Puttini 2014 {published data only}

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. CENTRAL

NCT01945034 {unpublished data only}

Pfizer (Sponsors). Placebo‐controlled, double‐blind evaluation of the efficacy and safety of ibuprofen 5% topical gel for the treatment of ankle sprain. clinicaltrials.gov/ct2/show/NCT01945034 (accessed 3 February 2015)2014. [CTG: NCT01945034]CENTRAL

NCT02100670 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT02100670 (accessed 3 February 2015)2014. [ClinicalTirals.gov: NCT02100670]CENTRAL

NCT02290821 {unpublished data only}

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. clinicaltrials.gov/ct2/show/NCT02290821 (accessed 3 February 2015)2015. [CTG: NCT02290821]CENTRAL

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References to other published versions of this review

Massey 2010

Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for acute pain in adults. Cochrane Database of Systematic Reviews 2010, Issue 6. [DOI: 10.1002/14651858.CD007402.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Airaksinen 1993

Methods

R, DB, PC, parallel groups

Gel applied to the painful area twice daily for 7 days

Assessment at baseline, 3, 7 days

Participants

Minor soft tissue injuries (< 7 days)

N = 56

M 45, F 11

Age not reported

Mean baseline pain at rest 25‐26 mm

Interventions

Ketoprofen gel, 2 x 5 g (125 mg) daily, n = 29

Placebo gel, n = 27

Rescue medication paracetamol 500 mg

No other treatment allowed

Outcomes

PGE: 5‐point scale but reported as "improved" or "same or worse" (responder = "improved")

Improvement in pain with movement: 100 mm VAS, reported as group mean

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No mention of early withdrawals or method of imputation

Size

High risk

< 50 participants per treatment group

Aoki 1984

Methods

R, DB, PC, AC, parallel groups

Gel applied to affected area 3 or 4 times daily, with no occlusion for 7 days

Assessment at baseline, 3, 7 days

Participants

Acute orthopaedic trauma (contusion, distortion, fracture, < 7 days)

N = 252 (203 analysed for efficacy)

M 98, F 105

Age range 8 to 86 years, 13% younger than 20 years

Baseline pain mild in 35%

Exclusions: 23 protocol violations, 26 reasons "not related" to drug. Equally distributed between groups

Interventions

Piroxicam gel 0.5%, 1 g 3 to 4 x daily, n = 84

Indomethacin gel 1%, 1 g 3 to 4 x daily, n = 84

Placebo gel, n = 84

No other medication or initiation of physical therapy allowed

Outcomes

PGE: 5‐point scale (responder = "better" and "much better")

Adverse events

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

"key code sealed until end of study"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Gels in "identical tubes"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

> 10% withdrawals "unrelated to treatment" and for "protocol violations". No further details, but no significant differences between groups

Size

Unclear risk

50 to 200 participants per treatment group

Auclair 1989

Methods

R, DB, PC, parallel groups

Gel massaged into skin over affected heel 3 times daily after cleaning with soap and water for up to 21 days

Assessment at baseline, 7, 21 days

Participants

Acute Achilles heel tendinitis (not associated with continuous pain at rest or > 1 month history)

N = 243 (227 analysed for efficacy)

M/F not reported

Mean age 29 years

Baseline pain: ˜ 10% had < 26 mm on palpation of tendon, ˜ 30% had mild or no pain on dorsiflexion of foot

Exclusions: failure to meet inclusion criteria, major protocol violations, failure to take study medication for full duration

Interventions

Niflumic acid gel 2.5%, 3 x 5 g daily, n = 117

Placebo gel, n = 110

No other analgesics and anti‐inflammatories, physiotherapy or supportive measures allowed

Outcomes

PGE: 5‐point scale (responder = "good" or "very good")

Pain improved or disappeared on dorsiflexion

Adverse events

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

10% excluded for "failing to meet entry criteria and protocol violations". No further details

Size

Unclear risk

50 to 200 participants per treatment group

Billigmann 1996

Methods

R, DB, PC, parallel groups

Gel applied 3 times daily with rubbing

Assessed at baseline, 3, 5, 7 days

Participants

Distortion of ankle joint

N = 160

M and F

Age 18+ years

Baseline pain not reported

Interventions

Ibuprofen microgel 5%, 3 x 10 cm (= 200 mg) daily, n = 80

Placebo gel, n = 80

Outcomes

Pain with movement: VAS (responder = decreased by 20%)

Complete remission

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient data to assess

Size

Unclear risk

50 to 200 participants per treatment group

Campbell 1994

Methods

R, DB, PC, parallel groups

Cream applied 4 times daily for 7 days (up to 14 days optional)

Self assessed using daily diary for 7 days, and up to 14 days

Participants

Acute ankle sprain (< 24 hours, no fracture)

N = 100 (51 analysed)

M 33, F 18

Mean age 29 years

Baseline pain at rest > 35 mm, on walking 80 mm

Exclusions: did not return diaries, protocol exclusions (25 ibuprofen, 24 placebo)

Interventions

Ibuprofen cream 5% (Proflex), 4 x 4" (10 cm) daily, n = 26

Placebo cream, n = 25

Advised to use rest and regular icing for 48 hours, then walking and exercise

Rescue medication: paracetamol

Outcomes

Improvement in walking ability: 4‐point scale (responder = "improvement")

Pain on walking: 100 mm VAS (mean data)

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

Randomisation carried out by sponsor. Tubes dispensed by hospital pharmacy who held the codes.

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical cream"

Incomplete outcome data (attrition bias)
All outcomes

High risk

> 40% lost to follow‐up. Approximately equal between groups

Size

High risk

< 50 participants per treatment arm as analysed

Chatterjee 1977

Methods

R, DB, PC, parallel groups

Cream applied to site of injury 3 times daily for 6 days

Assessment at baseline, 2, 6 days

Participants

Soft tissue injuries (recent)

N = 51

M/F not reported

Age not reported

Baseline pain on passive movement moderate or severe in all but 3 participants

Interventions

Benzydamine HCl cream 3%, 3 x daily, n = 25

Placebo cream, n = 25

(5 active, 6 placebo participants also received ultrasound)

No other topical agent allowed

Outcomes

Pain on passive movement: 4‐point scale (responder = "absent" or "slight")

Tenderness with pressure: 4‐point scale (responder = "absent" or "slight")

Adverse events

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"predetermined randomised schedule"

Allocation concealment (selection bias)

Low risk

Sealed copy of schedule held by investigator and duplicate copy kept by clinical trial co‐ordinator. Looked at only in event of adverse reaction (not necessary)

Blinding (performance bias and detection bias)
All outcomes

Low risk

"indistinguishable .... in appearance and consistency"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2% lost to follow‐up, no withdrawals due to adverse events. Responder analysis

Size

Unclear risk

< 50 participants per treatment arm

Costantino 2011

Methods

R, DB, PC, multicentre, parallel group

Plaster applied daily for 7 days
PI assessment daily, overall treatment efficacy and tolerability assessed at 3 and 7 days

Participants

Grade I or II ankle sprain (< 48 hours) with lateral external ligament involvement
PI on movement ≥ 50/100, oedema ≥ 20 mm difference between ankles

N = 430

M 249, F 175 (for analysis)

Mean age 35 years

Baseline PI on movement 72/100 (SD 12)

Interventions

DHEP/hep, n = 142
DHEP, n = 146
Placebo, n = 142

Rescue medication: paracetamol to maximum 3 g daily
No other treatments allowed

Outcomes

Mean change in PI on movement from baseline to 3 days

Mean reduction in oedema at 3 days

Tolerability at 3 days

Rescue medication

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Unclear risk

"sealed envelopes"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Shape, colour, size, and application method identical for all plasters

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Very few withdrawals, but used LOCF

Size

Unclear risk

50 to 200 participants per treatment arm

Coudreuse 2010

Methods

R, DB, PC, multicentre, parallel group

Plaster applied daily for 7 days

PI assessed twice daily over 3 days, then day 7. Overall treatment efficacy and tolerability assessed on days 3, 7

Participants

Ankle sprain (< 48 hours) with lateral external ligament involvement
PI on movement ≥ 50/100, oedema ≥ 20 mm difference between ankles

N = 240 (233 for analysis)

M 148, F 86, 6 unknown

Interventions

DHEP/hep, n = 120
Placebo, n = 120

Rescue medication: paracetamol to maximum 4 g daily
No other treatments allowed

Outcomes

Global efficacy at 7 days: 4‐point scale (responder = "excellent" or "good")

Mean change in PI on movement at 6 hours and 7 days

Mean change in oedema at 3 and 7 days

Tolerability

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Unclear risk

"sealed envelopes"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Appearance and odour identical for all plasters

Incomplete outcome data (attrition bias)
All outcomes

Low risk

ITT analysis, < 5% excluded for missing data, equal between groups

Size

Unclear risk

50 to 200 participants per treatment arm

Curioni 1985

Methods

R, DB, PC, AC, parallel groups

Gel rubbed into affected area until absorbed, twice daily for 10 days

Assessed at baseline, and daily to 10 days

Participants

Acute soft tissue injuries

N = 60

M 33, F 27

Median age 33 years

Baseline pain not given

Interventions

Ibuproxam gel 10%, n = 20

Ketoprofen gel, n = 20

Etofenamate gel, n = 20

Outcomes

PGE: 4‐point scale ("good" or "excellent")

Resolution of symptoms

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Medication supplied in identical tubes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Diebshlag 1990

Methods

R, DB, PC, AC, parallel groups

Gel applied 3 times daily, without occlusion, for 14 days

Assessment at baseline, 2, 3, 4, 8, 15 days

Participants

Ankle sprain (< 24 hours)

N = 37

M 24, F 13

Mean age 28 years

Baseline pain slight to moderate

Interventions

Ketorolac gel 2%, 3 x 3 g daily, n = 13

Etofenamate gel 5%, 3 x 3 g daily, n = 12

Placebo gel, n = 12

Rescue medication: paracetamol

No other analgesic or anti‐inflammatory medication, ice packs, or physiotherapy allowed

Outcomes

Reduction in PI: 100 mm VAS and 4‐point scale (responder = "improved")

Adverse events

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

"Medication assignment ... supplied in a sealed envelope." Opened only if serious participant event necessitation treatment disclosure occurred (not necessary)

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical appearance"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Dreiser 1988

Methods

R, DB, PC, parallel groups

Cream applied 3 times daily

Assessment at baseline, 7 days

Participants

Acute tendinitis (< 1 month)

N = 64

M 35, F 25

Mean age 36 years

Baseline spontaneous pain ≥ 60 mm

Interventions

Ibuprofen cream 5%, 3 x 4 cm daily, n = 32 (3 x 10 cm for large joints)

Placebo cream, n = 32

No other topical, systemic, or physical treatment allowed

Outcomes

PGE: scale not reported (responder = "improvement" or "complete relief")

Improvement in pain: VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Oxford Validity Score: 10/16

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing participants added back using BOCF

Size

High risk

< 50 participants per treatment arm

Dreiser 1989

Methods

R, DB, PC, parallel groups

Gel applied twice daily to affected area with light massage, then covered with standard compress

Assessed at baseline, 3, 7 days

Participants

Uncomplicated, recent ankle sprain

N = 60

M 36, F 24

Mean age 33 years

Mean baseline pain 54 mm

Interventions

Ketoprofen gel 2.5%, 2 x 5 cm daily, n = 30

Placebo gel, n = 30

No concomitant therapy other than simple oral analgesia allowed

Outcomes

PGE: 3‐point scale (responder = "better")

Improvement in pain: VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"drawing lots"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Treatments "identical in every way except that placebo did not contain active principle"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participant per treatment arm

Dreiser 1990

Methods

R, DB, PC, parallel groups

Gel lightly massaged into skin over affected area 3 times daily, then covered with standard compress

Assessed at baseline, 3, 7 days

Participants

Uncomplicated, ankle sprain (< 4 days)

N = 60 (59 analysed)

M 29, F 29 (not stated for 1 participant)

Mean age 33 years

Baseline pain ≥ moderately severe

Exclusions: 1 participant had only moderate pain at baseline

Interventions

Niflumic acid gel 2.5%, 3 x 5 g daily, n = 30

Placebo gel, n = 30

Concomitant treatment with systemic NSAIDs, local therapies, or physiotherapy were not allowed

Outcomes

PGE: 4‐point scale (responder = "cured" or "improved")

Improvement in pain: VAS (mean data)

Adverse events

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Dreiser 1994

Methods

R, DB, PC, parallel groups

Patch applied twice daily

Assessed at baseline, 3, 7 days

Participants

Traumatic ankle sprain (< 2 days)

N = 131

M 84, F 47

Mean age 34 years

Baseline pain ≥ 50 mm

Interventions

Flurbiprofen patch, 2 x 40 mg daily, n = 65

Placebo patch, n = 66

Rescue medication: paracetamol. Ice or light restraint allowed

Exclusions: 1 from flurbiprofen group for protocol violation

Outcomes

PGE: 4‐point scale (responder = "good" or "very good")

Improvement in pain: VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo patch was "non‐medicated (but otherwise identical)"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Fioravanti 1999

Methods

R, DB, AC, parallel groups

Gel lightly massaged into skin 3 times daily, and kept dry for 6 to 8 hours

Assessed at baseline, 3, 10 days

Participants

Peri and extra‐articular inflammatory diseases

N = 100

M 32, F 68

Mean age 49 years

Baseline spontaneous pain ≥ 40 mm

Interventions

DHEP lecithin gel, 3 x 5 g (= 65 mg) daily, n = 50

DHEP gel, 3 x 5 g (= 65 mg) daily, n = 50

Outcomes

PGE: 4‐point scale (responder = "good" or "excellent")

Pain on movement: mean

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

Unclear risk

50 participants per treatment arm

Fujimaki 1985

Methods

R, DB, PC, AC, parallel groups

Gel applied to affected area 3 or 4 times daily with no occlusion for up to 14 days

Assessed at baseline, 7, 14 days

Participants

Muscle pain or inflammation in neck, shoulder, back, chest and upper and lower extremities, or a combination

N = 271 (247 analysed)

M 97, F 149

Age < 20 to 89 years

Baseline pain mostly mild to moderate

Exclusions: 24 due to protocol violations, loss to follow‐up

Interventions

Piroxicam gel 0.5% 1 g, 3 to 4 x daily, n = 92

Indomethacin gel 1% 1 g, 3 to 4 x daily, n = 90

Placebo gel, n = 89

No concomitant oral or topical analgesic or anti‐inflammatory medication allowed. No physical therapy initiated after start of study

Outcomes

PGE: 5‐point scale (responder = "better" or "much better")

Physician rated improvement: 5‐point scale (responder = "marked improvement")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total =4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

Cartons numbered randomly and numbers held in a key code until study completion

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical tubes" packed in numbered carton. Gel bases slightly different in appearance, so dispensing physician did not have access to them

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

˜ 8% excluded from analysis for unknown reasons or lost to or inadequate follow‐up. Approximately equal between groups

Size

Unclear risk

50 to 200 participants per treatment arm

Gallacchi 1990

Methods

R, DB, AC, parallel groups

Gel applied to affected area 4 times daily, with light massage, for 14 days

Assessment at baseline, 7, 14 days

Participants

Painful inflammatory conditions

N = 50

M 20, F 30

Mean age 50 years

Baseline pain ≥ moderate severity

Interventions

Diclofenac gel 1%, 2 g 4 x daily, n = 25 (Flector)

Diclofenac sodium 1%, 2 g 4 x daily, n = 25 (Voltaren Emugel)

No other medication that could interfere with test drugs allowed

Outcomes

PGE: 5‐point scale (responder = "good" or "excellent")

Improvement in pain on pressure: 4‐point scale (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

González de Vega 2013

Methods

R, DB (for gels), SB (for ointment), AC, multicentre, parallel groups

2 g (˜ 6 cm of gel) applied over injured area x 3 daily for 14 days

Assessments at 0, 4, 7, 14 days of treatment, and day 42 follow‐up

Participants

Grade I or II ankle sprain (< 24 hours) with lateral external ligament involvement, PI on weight bearing ≥ 30/100

N = 449

M = 308, F = 112 (for analysis)

Mean age 28 years

Interventions

Traumeel gel, 3 x 2 g daily, n = 140

Traumeel ointment, n = 143 (not analysed in this review)
Diclofenac gel 1%, 3 x 2 g daily, n = 137

Rescue medication: paracetamol to maximum 2 g daily

Outcomes

Pain‐free on day 7

Global efficacy: 5‐point scale (responder = "good" and "very good") on day 14

Normal function on day 14: yes or no (responder = "yes")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2 (gels), W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Low risk

Central allocation, kits assigned in order received, and used envelopes (no further details)

Blinding (performance bias and detection bias)
All outcomes

Low risk

For gel comparison: "identical containers"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Used LOCF. Most withdrawals due to early recovery (within 14 days), approximately equal between groups

Size

Unclear risk

50 to 200 participants per treatment arm

Governali 1995

Methods

R, DB, AC, parallel groups

Gel or cream applied 3 times daily for up to 14 days

Assessed at baseline, 7, 14 days

Participants

Soft tissue injuries + 2 fractures

N = 30

M = 21, F = 9

Median age 38 years

Mean baseline pain on movement moderate to severe (2.8, scale 0 to 4)

Interventions

Ketoprofen gel 5%, 3 x 2 to 3 g daily, n = 15

Ketoprofen cream 1%, 3 x 2 to 3 g daily, n = 15

Outcomes

PGE: 5‐point scale (responder = "good" and "excellent")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total =3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Treatments were given in identical tubes and measurements made by blinded observers, but one was a cream and the other a gel

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Gualdi 1987

Methods

R, DB, AC, parallel groups

Gel applied twice daily for 10 days

Assessed at baseline, 4, 7, 10 days

Participants

Soft tissue injuries

N = 60

M = 37, F = 23

Mean age 32 years (range 13 to 78)

Mean baseline pain on movement moderate to severe (2.2, scale 0 to 3)

Interventions

Flunoxaprofen gel, 2 x 3 to 5 cm daily, n = 30

Ketoprofen gel, 2 x 3 to 5 cm daily, n = 30

Outcomes

Improvement in pain on pressure (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient data

Size

High risk

< 50 participants per treatment arm

Haig 1986

Methods

R, DB, PC, parallel groups

Cream applied lightly to affected area 6 times daily for 6 days

Assessed at baseline, 2, 4, 6 days

Participants

Soft tissue injuries (< 24 hours)

N = 43

M/F not reported

Age not reported

Baseline pain not reported

Interventions

Benzydamine cream 3%, 6 x daily, n = 21

Placebo cream, n = 22

Outcomes

Pain on movement: 4‐point scale (responder = "improved")

Adverse events

Notes

Oxford Quality Score: R1, DB2, W0. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding (performance bias and detection bias)
All outcomes

Low risk

"matching placebo"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants apparently included in analysis

Size

High risk

< 50 participants per treatment arm

Hoffmann 2012

Methods

R, DB, PC, multicentre, parallel group

Plaster applied x 1 daily (minimum of 20 consecutive hours of application per day) for 14 days

PI assessed daily, overall efficacy assessed at 7 and 14 days

Participants

Unilateral, mild to moderate muscle contusion of upper or lower limb (< 72 hours), PI ≥ 50/100, superficial haematoma ≤ 10 x 14 cm at injured site

N = 354

M 126, F 228

Mean age 39 years

Interventions

DHEP/hep plaster, x 1 daily, n = 121
DHEP plaster, x 1 daily, n = 115
Placebo plaster, n = 118

Rescue medication: paracetamol 500 mg (no limit reported)

Outcomes

PGE: 5‐point scale (responder = excellent or good) at 14 days

Mean reduction in PI at 3 and 8 days

Rescue medication

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not reported

Allocation concealment (selection bias)

Unclear risk

Method not reported: "Medication packed and labelled in order to render all participants and personnel fully blinded to treatment administered"

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Indistinguishable regarding appearance, shape, colour, size and odour"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No responder analysis reported, and imputation method not mentioned

Size

Unclear risk

50 to 200 participants per treatment arm

Hofman 2000

Methods

R, DB, AC, parallel groups

Gel applied to affected region 4 times daily, with gentle massage

Assessed at baseline, 8 days in clinic and daily diary

Participants

Soft tissue articular pain (≤ 15 days)

N = 142

M 19, F 123

Mean age 57 years

Mean baseline PI moderate to severe

Interventions

Diclofenac sodium gel 1%, 4 x 2 cm daily, n = 69

Lysine clonixinate gel 5%, 4 x 2 cm daily, n = 73

(2 cm = 22.5 mg)

No other analgesic, local treatment (including immobilisation, bandaging), or acupuncture

Rescue mediation allowed after 2 applications, if needed

Outcomes

PGE: 3‐point scale ("good")

PI: participant diary (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Diclofenac gel repackaged to maintain DB with lysine clonixinate gel. Minor differences between gels only apparent when directly compared

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Hosie 1993

Methods

R, DB, AC, parallel groups

Foam (approximately the size of a golf ball) applied, and 1 tablet taken, 3 times daily for 7 days and up to 14 days

Assessed at baseline, 7, 14 (if necessary) days

Participants

Acute lower back injury (< 1 month)

N = 287 (261 analysed for efficacy)

M 151, F 136

Mean age 37 years (range 18 to 63)

Most participants had moderate to severe pain on movement, one had none

Exclusions: 25 lost to follow up, one assessed at 14 days, but not 7 days

Interventions

Felbinac foam 3%, 3 x 2 g daily + placebo tablets, 3 x 1 daily, n = 140 (127 analysed for efficacy)

Ibuprofen tablets, 3 x 400 mg daily + placebo foam, 3 x 2 g daily, n = 147 (134 analysed for efficacy, but one had no pain at baseline)

No other oral, injectable, or topical analgesic or anti‐inflammatory medication. Ongoing physiotherapy to continue without change

Outcomes

Pain on movement: 5‐point scale (responder = "none" or "mild")

Spontaneous pain: 5‐point scale (responder = "none" or "mild")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"double dummy"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Imputation method not mentioned

Size

Unclear risk

50 to 200 participants per treatment arm

Jenoure 1997

Methods

R, DB, PC, parallel groups

Plaster applied to skin over affected area twice daily, and kept in place with an elastic bandage

Assessed at baseline, 7, 14 days, and after further 14 days without treatment

Participants

Humero‐radial epicondyl pain (tendinopathic) ‐ nearly all tennis elbow

N = 85

M 54, F 31

Mean age 45 years

Baseline pain: "mild" in ˜ 10% of placebo group and 29% of active group

Interventions

DHEP plaster (Tissugel), x 2 daily, n = 44

Placebo plaster x 2 daily, n = 41

Outcomes

Pain on pressure: 5‐point scale (responder = "none" or "mild")

Spontaneous pain: 5‐point scale (responder = "no pain")

Adverse events

Notes

Oxford Quality Score: R1, DB2, W0. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical characteristics"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No useable data

Size

High risk

< 50 participants per treatment arm

Joussellin 2003

Methods

R, DB, PC, parallel groups

Plaster applied to skin over affected area once daily

Assessed at baseline, 1, 2, 3, 7 days

Participants

Ankle sprain (< 48 hours)

N = 134

M 72, F 62

Age range 18 to 65 years

Baseline spontaneous pain ≥ 50 mm

Interventions

DHEP plaster (Flector Tissugel 1%), x 1 daily, n = 68

Placebo plaster, x 1 daily, n = 66

Rescue medication: paracetamol

Outcomes

PGE: 4‐point scale (responder = "excellent")

Pain on movement: VAS (mean)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Identical in size, appearance and used same formula as active patch, without active ingredient"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in responder analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Julien 1989

Methods

R, DB, PC, parallel groups

Gel applied to affected area twice daily, with light massage

Assessed at baseline, 3, 7 days in clinic and daily diary

Participants

Tendinitis

N = 60

M 29, F 31

Mean age 41 years

Baseline pain > 50 mm

Interventions

Ketoprofen gel 2.5%, 2 x 5 cm (= 50 mg) daily, n = 30

Placebo gel, 2 x 5 cm daily, n = 30

No concomitant therapy other than simple analgesia

Outcomes

PGE: 4‐point scale (responder = "improved" or "recovered")

Pain on movement: 4‐point scale (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB1, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random numbers table

Allocation concealment (selection bias)

Unclear risk

Randomisation code supplied by Menarini laboratories, remote from allocation

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in responder analysis

Size

High risk

< 50 participants per treatment arm

Klainguti 2010

Methods

R, DB, PC, multicentre, parallel group

Plaster applied x 1 daily (minimum 20 consecutive hours of application daily) for 10 days

PI assessed daily, Overall treatment efficacy and tolerability assessed at days 3 and 7

Participants

Unilateral, mild to moderate muscle contusion or strain of upper or lower limb (< 72 hours), superficial haematoma ≤ 140 cm2, PI ≥ 40/100

N = 185
M 90, F 95

Mean age 39 years

Interventions

DHEP/hep plaster, x 1 daily, n = 65
DHEP plaster, x 1 daily, n = 61
Placebo plaster, x 1 daily, n = 59

Outcomes

Overall treatment efficacy at 3 days: 5‐point scale (responder = "good" or "excellent")

Resolution of haematoma at 10 days: yes or no

Rescue medication

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Identical in size, appearance and odour"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Withdrawals < 5%. All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Kockelbergh 1985

Methods

R, DB, PC, parallel groups

Gel applied twice daily

Assessed at baseline, 3, 7 days

Participants

Acute soft tissue trauma (< 24 hours)

N = 74

M 60, F 14

Mean age 27 years

Baseline pain > 65 mm

Interventions

Ketoprofen gel 2.5%, 2 x 5 cm (= 15 mg) daily, n = 38

Placebo gel, 2 x 5 cm daily, n = 36

No concomitant treatment

Rescue medication: glafenine

Outcomes

PGE: 3‐point scale (responder = "good")

Spontaneous pain: 100 mm VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in responder analysis

Size

High risk

< 50 participants per treatment arm

Kuehl 2011

Methods

R, DB, PC, multicentre, parallel groups

Plaster applied x 2 daily for 14 days or until resolution

PI assessed daily. Overall treatment efficacy assessed at 14 days

Participants

Mild or moderate sprain, strain or contusion (< 7 days), PI ≥ 5/10

N = 418

M 206, F 212
Mean age 39 years

Interventions

DHEP patch, x 2 daily, n = 207
Placebo patch, x 2 daily, n = 211

Rescue medication: no analgesic allowed (or ice/wrapping): use = discontinuation

Outcomes

Resolution of injury (VAS ≤ 2/10)

Overall tolerability: 5‐point scale (responder = "good" or "excellent")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical in appearance with same content except diclofenac"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Used LOCF, high withdrawal rate (43%). Did not report all efficacy outcomes measured

Size

Low risk

> 200 participants per treatment arm

Li 2013

Methods

R, DB, PC, multicentre, parallel groups

Plaster applied x 2 daily for 7 days

PI assessed daily, overall treatment efficacy and tolerability assessed at 7 days

Participants

Mild or moderate ankle or knee sprain, muscle strain or contusion (< 72 hours), PI ≥ 50/100
N = 384

M 144, F 240
Mean age 42 years

Interventions

DHEP plaster, x 2 daily, n = 192
Placebo plaster, x 2 daily, n = 192

Rescue medication: paracetamol to maximum 2 g daily

Outcomes

≥ 50% reduction in PI at 7 days

Overall treatment efficacy: 5‐point scale (responder = "good" or "excellent")

Overall tolerability: 5‐point scale (responder = "good" or "excellent")

Rescue medication

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Unclear risk

Method not fully described: "sealed envelopes", "concealed from investigators and participants"

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical in texture, size, color and odor"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Withdrawals 2%. Methods states LOCF, but appears to describe BOCF for withdrawals

Size

Unclear risk

50 to 200 participants per treatment arm

Linde 1985

Methods

R, DB, PC, parallel groups

Cream applied x 3 daily for 5 days, with elastic support for the first 3 days

Assessed at baseline 4, 8 days

Participants

Sprained ankle (< 24 hours)

N = 100

M 58, F 42

Mean age 28 years

Baseline pain: all participants had "walking pain"

Interventions

Benzydamine 3% cream, x 3 daily, n = 50

Placebo gel, x 3 daily, n = 50

Outcomes

Pain on movement: responder = "free of walking pain"

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1 Total = 3/5

*Paper describes a benzydamine cream and a placebo gel

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described. Paper describes a benzydamine cream and a placebo gel

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in responder analysis

Size

Unclear risk

50 participants per treatment arm

Machen 2002

Methods

R, DB, PC, parallel groups

Gel gently ("minimal rub", not vigorously) massaged into skin over affected site until absorbed 3 times daily until symptoms disappeared or for maximum of 7 days

Assessment at baseline and once daily using diary cards to 7 days

Participants

Soft tissue injury (< 2 weeks and untreated)

N = 85 (81 analysed)

M 42, F 39

Mean age 41 years

Baseline pain > 50 mm

4 placebo participants lost to follow‐up

Interventions

Ibuprofen gel 5%, x 3 daily, n = 40

Placebo gel, x 3 daily, n = 41

Initiation of other medication or physiotherapy not allowed during study

Outcomes

PGE: 5‐point scale (responder = "marked improvement" or "complete clearance")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Gels had similar physical characteristics and were supplied in identical tubes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

< 5% missing participants. Remaining participants included in responder analysis

Size

High risk

< 50 participants per treatment arm

Mahler 2003

Methods

R, DB, AC, parallel groups

Gel applied with gentle massage to affected area 3 times daily, without occlusion, for 10 days

Assessed at baseline, 3, 10 days in clinic and daily patient diary

Participants

First‐degree ankle or knee sprains, first‐degree muscle strains and mild‐to‐moderate contusions

n = 100

M 69, F 31

Mean age 32 years

Mean baseline pain with activity ≥ 65 mm

Interventions

DHEP lethicin gel, 3 x 5 g (= 65 mg) daily, n = 52

DHEP gel, 3 x 5 g (= 65 mg) daily, n = 48

All participants treated with ice at site of inflammation for first 48 hours, but no immobilisation allowed

Rescue medication: paracetamol 500 mg if strictly necessary

Outcomes

PGE: 4‐point scale (responder = "good" or "excellent")

Pain on movement: 100‐mm VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Computer‐generated randomization list"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Pharmaceutically inert colouring agents added to reference formulation so that gels were indistinguishable

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in responder analysis

Size

High risk

< 50 participants in each treatment arm

Mazières 2005a

Methods

R, DB, PC, parallel groups

New patch applied directly to skin over painful area each morning

Assessed at baseline, 3, 7, 14 days

Participants

Symptomatic tendonitis in upper or lower limbs, not requiring surgery (≤ 15 days)

N = 172

M 72, F 100

Mean age 46 years

Baseline pain with activity ≥ 40 mm

Interventions

Ketoprofen patch 100 mg, x 1 daily, n = 87

Placebo patch, x 1 daily, n = 85

No analgesic or steroid by any route or other topical medication or physical therapy allowed

Rescue medication permitted, but not within 12 hours of assessment

Outcomes

PGE: 4‐point scale (responder = "good" or "excellent")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer generated global randomization code"

Allocation concealment (selection bias)

Low risk

"The randomization list and code envelopes were prepared by the company appointed for clinical supplies packaging. The random code was disclosed only after study completion and database closure"

Blinding (performance bias and detection bias)
All outcomes

Low risk

"the same indistinguishable patch with no ingredient"

Incomplete outcome data (attrition bias)
All outcomes

High risk

LOCF, withdrawals 12%. All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Mazières 2005b

Methods

R, DB, PC, parallel groups

New patch applied directly to skin over painful area each morning

Assessed at baseline, 3, 7, 14 days

Participants

Painful, benign ankle sprain (≤ 48 hours)

N = 163

M 83, F 80

Mean age 37 years

Baseline spontaneous pain ≥ 50 mm

Interventions

Ketoprofen patch 100 mg, x 1 daily, n = 81

Placebo patch, x 1 daily, n = 82

No analgesic or steroid by any route or other topical medication or physical therapy allowed

Rescue medication permitted, but not within 12 hours of assessment

Outcomes

PGE: 4‐point scale (responder = "good" or "excellent")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer‐generated global randomization code"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

The same transdermal patch with no active ingredient

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

LOCF, withdrawals 5% to 6%. All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

McLatchie 1989

Methods

R, DB, PC, parallel groups

Gel applied to injured site 3 times daily for 7 days

Assessment at baseline 4, 7 days at clinic, daily patient diary

Participants

Acute soft tissue injury (< 48 hours)

N = 231

M 143, F 88

Mean age 33 years

Baseline pain moderate to severe

Interventions

Felbinac gel 3%, 3 x 3 cm daily, n = 118

Placebo gel, 3 x 3 cm daily, n = 113

Rescue medication: paracetamol

Outcomes

Patient diary: mean change

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"tubes identical in all aspects"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No usable efficacy data

Size

Unclear risk

50 to 200 participants per treatment arm

Morris 1991

Methods

R, DB, PC, parallel groups

Gel applied to site of injury 3 times daily for 7 days

Assessed at baseline, 7 days at clinic, and daily patient diary

Participants

Acute soft tissue injury (< 3 days)

N = 100 (84 analysed for efficacy)

M 70, F 14

Mean age 25 years

Baseline pain moderate to severe

Exclusions: 1 participant in placebo group lost to follow‐up, 15 protocol violations

Interventions

Felbinac gel 3%, 3 x 1 cm daily, n = 41

Placebo gel, n = 43

Ice, joint immobilisation, bandaging and compression allowed

No concomitant oral NSAID, occlusive dressing, physiotherapy, or liniments allowed

Rescue medication: paracetamol

Outcomes

PGE: 5‐point scale (responder = "good" and "very good")

Change in PI: patient diary 10 cm VAS (mean data)

Adverse events

Withdrawals and exclusions

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

"Randomisation was undertaken at the production facility and a sealed copy of the list supplied to the investigator for reference, only in defined circumstances"

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical tubes and outer boxes", "placebo was a similarly constituted gel"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All relevant participants included in analysis

Size

High risk

< 50 participants per treatment arm

NCT01255423

Methods

R, DB, PC, parallel group study

Gel applied 4 x daily

Participants

Acute lateral ankle sprain, Grade I to II, ≤ 12 hours
N = 206

Mean (± SD) age 31 years (± 13)
M 87, F 119
Baseline PI not reported

Interventions

Diclofenac sodium gel 1% x 4 daily, n = 104
Placebo gel, n = 102

Outcomes

Mean PI on movement

Adverse events

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method of blinding not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for

Size

Unclear risk

50 to 200 participants per treatment arm

NCT01272934

Methods

R, DB, PC, parallel group study

Gel applied 4 x daily

Participants

Acute lateral ankle sprain, Grade I to II, ≤ 12 hours
N = 205

M 101, F 104
Mean (± SD) age 32 years (± 11)

Baseline PI not reported

Interventions

Diclofenac sodium gel 1%, x 4 daily, n = 102
Placebo gel, x 4 daily, n = 103

Outcomes

Mean PI on movement

Adverse events

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method of blinding not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for

Size

Unclear risk

50 to 200 participants per treatment arm

NCT01272947

Methods

R, DB, PC parallel groups

Gel applied 4 x daily

Participants

Acute blunt soft tissue injuries/contusions of the limbs, < 3 hours
N = 204

M 101, F 103
Mean (± SD) age 30 years (± 11)

Baseline PI not reported

Interventions

Diclofenac sodium gel 1%, x 4 daily, n = 104
Placebo gel, x 4 daily, n = 100

Outcomes

Mean PI on movement

Adverse events

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method of blinding not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for

Size

Unclear risk

50 to 200 participants per treatment arm

Noret 1987

Methods

R, DB, PC parallel groups

Gel applied twice daily for 7 days

Assessment at baseline, 3, 8 days

Participants

Minor sports injuries (< 24 hours)

N = 98 (93 analysed)

M 71, F 27

Mean age 29 years

Baseline pain > 60 mm

Interventions

Ketoprofen gel 2.5%, 2 x 5 cm daily (= 15 mg), n = 48

Placebo gel, n = 45

No other treatment given

Outcomes

PGE: 4‐point scale (responder = "good" and "excellent")

Spontaneous pain: 100 mm VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

"allocated according to a randomization list and a corresponding code in a sealed envelope"

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Parrini 1992

Methods

R, DB, PC, parallel groups

Foam (the size of a walnut, or a 1‐second spray) applied with massage 3 x daily for 7 days

Participants

Articular trauma, strains, distortions

N = 169

M 94, F 75

Mean age 37 years

Mean baseline pain on movement 3.1 (scale 1 to 4)

Interventions

Ketoprofen foam 15%, 3 x 2 g (= 600 mg) daily, n = 83

Placebo foam, 3 x 2 g, n = 86

Outcomes

Pain on movement: 4‐point scale (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB1, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"patients were randomised according to the method of random numbers" [translated]

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No usable efficacy data

Size

Unclear risk

50 to 200 participants per treatment arm

Picchio 1981

Methods

R, DB, AC, parallel groups

Cream applied with slight massage until completely absorbed, 3 times daily for up to 16 days

Assessed at baseline, 4, 8, 12, 16 days

Participants

Acute sports injuries

N = 40

M 24, F 16

Mean age 22 years (range 12 to 46)

Most participants had mild to moderate baseline pain (12 and 9 with slight pain on movement)

Interventions

Ibuprofen gel 10%, 3 x daily, n = 20

Ketoprofen gel 1%, 3 x daily, n = 20

Outcomes

Pain on movement (responder = "none")

Adverse events

Notes

Oxford Quality Score: R1, DB2, W0. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"tubes were identical in appearance"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Predel 2004

Methods

R, DB, PC, parallel groups

New patch applied to injured area twice daily for 7 days. Contact of patch with humidity or water to be avoided

Assessment at baseline 3, 7 days

Participants

Traumatic blunt soft tissue injuries (< 3 hours, no treatment)

N = 120

M 73, F 47

Mean age 32 years

Baseline pain > 60 mm

Interventions

Diclofenac sodium patch, 2 x daily (140 mg per patch), n = 60

Placebo patch, 2 x daily, n = 60

NSAIDs, analgesics, psychotropic agents, other topical preparations, and bandages not allowed

Outcomes

PGE: 4‐point scale (responder = "good" and "excellent")

Pain on movement: 10 cm VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer generated block randomisation list

Allocation concealment (selection bias)

Low risk

An independent statistician produced randomisation list, and an independent contract research organisation packaged medication according to list. Nobody else had access to the randomisation list until the database was closed

Blinding (performance bias and detection bias)
All outcomes

Low risk

"The placebo patch was visually indistinguishable from the active patch." To avoid unblinding due to different smell, any study nurse involved with medication was not involved in outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Withdrawals < 1%. All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Predel 2012

Methods

R, DB, PC, parallel groups
Treatment for 7 days
Assessed at baseline, 1, 3, 5 and 8 days

Participants

Grade I or II ankle sprain with lateral external ligament involvement, < 12 hours
PI on movement ≥ 50/100
N = 242

M 152, F 90
Mean age 32 years

Mean baseline pain on movement = 75/100

Interventions

Diclofenac gel (Voltaren Emulgel 2.32%), 2 x 5 cm + 1 x 5 cm placebo gel daily, n = 80
Diclofenac gel (Voltaren Emulgel 2.32%), 3 x 5 cm daily, n = 80
Placebo gel, 3 x 5 cm daily, n = 82

Rescue medication: paracetamol (to maximum 2 g daily)
No ice or bandages after randomisation

Outcomes

≥ 50% reduction in PI on movement at 5 days

PGE: 5‐point scale (responder = "good" or 'very good")

Patient satisfaction: 5‐point scale (responder = "good" or 'very good" or "excellent")

Rescue medication

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical in composition, appearance, texture and smell"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

LOCF, but withdrawals < 3% in all treatment arms

Size

Unclear risk

50 to 200 participants per treatment arm

Predel 2013a

Methods

R, DB, PC, parallel groups
Treatment for 14 days
Assessed at baseline, 3, 7, 10 and 14 days (± 1 day)

Participants

Uncomplicated, one‐sided ankle sprain with swelling ≥ 12 mm (2 to 18 hours)
PI on movement, tenderness, joint mobility (scale 0 to 3) summed as ≥ 5 and ≤ 7
N = 232

M 126, F 106
Mean age 29 years

Interventions

Diclofenac 4% spray gel, 3 x 4 to 5 sprays daily (96 to 120 mg diclofenac sodium), n = 118
Placebo spray gel, 3 x 4 to 5 sprays daily, n = 114

Rescue medication: paracetamol 500 mg (maximum 10 tablets per week)
No ice or bandaging allowed

Outcomes

None or slight PI on movement at 3 and 7 days

PGE: 4‐point scale (responder = "very good" at 14 days)

> 50% reduction in swelling at 10 days

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"placebo (vehicle only, no active ingredient)"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

LOCF for full or early cure. Withdrawals < 2%

Size

Unclear risk

50 to 200 participants per treatment arm

Predel 2013b

Methods

R, DB, PC, parallel groups
2 g gel applied with fingertips over affected area and massaged in for 1 minute. Treatment for 5 days
Assessed at baseline, 2, 3, 5 days

Participants

Uncomplicated neck pain originating from cervical joints and accompanying soft tissues (≥ 12 hours but < 3 months), PI ≥ 50/100
N = 72

M 33, F 39
Mean age 34 years

Interventions

Diclofenac gel (Voltaren Emulgel), 4 x 2 g daily, n = 36
Placebo gel, 4 x 2 g daily, n = 36

Rescue medication: paracetamol up to 2 g daily
No concomitant therapies allowed

Outcomes

≥ 50% decrease in PI on movement after 48 hours
PGE: 5‐point scale (responder = "good" or "excellent" at 5 days

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sponsor "produced randomisation list"

Allocation concealment (selection bias)

Low risk

Automated remote system

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical in packaging, labelling, schedule of administration, appearance and odour"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing data

Size

High risk

< 50 participants per treatment arm

Ramesh 1983

Methods

R, DB, PC, parallel groups

Cream applied to painful area and rubbed into skin over a large area for up to 10 days

Assessment at baseline, 3, 7, 10 days

Participants

Strains, sprains, contusions, compressions

N = 80

M 42, F 38

Age 11 to 81 years

Baseline pain: 5 ibuprofen, 2 placebo participants had no or slight pain

Interventions

Ibuprofen cream 5%, 3 to 4 x 5 to 10 cm daily, n = 40

Placebo cream, 3 to 4 x 5 to 10 cm daily, n = 40

Adjuvant therapy was not administered

Outcomes

Pain on movement: 4‐point scale (responder = "none" or "slight")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

Randomisation key in sealed envelope, available for emergencies, but opened only after completion

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical appearance and odour"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Rowbotham 2003

Methods

R, DB, PC, parallel groups

New patches applied to the affected painful area for 12 consecutive hours twice daily, for up to 14 days

Assessed at baseline, 14 days in clinic and daily patient diary

Participants

Minor sports injuries (sprains, sprains, contusions, < 72 hours)

N = 372

M 253, F 119

Mean age 33 years

Baseline pain at rest ≥ 5/10

Interventions

DHEP patch (Flector Tissuegel), 2 x daily (equivalent to diclofenac sodium 140 mg per patch), n = 191

Placebo patch, 2 x daily, n = 181

Outcomes

PGE: 5‐point scale (responder = "good" and "excellent")

Pain resolved: < moderate for 2 days

Spontaneous pain: 10 cm VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"Système identique" without diclofenac

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information about imputation. All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Russell 1991

Methods

R, DB, PC, parallel groups

Affected area washed with soap and water and dried, then gel applied and carefully rubbed into skin, 4 times daily for at least 7 days

Assessed at baseline, 4, 8, 15 (if necessary) days at clinic, and daily patient diary

Participants

Acute soft tissue injuries (recent, not recurrent)

N = 214 (200 analysed)

M 95, F 105

Mean age 40 years

Baseline pain > 65 mm

Interventions

Piroxicam gel 0.5%, 4 x 5 mg daily, n = 100

Placebo gel, n = 100

No other NSAIDs or analgesic drugs, including liniments containing salicylates, allowed. Ancillary therapy at the discretion of the investigator

Outcomes

PGE: 4‐point scale (responder = "good" and "excellent")

Spontaneous pain: mean reduction

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer generated randomization code"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical base formulation"

Incomplete outcome data (attrition bias)
All outcomes

High risk

High withdrawal rate (8% with piroxicam, 50% with placebo). No information about imputation

Size

Unclear risk

50 to 100 participants per treatment group

Saillant 1998

Methods

R, DB, PC, parallel groups
Treatment for 7 days
Assessed at baseline, 1, 2, 3, and 7 days

Participants

Ankle sprain (< 48 hours)
N = 140
M 72, F 62
Age 18 to 65 years
Baseline spontaneous pain ≥ 50 mm

Interventions

(1) DHEP plaster (Flector Tissugel 1%), 1 x daily, n = 70
(2) Placebo plaster, 1 x daily, n = 70

Rescue medication: paracetamol (to maximum 3 g daily)
Ice allowed

Outcomes

≥ 30% decrease in PI at 7 days

PGE: 4‐point scale (responder = "excellent")

No or low pain on passive stretch

Single foot leaning OK without pain

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical in size, appearance, and used same formula as active patch, without active ingredient

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Used LOCF for primary outcome. Withdrawals < 7% and equal between groups. All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Sanguinetti 1989

Methods

R, DB, PC, parallel groups

Gel applied 3 times daily for 7 consecutive days

Assessment at baseline, 7 days

Participants

Soft tissue trauma (< 48 hours)

N = 82

M = 47, F = 35

Mean age 34 years

Baseline pain moderate to severe

Interventions

Felbinac* gel 3%, 3 x daily, n = 42

Placebo gel, 3 x daily, n = 40

No other NSAID, steroid, other topical application allowed

Rescue medication: paracetamol

* felbinac is an active metabolite of the NSAID fenbufen

Outcomes

PGE: scale not reported (responder = "good" and "very good")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"indistinguishable in appearance, colour or odour"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Sinniger 1981

Methods

R, DB, PC, parallel groups

Cream applied 2 to 3 times daily, with gentle massage, or if massage not possible (too painful) with protective dressing

Assessment at baseline, 5, 10 days

Participants

Minor soft tissue injuries

N = 20

M 11, F 9

Mean age 40 years

Baseline pain not reported

Interventions

Fentiazac cream 5%, 2 to 3 x daily, n = 10

Placebo cream, 2 to 3 x daily, n = 10

All participants told to rest

No other local and systemic treatments allowed

Rescue medication: analgesic if actually needed

Outcomes

Pain relief: scale not reported (responder = total pain relief)

% improvement in pain on movement: pain scale not reported (mean data)

Adverse events

Notes

Oxford Quality Score: R1, DB1, W0. Total = 2/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Spacca 2005

Methods

R, DB, PC, parallel groups

Gel applied 3 times daily, with gentle massage until complete absorption, for up to 10 days

Assessment at baseline, 10 days in clinic, and daily patient diary

Participants

Shoulder periarthritis or lateral epicondylitis (< 5 days)

N = 155

M 74, F 81

Mean age 51 years

Baseline pain with activity > 70 mm

Interventions

DHEP lecithin gel (Effigel), 3 x 5 g daily, n = 79

Placebo gel, 3 x 5 g daily, n = 76

Rescue medication (paracetamol) allowed if pain unbearable

No other analgesic or anti‐inflammatory drug allowed

Outcomes

Improvement in pain: 100 mm VAS (mean data)

Adverse events

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No usable efficacy data

Size

Unclear risk

50 to 200 participants per treatment arm

Sugioka 1984

Methods

R, DB, AC, parallel groups

Gel applied to affected area 3 to 4 times daily, without occlusion, for 14 days

Assessed at baseline, 7, 14 days

Participants

Non‐traumatic diseases of muscle or tendon

N = 366 (340 analysed for efficacy)

M 115, F 202 (completers)

Age range 12 to 84 years (most 30 to 70)

Baseline pain on movement "none" or "mild" in about 1/3 of participants

Exclusions for protocol violations: 8 piroxicam, 18 indomethacin

Interventions

Piroxicam gel 0.5%, 3 to 4 x 1 g daily, n = 183

Indomethacin gel 1%, 3 to 4 x 1 g daily, n = 183

No concomitant anti‐inflammatory or analgesic drug, including steroids, or initiation of physical therapy allowed

Outcomes

PGE: 5‐point scale (responder = "better" or "much better")

Pain on movement: 4‐point scale (responder = "reduced" or "disappeared")

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

Key code sealed and retained until end of study

Blinding (performance bias and detection bias)
All outcomes

Low risk

"both packages were of the same appearance and indistinguishable", and investigators did not see contents

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All relevant participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Thorling 1990

Methods

R, DB, PC, parallel groups

Participants given specific instructions on how to apply gel (not reported) to affected area 2 to 6 times daily as required

Assessment at baseline, 3, 7 days in clinic

Participants

Soft tissue injuries (< 48 hours)

N = 120

M 85, F 35

Mean age 27 years

Baseline pain moderate to severe

Interventions

Naproxen gel 10%, 2 to 6 x daily, n = 60

Placebo gel, 2 to 6 x daily, n = 60

Rescue medication: paracetamol 500 mg

Outcomes

PGE: 5‐point scale (responder = "good" and "very good")

Pain on passive movement: 4‐point scale (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"supplied in unmarked tubes"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

Unclear risk

50 to 200 participants per treatment arm

Tonutti 1994

Methods

R, DB, AC, parallel groups

Gel applied 3 times daily for 2 to 3 weeks

Assessed at baseline, and intervals of 7 days

Participants

Muscle or joint trauma

N = 30

M 20, F 10

Mean age 34 years

1 participant had injury of mild severity. Mean baseline pain on active movement 2.8 (scale 0 to 4)

Interventions

Ketoprofen gel 5%, 3 x 2 to 3 g daily, n = 15

Etofenamate gel 5%, 3 x 2 to 3 g, n = 15

No concomitant treatment with NSAID, aspirin, steroid or physical therapy

Outcomes

PGE: 4‐point scale (responder = "good" and "excellent")

Pain on movement: 5‐point scale (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding (performance bias and detection bias)
All outcomes

Low risk

"the two drugs were packed in indistinguishable tubes"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Vecchiet 1991

Methods

R, DB, PC, parallel groups

Gel applied to the skin on and around painful area and gently rubbed in until absorbed, twice daily for up to 10 days

Assessed at baseline, 5, 10 days

Participants

Soft tissue trauma (minor sports injuries)

N = 60

M 60

Mean age 25 years

Mean baseline pain on active movement: moderate

Interventions

Meclofenamic acid gel 5%, 2 x 10 cm daily (= 4 g), n = 30

Placebo gel, 2 x 10 cm daily, n = 30

Both groups treated with ice, rest, and bandage for first 48 hours before starting test treatment

Rescue medication: paracetamol

Outcomes

PGE: 4‐point scale (responder = "good" and "excellent")

Pain on movement: 4‐point scale (mean data)

Withdrawals

Notes

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

High risk

< 50 participants per treatment arm

Whitefield 2002

Methods

R, DB (double dummy), AC, parallel groups

Gel applied to affected site, with gentle massage, and 1 tablet taken 3 times daily for at least 7 days

Assessed at baseline, 7, 14 (if necessary) days in clinic, and daily patient diary

Participants

Soft tissue injuries (< 24 hours)

N = 100

M 95, F 5

Mean age 26 years (range 18 to 50)

Mean baseline pain on movement 2.2 cm

Interventions

Ibuprofen gel 5% + placebo tablet 3 x daily, n = 50

Ibuprofen 400 mg tablet + placebo gel 3 x daily, n = 50

No other medication or physical therapy was prescribed and no other analgesics were allowed

Outcomes

PGE: 3‐point scale (responder = "excellent")

Change in condition of injury site: 5‐point scale (responder = "completely better")

Adverse events

Withdrawals

Notes

Oxford Quality Score: R1, DB2, W1. Total = 4/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo tablets Identical in appearance to active tablets. Active and placebo gels had similar physical characteristics and were supplied in identical tubes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis

Size

Unclear risk

50 participants per treatment arm

Ăkermark 1990

Methods

R, DB (double dummy), PC, AC, parallel groups

Spray applied to affected area, and capsules taken 3 times daily for 2 weeks

Assessment at baseline, 3 or 4, 7, and 14 days

Participants

Superficial overuse sports injuries (symptom onset 7.4 weeks)

N = 70

M 44, F 18 (completers)

Mean age 30 years

Baseline pain on palpation mostly slight to moderate

Interventions

Elmetacin spray (indomethacin 1%), 3 to 5 x 0.5 to 1.5 ml daily + placebo capsules, n = 23

Indomethacin capsules, 3 x 25 mg daily + placebo spray, n = 23

Placebo spray and capsules, n = 24

Rescue medication: paracetamol

Outcomes

No pain on palpation (= responder)

Participant improvement: 100 mm VAS (mean data)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"random number code"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

"identical in appearance"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Responder analysis, < 5% withdrawals

Size

High risk

< 50 participants per treatment group

AC: active control; BOCF: baseline observation carried forward; DB: double‐blind; DHEP: diclofenac hydroxyethylpyrrolidine, or diclofenac epolamine; F: female; HCl: hydrochloride; hep: heparin; LOCF: last observation carried forward; M: male; N: number of participants in study; n: number of participants in treatment arm; PC: placebo control; PGE: Participant Global Evaluation; PI: pain intensity; R: randomised; VAS: visual analogue scale; W: withdrawals.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ambrus 1987

No usable dichotomous data

Anon 1993

Not double‐blind

Ascherl 1982

No usable dichotomous data

Bagliani 1976

Not an RCT

Baracchi 1982

No usable data

Burnham 1998

<10 participants/treatment arm in first period of crossover study

Böhmer 1995

Active control invalid

Cesarone 2008

Not an RCT

Coulibaly 2009

Not double‐blind

Diebschlag 1985

No usable dichotomous data

Diebschlag 1986

Inappropriate randomisation

Diebschlag 1992

No usable dichotomous data

Fantato 1971

No usable dichotomous data

Galer 2000

No usable data

Hallmeier 1986

Not double‐blind

Hallmeier 1988

Not double‐blind

Kaneko 1999

Inappropriate randomisation ‐ quasi‐randomised

Kockelbergh 1985b

Treatment not applied daily

Kuwabara 2013

Used NSAID‐lidocaine combination (conference abstract)

Lee 1991

Not an RCT

Link 1996

No usable dichotomous data

May 2007

No usable dichotomous data

Oakland 1993

Inappropriate comparator

Odaglia 1987

Not an RCT

Picardi 1993

Not an RCT

Taboada 1992

Dose and duration of treatment unclear

Vanderstraeten 1990

Not double‐blind

Vinciguerra 2008

Not an RCT

Von Klug 1977

Chronic and acute outcomes combined

RCT: randomised controlled trial.

Characteristics of studies awaiting assessment [ordered by study ID]

NCT00351104

Methods

R, DB, PC, parallel groups

Participants

Ankle sprain or strain, Grade I or II. Age ≥ 18 years

N = 220

Interventions

Ketoprofen patch 20% x 1 daily
Placebo patch x 1 daily
Treatment for 21 days

Outcomes

Assessments days 3, 7, 21
PI (0‐10) at rest and during activities
PGE
Function
Rescue medication

Notes

Sponsor: Endo Pharmaceuticals

Estimated completion February 2007. No results

NCT00352625

Methods

R, DB, PC, parallel groups

Participants

Shoulder, elbow, or knee tendonitis or bursitis. Age ≥ 18 years

N = 330

Interventions

Ketoprofen patch 20% x 1 daily
Placebo patch x 1 daily
Treatment for 21 days

Outcomes

Assessments days 3, 7, 21
PI (0‐10) at rest and during activities
PGE
Function
Rescue medication

Notes

Sponsor: Endo Pharmaceuticals

Estimated completion February 2007. No results

NCT00426985

Methods

R, DB, PC, parallel groups

Participants

Shoulder, elbow, or knee tendonitis or bursitis. Age ≥ 18 years

Interventions

Ketoprofen patch 20% x 1 daily
Placebo patch
Treatment for 21 days

Outcomes

PI during activity
PI at rest
PGE
Rescue medication

Safety

Notes

Study terminated May 2008, but "sufficient number of subjects accrued to conduct analysis". No results

NCT00640705

Methods

R, DB, PC, parallel groups

Participants

Ankle sprain or strain, Grade I or II, ≤ 48 hours, PI 5/10 to 9/10. Age 18 to 75 years

N = 170

Interventions

Diclofenac sodium patch (15 mg) x 1 daily
Placebo
Treatment for 7 days

Outcomes

Efficacy

Safety

Notes

Study terminated July 2008 (Sponsor decision ‐ no further details). No results posted

NCT00640939

Methods

R, DB, PC, parallel groups

Participants

Shoulder, elbow, or knee tendonitis or bursitis. Age 18 to 75 years
Baseline pain mild to moderate, but states 5/10 to 9/10

N = 308

Interventions

Diclofenac sodium patch 1% (15 mg) x 1 daily
Placebo patch x 1 daily

Duration of treatment not reported, probably 14 days

Outcomes

Efficacy

Safety

Notes

Sponsor: Cerimon Pharmaceuticals

Estimated completion April 2008. No results

NCT00680472

Methods

R, DB, PC, parallel groups

Participants

Acute unilateral shoulder pain, requiring treatment for ≥ 2 weeks. Age ≥ 18 years

N = 368

Interventions

Ketoprofen patch (HKT‐500) x 1 daily
Placebo x 1 daily
Treatment for 14 days

Outcomes

Pain

Safety

Notes

Sponsor: Hisamitsu Pharmaceutical Co., Inc.

Estimated completion October 2008. No results

NCT00680784

Methods

R, DB, PC, parallel groups

Participants

Acute benign ankle sprain, Grade I‐II, ≤ 48 hours. Age ≥ 18 years

N = 260

Interventions

Ketoprofen patch (HKT‐500) x 1 daily
Placebo patch x 1 daily
Treatment for 14 days

Outcomes

Pain

Safety

Notes

Sponsor: Hisamitsu Pharmaceutical Co., Inc.

Estimated completion November 2008. No results

NCT00765700

Methods

R, DB, PC, parallel groups

Participants

Acute sprain or strain of upper and lower extremities, mild to moderate injuries, ≤ 72 hours. Age 18 to 70 years

N = 364

Interventions

Ketoprofen cream 10% 1 g x 3 daily
Placebo cream x 3 daily
Treatment for 7 days

Outcomes

Pain

Safety

Notes

Sponsor: Imprimis Pharmaceuticals, Inc.

Estimated completion September 2009. No results

NCT00869063

Methods

R, DB, PC, parallel groups

Participants

Wrist sprain, strain, or contusion (mild to moderate), "recent". Age 17 to 75 years

N = 214

Interventions

Diclofenac sodium patch 1% x 1 daily
Placebo patch x 1 daily
Treatment for 7 days

Outcomes

Change in PI during activity at 3 and 7 days

Safety

Notes

Sponsor: Cerimon Pharmaceuticals

Estimated completion September 2009. No results

NCT00869180

Methods

R, DB, PC, parallel groups

Participants

Unilateral, ankle sprain (mild or moderate), "recent". Age 17 to 75 years

N = 219

Interventions

Diclofenac sodium patch x 1 daily
Placebo patch x 1 daily
Treatment for 7 days

Outcomes

Change in PI during activity at 3 and 7 days

Notes

Sponsor: Cerimon Pharmaceuticals

Estimated completion August 2009. No results

NCT00931866

Methods

R, DB, PC, parallel groups

Participants

Unilateral soft tissue injury between mid‐bicep to wrist or mid‐thigh to ankle (mild to moderate), "recent". Age 18 to 75 years

N = 407

Interventions

Diclofenac sodium patch x 1 daily
Placebo patch x 1 daily
Treatment for 14 days

Outcomes

Change in PI during activity at 7 and 14 days
PI
PGE
Rescue medication

Safety

Notes

Sponsor: Cerimon Pharmaceuticals

Estimated completion December 2009. No results

NCT01874626

Methods

R, DB, PC, parallel groups

Participants

Acute ankle sprain, Grade I or II ≤ 24 hours. Age ≥ 16 years. Baseline PI ≥ 5/10

N = 305

Interventions

Ibuprofen cream 200 mg in 2.7 g cream x 4 daily
Placebo cream x 4 daily
Treatment for 7 days

Outcomes

PI on movement daily to 7 days
PGE 7 days

Systemic and local adverse events

Notes

Estimated completion January 2014. No results

NCT01957215

Methods

R, DB, PC, parallel groups

Participants

Acute lateral ankle sprain, Grade I‐II, ≤ 24 hours, PI ≥ 5/10. Age 18 to 65 years

N = 270

Interventions

Indomethacin patch x 2 daily
Placebo patch x 2 daily

Duration of treatment not reported, probably 7 days

Outcomes

PI on movement daily
PR daily
PGE
Rescue medication

Notes

Estimated completion September 2014. No results

NCT02324270

Methods

R, DB, PC and AC, parallel groups

Participants

Uncomplicated acute ankle sprain, Grade I or II, < 48 hours, PI > 50/100. Age 18 to 65 years

N = 658

Interventions

Diclofenac epolamine (Flector) 1.3% patch
Generic diclofenac epolamine 1.3% patch
Placebo patch

Duration of treatment not reported

Outcomes

Bioequivalence study
Change from baseline in PI (VAS) at 3 days

Application site reactions

Notes

Estimated completion December 2014. No results

Sarzi‐Puttini 2014

Methods

R, DB, AC, parallel group, non‐inferiority study

Duration 7 days

Participants

Acute musculoskeletal injury (mainly muscular, joint, tendon)

N = 697

M 271, F 426

Mean age 52 years

Interventions

Ketoprofen (SKP‐021) patch, ketoprofen 30 mg

Diclofenac (Voltadola), patch diclofenac sodium 140 mg

Patches applied twice daily for 7 days

Outcomes

≥ 50% reduction in PI from baseline to end of study (100 mm VAS)

Patient overall rating

Clinical symptoms (4‐point scale)

Time to response

Adverse events, skin reactions

Serious adverse events

Notes

"The analysis of the data of this trial showed that the two formulations were equally effective and well tolerated in the treatment of acute musculoskeletal injuries."

AC: active‐controlled; DB: double‐blind; F: female; M: male; N: number of participants in study; PC: placebo‐controlled; PGE: Patient Global Evaluation of treatment; PI: pain intensity; R: randomised; VAS: visual analogue scale.

Characteristics of ongoing studies [ordered by study ID]

NCT01945034

Trial name or title

Placebo‐controlled, double‐blind evaluation of the efficacy and safety of ibuprofen 5% topical gel for the treatment of ankle sprain

Methods

R, DB, PC, parallel groups

Participants

Ankle sprain, Grade I or II, age ≥ 12 years

Estimated enrolment 280

Interventions

Ibuprofen gel 5% x 2 daily

Ibuprofen gel 5% x 3 daily
Placebo gel
Treatment for 7 days, with additional 3 days as needed

Outcomes

PI on weight bearing and rest at 7 days
PGE at 10 days
Rescue medication

Safety

Starting date

November 2013

Contact information

Pfizer

Notes

Estimated completion February 2015

Includes participants aged ≥ 12 years

NCT02100670

Trial name or title

A clinical study to assess the efficacy and onset of pain relief of topical MFC51123 diclofenac‐menthol gel versus controls in ankle sprain

Methods

R, DB, PC, and AC, parallel groups

Participants

Acute lateral ankle sprain, Grade I or II, ≤ 24 hours, PI ≥ 5/10. Age 16 to 65 years

Estimated enrolment 400

Interventions

Diclofenac sodium 1% + methanol 3% gel
Diclofenac sodium 1% + methanol 0.09% gel
Methanol 3% gel
Placebo + 0.09% methanol gel
Treatment for 10 days with 4 g gel x 4 daily

Outcomes

PR
PID on movement (0 to 10 days)
PGE
Time to complete recovery

Adverse events

Starting date

November 2013

Contact information

[email protected]

Notes

Estimated completion November 2014

NCT02290821

Trial name or title

A randomised, 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

Methods

R, DB, PC, parallel groups

Participants

Acute blunt soft tissue injuries or contusions of the limbs, ≤ 6 hours ("fresh"). Age ≥ 16 years

Estimated enrolment 200

Interventions

Diclofenac sodium gel 1% x 4 daily
Placebo gel

Duration of treatment not reported

Outcomes

Pain

Safety

Starting date

December 2014

Contact information

Novartis

Notes

Estimated completion August 2015

AC: active control; DB: double‐blind; PC: placebo‐controlled; PGE: Patient Global Evaluation of treatment; PI: pain intensity; PID: pain intensity difference; PR: pain relief; R: randomised

Data and analyses

Open in table viewer
Comparison 1. Individual NSAID versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

29

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 Individual NSAID versus placebo, Outcome 1 Clinical success.

Comparison 1 Individual NSAID versus placebo, Outcome 1 Clinical success.

1.1 Diclofenac

10

2050

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [1.49, 1.72]

1.2 Ibuprofen

5

436

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.33, 2.01]

1.3 Ketoprofen

7

683

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.77]

1.4 Piroxicam

3

504

Risk Ratio (M‐H, Fixed, 95% CI)

1.48 [1.27, 1.73]

1.5 Indomethacin

3

341

Risk Ratio (M‐H, Fixed, 95% CI)

1.26 [1.03, 1.55]

1.6 Benzydamine

3

193

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.96, 1.38]

2 Local adverse events Show forest plot

33

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Individual NSAID versus placebo, Outcome 2 Local adverse events.

Comparison 1 Individual NSAID versus placebo, Outcome 2 Local adverse events.

2.1 Diclofenac

15

3271

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.56, 1.10]

2.2 Ibuprofen

3

321

Risk Ratio (M‐H, Fixed, 95% CI)

2.30 [0.98, 5.43]

2.3 Ketoprofen

8

852

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.83, 1.70]

2.4 Piroxicam

3

522

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.17, 1.08]

2.5 Felbinac

3

397

Risk Ratio (M‐H, Fixed, 95% CI)

1.91 [0.49, 7.50]

2.6 Indomethacin

3

354

Risk Ratio (M‐H, Fixed, 95% CI)

2.65 [0.91, 7.73]

Open in table viewer
Comparison 2. Diclofenac versus placebo (effect of formulation)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

10

2050

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [1.49, 1.72]

Analysis 2.1

Comparison 2 Diclofenac versus placebo (effect of formulation), Outcome 1 Clinical success.

Comparison 2 Diclofenac versus placebo (effect of formulation), Outcome 1 Clinical success.

1.1 Plaster ‐ Flector

4

1030

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.36, 1.71]

1.2 Plaster ‐ other

3

474

Risk Ratio (M‐H, Fixed, 95% CI)

1.55 [1.37, 1.75]

1.3 Gel ‐ Emulgel

2

314

Risk Ratio (M‐H, Fixed, 95% CI)

3.84 [2.68, 5.50]

1.4 Gel ‐ other

1

232

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.05, 1.27]

Open in table viewer
Comparison 3. Ibuprofen versus placebo (effect of formulation)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

5

436

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.33, 2.01]

Analysis 3.1

Comparison 3 Ibuprofen versus placebo (effect of formulation), Outcome 1 Clinical success.

Comparison 3 Ibuprofen versus placebo (effect of formulation), Outcome 1 Clinical success.

1.1 Cream

3

195

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.03, 1.59]

1.2 Gel

2

241

Risk Ratio (M‐H, Fixed, 95% CI)

2.66 [1.69, 4.21]

Open in table viewer
Comparison 4. Ketoprofen versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

7

683

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.77]

Analysis 4.1

Comparison 4 Ketoprofen versus placebo, Outcome 1 Clinical success.

Comparison 4 Ketoprofen versus placebo, Outcome 1 Clinical success.

1.1 Plaster

2

335

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [1.04, 1.40]

1.2 Gel

5

348

Risk Ratio (M‐H, Fixed, 95% CI)

2.19 [1.74, 2.75]

Open in table viewer
Comparison 5. All topical NSAIDs versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Local adverse events Show forest plot

42

6740

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.80, 1.21]

Analysis 5.1

Comparison 5 All topical NSAIDs versus placebo, Outcome 1 Local adverse events.

Comparison 5 All topical NSAIDs versus placebo, Outcome 1 Local adverse events.

2 Systemic adverse events Show forest plot

36

5576

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.73, 1.26]

Analysis 5.2

Comparison 5 All topical NSAIDs versus placebo, Outcome 2 Systemic adverse events.

Comparison 5 All topical NSAIDs versus placebo, Outcome 2 Systemic adverse events.

3 Adverse event withdrawals Show forest plot

42

6405

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.64, 1.59]

Analysis 5.3

Comparison 5 All topical NSAIDs versus placebo, Outcome 3 Adverse event withdrawals.

Comparison 5 All topical NSAIDs versus placebo, Outcome 3 Adverse event withdrawals.

Open in table viewer
Comparison 6. Topical NSAID versus active comparator

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success ‐ topical piroxicam vs topical indomethacin Show forest plot

3

641

Risk Ratio (M‐H, Fixed, 95% CI)

1.24 [1.07, 1.44]

Analysis 6.1

Comparison 6 Topical NSAID versus active comparator, Outcome 1 Clinical success ‐ topical piroxicam vs topical indomethacin.

Comparison 6 Topical NSAID versus active comparator, Outcome 1 Clinical success ‐ topical piroxicam vs topical indomethacin.

2 Local adverse events ‐ topical piroxicam vs topical indomethacin Show forest plot

3

671

Risk Ratio (M‐H, Fixed, 95% CI)

0.21 [0.09, 0.47]

Analysis 6.2

Comparison 6 Topical NSAID versus active comparator, Outcome 2 Local adverse events ‐ topical piroxicam vs topical indomethacin.

Comparison 6 Topical NSAID versus active comparator, Outcome 2 Local adverse events ‐ topical piroxicam vs topical indomethacin.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figures and Tables -
Figure 3

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Forest plot of comparison: 2 Individual NSAID versus placebo, outcome: 2.1 Clinical success.
Figures and Tables -
Figure 4

Forest plot of comparison: 2 Individual NSAID versus placebo, outcome: 2.1 Clinical success.

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.
Figures and Tables -
Figure 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.

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.
Figures and Tables -
Figure 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.

Comparison 1 Individual NSAID versus placebo, Outcome 1 Clinical success.
Figures and Tables -
Analysis 1.1

Comparison 1 Individual NSAID versus placebo, Outcome 1 Clinical success.

Comparison 1 Individual NSAID versus placebo, Outcome 2 Local adverse events.
Figures and Tables -
Analysis 1.2

Comparison 1 Individual NSAID versus placebo, Outcome 2 Local adverse events.

Comparison 2 Diclofenac versus placebo (effect of formulation), Outcome 1 Clinical success.
Figures and Tables -
Analysis 2.1

Comparison 2 Diclofenac versus placebo (effect of formulation), Outcome 1 Clinical success.

Comparison 3 Ibuprofen versus placebo (effect of formulation), Outcome 1 Clinical success.
Figures and Tables -
Analysis 3.1

Comparison 3 Ibuprofen versus placebo (effect of formulation), Outcome 1 Clinical success.

Comparison 4 Ketoprofen versus placebo, Outcome 1 Clinical success.
Figures and Tables -
Analysis 4.1

Comparison 4 Ketoprofen versus placebo, Outcome 1 Clinical success.

Comparison 5 All topical NSAIDs versus placebo, Outcome 1 Local adverse events.
Figures and Tables -
Analysis 5.1

Comparison 5 All topical NSAIDs versus placebo, Outcome 1 Local adverse events.

Comparison 5 All topical NSAIDs versus placebo, Outcome 2 Systemic adverse events.
Figures and Tables -
Analysis 5.2

Comparison 5 All topical NSAIDs versus placebo, Outcome 2 Systemic adverse events.

Comparison 5 All topical NSAIDs versus placebo, Outcome 3 Adverse event withdrawals.
Figures and Tables -
Analysis 5.3

Comparison 5 All topical NSAIDs versus placebo, Outcome 3 Adverse event withdrawals.

Comparison 6 Topical NSAID versus active comparator, Outcome 1 Clinical success ‐ topical piroxicam vs topical indomethacin.
Figures and Tables -
Analysis 6.1

Comparison 6 Topical NSAID versus active comparator, Outcome 1 Clinical success ‐ topical piroxicam vs topical indomethacin.

Comparison 6 Topical NSAID versus active comparator, Outcome 2 Local adverse events ‐ topical piroxicam vs topical indomethacin.
Figures and Tables -
Analysis 6.2

Comparison 6 Topical NSAID versus active comparator, Outcome 2 Local adverse events ‐ topical piroxicam vs topical indomethacin.

Summary of findings for the main comparison. Topical NSAIDs compared with topical placebo for acute musculoskeletal pain in adults

Topical NSAIDs compared with topical placebo for acute musculoskeletal pain in adults

Patient or population: adults with strains, sprains, or muscle pull

Settings: community

Intervention: topical NSAID (topical diclofenac, ibuprofen, and ketoprofen gels only shown here for efficacy)

Comparison: topical placebo

Outcomes

Probable outcome with
intervention

Probable outcome with
comparator

RR, NNT, NNTp, or NNH
(95% CI)

No of studies, participants

Quality of the evidence
(GRADE)

Comments

Topical diclofenac gel (as Emulgel)

Clinical success (eg 50% reduction in pain)

780 in 1000

200 in 1000

RR

3.4 (2.7 to 55)

NNT

1.8 (1.5 to 2.1)

2 studies

314 participants

High

Consistent results in 2 moderately sized recent studies of high quality

Topical ibuprofen gel

Clinical success (eg 50% reduction in pain)

420 in 1000

160 in 1000

RR

2.7 (1.7 to 4.2)

NNT

3.9 (2.7 to 6.7)

2 studies

241 participants

Moderate

Modest effect size and numbers of participants

Topical ketoprofen gel

Clinical success (eg 50% reduction in pain)

720 in 1000

330 in 1000

RR

2.2 (1.7 to 2.8)

NNT

2.5 (2.0 to 3.4)

5 studies

348 participants

Moderate

Modest effect size and numbers of participants, but studies small, with none recent

All topical NSAIDs

Local adverse events

46 in 1000

50 in 1000

RR

1.0 (0.80 to 1.2)

NNH not calculated

42 studies

6125 participants

High

Large number of studies and participants with consistent results

All topical NSAIDs

Systemic adverse events

32 in 1000

35 in 1000

RR

1.0 (0.7 to 1.3)

NNH not calculated

38 studies

5372 participants

High

Large number of studies and participants with consistent results

All topical NSAIDs

Withdrawals ‐ adverse events

11 in 1000

11 in 1000

RR

1.0 (0.7 to 1.7)

NNH not calculated

42 studies

5790 participants

High

Large number of studies and participants with consistent results

Serious adverse events

1 in total

0 in total

Not calculated

All data

Low

Small numbers of events

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

CI: confidence interval; RR: risk ratio; NNT: number needed to treat for an additional beneficial outcome; NNTp: number needed to treat to prevent an event happening; NNH: number needed to treat for an additional harmful outcome.

Figures and Tables -
Summary of findings for the main comparison. Topical NSAIDs compared with topical placebo for acute musculoskeletal pain in adults
Comparison 1. Individual NSAID versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

29

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Diclofenac

10

2050

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [1.49, 1.72]

1.2 Ibuprofen

5

436

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.33, 2.01]

1.3 Ketoprofen

7

683

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.77]

1.4 Piroxicam

3

504

Risk Ratio (M‐H, Fixed, 95% CI)

1.48 [1.27, 1.73]

1.5 Indomethacin

3

341

Risk Ratio (M‐H, Fixed, 95% CI)

1.26 [1.03, 1.55]

1.6 Benzydamine

3

193

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.96, 1.38]

2 Local adverse events Show forest plot

33

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Diclofenac

15

3271

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.56, 1.10]

2.2 Ibuprofen

3

321

Risk Ratio (M‐H, Fixed, 95% CI)

2.30 [0.98, 5.43]

2.3 Ketoprofen

8

852

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.83, 1.70]

2.4 Piroxicam

3

522

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.17, 1.08]

2.5 Felbinac

3

397

Risk Ratio (M‐H, Fixed, 95% CI)

1.91 [0.49, 7.50]

2.6 Indomethacin

3

354

Risk Ratio (M‐H, Fixed, 95% CI)

2.65 [0.91, 7.73]

Figures and Tables -
Comparison 1. Individual NSAID versus placebo
Comparison 2. Diclofenac versus placebo (effect of formulation)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

10

2050

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [1.49, 1.72]

1.1 Plaster ‐ Flector

4

1030

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.36, 1.71]

1.2 Plaster ‐ other

3

474

Risk Ratio (M‐H, Fixed, 95% CI)

1.55 [1.37, 1.75]

1.3 Gel ‐ Emulgel

2

314

Risk Ratio (M‐H, Fixed, 95% CI)

3.84 [2.68, 5.50]

1.4 Gel ‐ other

1

232

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.05, 1.27]

Figures and Tables -
Comparison 2. Diclofenac versus placebo (effect of formulation)
Comparison 3. Ibuprofen versus placebo (effect of formulation)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

5

436

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.33, 2.01]

1.1 Cream

3

195

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.03, 1.59]

1.2 Gel

2

241

Risk Ratio (M‐H, Fixed, 95% CI)

2.66 [1.69, 4.21]

Figures and Tables -
Comparison 3. Ibuprofen versus placebo (effect of formulation)
Comparison 4. Ketoprofen versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success Show forest plot

7

683

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.77]

1.1 Plaster

2

335

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [1.04, 1.40]

1.2 Gel

5

348

Risk Ratio (M‐H, Fixed, 95% CI)

2.19 [1.74, 2.75]

Figures and Tables -
Comparison 4. Ketoprofen versus placebo
Comparison 5. All topical NSAIDs versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Local adverse events Show forest plot

42

6740

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.80, 1.21]

2 Systemic adverse events Show forest plot

36

5576

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.73, 1.26]

3 Adverse event withdrawals Show forest plot

42

6405

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.64, 1.59]

Figures and Tables -
Comparison 5. All topical NSAIDs versus placebo
Comparison 6. Topical NSAID versus active comparator

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success ‐ topical piroxicam vs topical indomethacin Show forest plot

3

641

Risk Ratio (M‐H, Fixed, 95% CI)

1.24 [1.07, 1.44]

2 Local adverse events ‐ topical piroxicam vs topical indomethacin Show forest plot

3

671

Risk Ratio (M‐H, Fixed, 95% CI)

0.21 [0.09, 0.47]

Figures and Tables -
Comparison 6. Topical NSAID versus active comparator