Reviews
1 September 2015

Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials

Publication: Annals of Internal Medicine
Volume 163, Number 5

Abstract

Background:

Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials.

Objective:

To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.

Data Sources:

MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.

Study Selection:

149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos.

Data Extraction:

Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.

Data Synthesis:

Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.

Limitations:

Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos.

Conclusion:

All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results.

Primary Funding Source:

Agency for Healthcare Research and Quality.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Bijlsma JWWelsing PM. The art of medicine in treating osteoarthritis: I will please [Editorial]. Ann Rheum Dis. 2008;67:1653-5. [PMID: 19005153]  doi: 10.1136/ard.2008.097006
2.
Koshi EBShort CA. Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract. 2007;7:4-20. [PMID: 17305673]
3.
Hróbjartsson AGøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344:1594-602. [PMID: 11372012]
4.
Wampold BEMinami TTierney SCBaskin TWBhati KS. The placebo is powerful: estimating placebo effects in medicine and psychotherapy from randomized clinical trials. J Clin Psychol. 2005;61:835-54. [PMID: 15827993]
5.
Hahn RA. The nocebo phenomenon: concept, evidence, and implications for public health. Prev Med. 1997;26:607-11. [PMID: 9327466]
6.
Cipriani ABarbui CSalanti GRendell JBrown RStockton Set al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378:1306-15. [PMID: 21851976]  doi: 10.1016/S0140-6736(11)60873-8
7.
Naudet FMillet BCharlier PReymann JMMaria ASFalissard B. Which placebo to cure depression? A thought-provoking network meta-analysis. BMC Med. 2013;11:230. [PMID: 24160565]  doi: 10.1186/1741-7015-11-230
8.
Meissner KFässler MRücker GKleijnen JHróbjartsson ASchneider Aet al. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern Med. 2013;173:1941-51. [PMID: 24126676]  doi: 10.1001/jamainternmed.2013.10391
9.
Bannuru RRSchmid CHKent DMVaysbrot EEWong JBMcAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162:46-54. [PMID: 25560713]  doi: 10.7326/M14-1231
10.
Manyanga TFroese MZarychanski RAbou-Setta AFriesen CTennenhouse Met al. Pain management with acupuncture in osteoarthritis: a systematic review and meta-analysis. BMC Complement Altern Med. 2014;14:312. [PMID: 25151529]  doi: 10.1186/1472-6882-14-312
11.
Higgins JPTAltman DGSterne JA. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. The Cochrane Collaboration; 2011.
12.
Juhl CLund HRoos EMZhang WChristensen R. A hierarchy of patient-reported outcomes for meta-analysis of knee osteoarthritis trials: empirical evidence from a survey of high impact journals. Arthritis. 2012;2012:136245. [PMID: 22792458]  doi: 10.1155/2012/136245
13.
Bannuru RRNatov NSDasi URSchmid CHMcAlindon TE. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis—meta-analysis. Osteoarthritis Cartilage. 2011;19:611-9. [PMID: 21443958]  doi: 10.1016/j.joca.2010.09.014
14.
Cooper HHedges LV. The Hand Book of Research Synthesis. New York: Russell Sage Foundation Publications; 1994.
15.
Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Res Synth Methods. 2012;3:80-97. [PMID: 26062083]  doi: 10.1002/jrsm.1037
16.
Dias SSutton AJAdes AEWelton NJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Making. 2013;33:607-17. [PMID: 23104435]  doi: 10.1177/0272989X12458724
17.
Dias SWelton NJCaldwell DMAdes AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29:932-44. [PMID: 20213715]  doi: 10.1002/sim.3767
18.
Thorlund KWalter SDJohnston BCFurukawa TAGuyatt GH. Pooling health-related quality of life outcomes in meta-analysis-a tutorial and review of methods for enhancing interpretability. Res Synth Methods. 2011;2:188-203. [PMID: 26061786]  doi: 10.1002/jrsm.46
19.
Pham Tvan der Heijde DAltman RDAnderson JJBellamy NHochberg Met al. OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage. 2004;12:389-99. [PMID: 15094138]
20.
Dias SSutton AJWelton NJAdes AE. Evidence synthesis for decision making 3: heterogeneity—subgroups, meta-regression, bias, and bias-adjustment. Med Decis Making. 2013;33:618-40. [PMID: 23804507]  doi: 10.1177/0272989X13485157
21.
Conaghan PGDickson JBolten WCevc GRother M. A multicentre, randomized, placebo- and active-controlled trial comparing the efficacy and safety of topical ketoprofen in Transfersome gel (IDEA-033) with ketoprofen-free vehicle (TDT 064) and oral celecoxib for knee pain associated with osteoarthritis. Rheumatology (Oxford). 2013;52:1303-12. [PMID: 23542612]  doi: 10.1093/rheumatology/ket133
22.
Zhang WRobertson JJones ACDieppe PADoherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67:1716-23. [PMID: 18541604]  doi: 10.1136/ard.2008.092015
23.
Morison RAWoodmansey AYoung AJ. Placebo responses in an arthritis trial. Ann Rheum Dis. 1961;20:179-85. [PMID: 13772684]
24.
Traut EFPassarelli EW. Placebos in the treatment of rheumatoid arthritis and other rheumatic conditions. Ann Rheum Dis. 1957;16:18-22. [PMID: 13412002]
25.
Kaptchuk TJStason WBDavis RBLegedza ARSchnyer RNKerr CEet al. Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ. 2006;332:391-7. [PMID: 16452103]
26.
Grenfell RFBriggs AHHolland WC. A double-blind study of the treatment of hypertension. JAMA. 1961;176:124-8. [PMID: 13708477]
27.
National Clinical Guideline Centre. Osteoarthritis. Care and management in adults. London, United Kingdom: National Institute for Health and Care Excellence; 2014.
28.
Hochberg MCAltman RDApril KTBenkhalti MGuyatt GMcGowan Jet alAmerican College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:465-74. [PMID: 22563589]
29.
McAlindon TEBannuru RRSullivan MCArden NKBerenbaum FBierma-Zeinstra SMet al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22:363-88. [PMID: 24462672]  doi: 10.1016/j.joca.2014.01.003
30.
Jonas WB. Reframing placebo in research and practice. Philos Trans R Soc Lond B Biol Sci. 2011;366:1896-904. [PMID: 21576147]  doi: 10.1098/rstb.2010.0405
31.
Finniss DGKaptchuk TJMiller FBenedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375:686-95. [PMID: 20171404]  doi: 10.1016/S0140-6736(09)61706-2
32.
Thomas KB. General practice consultations: is there any point in being positive? Br Med J (Clin Res Ed). 1987;294:1200-2. [PMID: 3109581]
33.
Miller FGRosenstein DL. The nature and power of the placebo effect. J Clin Epidemiol. 2006;59:331-5. [PMID: 16549251]
34.
Case JPBaliunas AJBlock JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium. Arch Intern Med. 2003;163:169-78. [PMID: 12546607]
35.
Miceli-Richard CLe Bars MSchmidely NDougados M. Paracetamol in osteoarthritis of the knee. Ann Rheum Dis. 2004;63:923-30. [PMID: 15249319]
36.
Pincus TKoch GLei HMangal BSokka TMoskowitz Ret al. Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis. Ann Rheum Dis. 2004;63:931-9. [PMID: 15082468]
37.
Altman RDZinsenheim JRTemple ARSchweinle JE. Three-month efficacy and safety of acetaminophen extended-release for osteoarthritis pain of the hip or knee: a randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage. 2007;15:454-61. [PMID: 17142063]
38.
Herrero-Beaumont GIvorra JADel Carmen Trabado MBlanco FJBenito PMartín-Mola Eet al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum. 2007;56:555-67. [PMID: 17265490]
39.
Yocum DFleischmann RDalgin PCaldwell JHall DRoszko P. Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam Osteoarthritis Investigators. Arch Intern Med. 2000;160:2947-54. [PMID: 11041902]
40.
Ghosh SPaul SDas NBhattacharyya TK. A study on the effects of diclofenac sodium and etoricoxib in the treatment of osteoarthritis. J Indian Med Assoc. 2007;105:260-2. [PMID: 17915794]
41.
Davies GMWatson DJBellamy N. Comparison of the responsiveness and relative effect size of the western Ontario and McMaster Universities Osteoarthritis Index and the short-form Medical Outcomes Study Survey in a randomized, clinical trial of osteoarthritis patients. Arthritis Care Res. 1999;12:172-9. [PMID: 10513507]
42.
Day RMorrison BLuza ACastaneda OStrusberg ANahir Met al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group. Arch Intern Med. 2000;160:1781-7. [PMID: 10871971]
43.
Saag Kvan der Heijde DFisher CSamara ADeTora LBolognese Jet al. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Osteoarthritis Studies Group. Arch Fam Med. 2000;9:1124-34. [PMID: 11115219]
44.
Wiesenhutter CWBoice JAKo ASheldon EAMurphy FTWittmer BAet alProtocol 071 Study Group. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2005;80:470-9. [PMID: 15819283]
45.
Puopolo ABoice JAFidelholtz JLLittlejohn TWMiranda PBerrocal Aet al. A randomized placebo-controlled trial comparing the efficacy of etoricoxib 30 mg and ibuprofen 2400 mg for the treatment of patients with osteoarthritis. Osteoarthritis Cartilage. 2007;15:1348-56. [PMID: 17631392]
46.
Dore RBallard IConstantine GMcDonald P. Efficacy and safety of etodolac and naproxen in patients with osteoarthritis of the knee: a double-blind, placebo-controlled study. Clin Ther. 1995;17:656-66. [PMID: 8565029]
47.
Fleischmann RMFlint KConstantine GKolecki B. A double-masked comparison of Naprelan and nabumetone in osteoarthritis of the knee. Naprelan Study Group. Clin Ther. 1997;19:642-55. [PMID: 9377610]
48.
Bensen WGFiechtner JJMcMillen JIZhao WWYu SSWoods EMet al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc. 1999;74:1095-105. [PMID: 10560596]
49.
Zhao SZMcMillen JIMarkenson JADedhiya SDZhao WWOsterhaus JTet al. Evaluation of the functional status aspects j of health-related quality of life of patients with osteoarthritis treated with celecoxib. Pharmacotherapy. 1999;19:1269-78. [PMID: 10555933]
50.
Kivitz AEisen GZhao WWBevirt TRecker DP. Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis. J Fam Pract. 2002;51:530-7. [PMID: 12100776]
51.
Lohmander LSMcKeith DSvensson OMalmenäs MBolin LKalla Aet alSTAR Multinational Study Group. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis. 2005;64:449-56. [PMID: 15345500]
52.
Svensson OMalmenäs MFajutrao LRoos EMLohmander LS. Greater reduction of knee than hip pain in osteoarthritis treated with naproxen, as evaluated by WOMAC and SF-36. Ann Rheum Dis. 2006;65:781-4. [PMID: 16269428]
53.
Schnitzer TJKivitz AJLipetz RSSanders NHee A. Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of osteoarthritis of the knee. Arthritis Rheum. 2005;53:827-37. [PMID: 16342089]
54.
Reginster JYMalmstrom KMehta ABergman GKo ATCurtis SPet al. Evaluation of the efficacy and safety of etoricoxib compared with naproxen in two, 138-week randomised studies of patients with osteoarthritis. Ann Rheum Dis. 2007;66:945-51. [PMID: 17142385]
55.
Leung ATMalmstrom KGallacher AESarembock BPoor GBeaulieu Aet al. Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: A randomized, double-blind, placebo and active-comparator controlled 12-week efficacy trial. Curr Med Res Opin. 2002;18:49-58. [PMID: 12017209]
56.
Schnitzer TJKivitz AFrayssinet HDuquesroix B. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter study. Osteoarthritis Cartilage. 2010;18:629-39. [PMID: 20202489]  doi: 10.1016/j.joca.2009.12.013
57.
Schnitzer TJHochberg MCMarrero CEDuquesroix BFrayssinet HBeekman M. Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. Semin Arthritis Rheum. 2011;40:285-97. [PMID: 20828790]  doi: 10.1016/j.semarthrit.2010.06.002
58.
Hochberg MCFort JGSvensson OHwang CSostek M. Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials. Curr Med Res Opin. 2011;27:1243-53. [PMID: 21524238]  doi: 10.1185/03007995.2011.580340
59.
McKenna FBorenstein DWendt HWallemark CLefkowith JBGeis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol. 2001;30:11-8. [PMID: 11252686]
60.
Essex MNBhadra PSands GH. Efficacy and tolerability of celecoxib versus naproxen in patients with osteoarthritis of the knee: a randomized, double-blind, double-dummy trial. J Int Med Res. 2012;40:1357-70. [PMID: 22971487]
61.
Essex MNO'Connell MBhadra Brown P. Response to nonsteroidal anti-inflammatory drugs in African Americans with osteoarthritis of the knee. J Int Med Res. 2012;40:2251-66. [PMID: 23321182]
62.
Essex MNO'Connell MABehar RBrown PB. Response to nonsteroidal anti-inflammatory agents in Asian patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2013;21 (Suppl):S252-3.
63.
Essex MNBehar RO'Connell MABrown PB. Efficacy and tolerability of celecoxib and naproxen versus placebo in Hispanic patients with knee osteoarthritis. Int J Gen Med. 2014;7:227-35. [PMID: 24876792]  doi: 10.2147/IJGM.S61297
64.
Williams GWEttlinger RERuderman EMHubbard RCLonien MEYu SSet al. Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib: a randomized, controlled trial. J Clin Rheumatol. 2000;6:65-74. [PMID: 19078452]
65.
McKenna FWeaver AFiechtner JJBello AEFort JG. COX-2 specific inhibitors in the management of osteoarthritis of the knee: a placebo-controlled, randomized, double-blind study. J Clin Rheumatol. 2001;7:151-9. [PMID: 17039120]
66.
Williams GWHubbard RCYu SSZhao WGeis GS. Comparison of once-daily and twice-daily administration of celecoxib for the treatment of osteoarthritis of the knee. Clin Ther. 2001;23:213-27. [PMID: 11293555]
67.
Gibofsky AWilliams GWMcKenna FFort JG. Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial. Arthritis Rheum. 2003;48:3102-11. [PMID: 14613272]
68.
Tannenbaum HBerenbaum FReginster JYZacher JRobinson JPoor Get al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Ann Rheum Dis. 2004;63:1419-26. [PMID: 15020310]
69.
Fleischmann RSheldon EMaldonado-Cocco JDutta DYu SSloan VS. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib. Clin Rheumatol. 2006;25:42-53. [PMID: 16132165]
70.
Lehmann RBrzosko MKopsa PNischik RKreisse AThurston Het al. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib. Curr Med Res Opin. 2005;21:517-26. [PMID: 15899100]
71.
Sheldon EBeaulieu APaster ZDutta DYu SSloan VS. Efficacy and tolerability of lumiracoxib in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind comparison with celecoxib and placebo. Clin Ther. 2005;27:64-77. [PMID: 15763607]
72.
Birbara CRuoff GSheldon EValenzuela CRodgers APetruschke RAet al. Efficacy and safety of rofecoxib 12.5 mg and celecoxib 200 mg in two similarly designed osteoarthritis studies. Curr Med Res Opin. 2006;22:199-210. [PMID: 16393445]
73.
Clegg DOReda DJHarris CLKlein MAO'Dell JRHooper MMet al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808. [PMID: 16495392]
74.
Bingham CO 3rdSebba AIRubin BRRuoff GEKremer JBird Set al. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology (Oxford). 2007;46:496-507. [PMID: 16936327]
75.
Boswell DJOstergaard KPhilipson RSHodge RABlum DBrown JCet al. Evaluation of GW406381 for treatment of osteoarthritis of the knee: two randomized, controlled studies. Medscape J Med. 2008;10:259. [PMID: 19099009]
76.
Asmus MJEssex MNBrown PBMallen SR. Efficacy and tolerability of celecoxib in patients with osteoarthritis who previously did not respond to or did not tolerate naproxen and ibuprofen: results from 2 identically designed randomized trials. Osteoarthritis Cartilage. 2013;21(Suppl):S253.
77.
Bradley JDBrandt KDKatz BPKalasinski LARyan SI. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325:87-91. [PMID: 2052056]
78.
Williams HJWard JREgger MJNeuner RBrooks RHClegg DOet al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum. 1993;36:1196-206. [PMID: 8216413]
79.
Pincus TKoch GGSokka TLefkowith JWolfe FJordan JMet al. A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis Rheum. 2001;44:1587-98. [PMID: 11465710]
80.
Doherty MHawkey CGoulder MGibb IHill NAspley Set al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis. 2011;70:1534-41. [PMID: 21804100]  doi: 10.1136/ard.2011.154047
81.
Geba GPWeaver ALPolis ABDixon MESchnitzer TJVioxx, Acetaminophen, Celecoxib Trial (VACT) Group. Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial. JAMA. 2002;287:64-71. [PMID: 11754710]
82.
Schnitzer TJWeaver ALPolis ABPetruschke RAGeba GPVACT-1 and VACT-2 (Protocols 106 and 150) Study Groups. Efficacy of rofecoxib, celecoxib, and acetaminophen in patients with osteoarthritis of the knee. A combined analysis of the VACT studies. J Rheumatol. 2005;32:1093-105. [PMID: 15940774]
83.
Adams MEAtkinson MHLussier AJSchulz JISiminovitch KAWade JPet al. The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage. 1995;3:213-25. [PMID: 8689457]
84.
Altman RDMoskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol. 1998;25:2203-12. [PMID: 9818665]
85.
Dickson DJHosie GEnglish JR. A double blind, placebo-controlled comparison of hylan GF-20 against diclofenac in knee OA. J Clin Res. 2001;4:41-52.
86.
Petrella RJDiSilvestro MDHildebrand C. Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med. 2002;162:292-8. [PMID: 11822921]
87.
Ishijima MNakamura TShimizu KHayashi KKikuchi HSoen Set alResearch Group of Cartilage Metabolism. Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial. Arthritis Res Ther. 2014;16:R18. [PMID: 24443804]  doi: 10.1186/ar4446
88.
Novartis N. A randomized, double blind, placebo and Naproxen controlled, multi-center, study to determine the safety, tolerability, pharmacokinetics and effect on pain of a single intra-articular administration of Canakinumab in patients with osteoarthritis in the knee. [CACZ885C2201]. Novartis Clinical Trial Results Database. 2012.
89.
Leardini GFranceschini MMattara LBruno RPebrellini A. Intra-articular sodium hyaluronate (Hyalgan) in gonarthrosis: a controlled study comparing methylprednisolone acetate. Clin Trials J. 1987;24:341-50.
90.
Leardini GMattara LFranceschini MPerbellini A. Intra-articular treatment of knee osteoarthritis. A comparative study between hyaluronic acid and 6-methyl prednisolone acetate. Clin Exp Rheumatol. 1991;9:375-81. [PMID: 1934686]
91.
Pietrogrande VMelanotte PLD'Agnolo BUlivi MBenigni GATurchetto L. Htiluronic acid versus methylprednisolone intra-articularly injected for treatment of osteoarthritis of the knee. Curr Ther Re. 1991;50:691-701.
92.
Jones ACPattrick MDoherty SDoherty M. Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis. Osteoarthritis Cartilage. 1995;3:269-73. [PMID: 8689462]
93.
Tekeoglu IAdak BGoksoy TTosun N. Effects of intra-articular injection of sodium hyaluronate (Orthovisc) and betamethasone on osteoarthritis of the knee. J Rheum Med Rehab. 1998;9 4 220-224.
94.
Frizziero LPasquali Ronchetti I. Intra-articular treatment of osteoarthritis of the knee: an arthroscopic and clinical comparison between sodium hyaluronate (500-730 kDa) and methylprednisolone acetate. J Orthop Traumatol. 2002;3:89-96.
95.
Tasciotaoglu FOner C. Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis. Clin Rheumatol. 2003;22:112-7. [PMID: 12740675]
96.
Caborn DRush JLanzer WParenti DMurray CSynvisc 901 Study Group. A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee. J Rheumatol. 2004;31:333-43. [PMID: 14760806]
97.
Skwara APonelis RTibesku CORosenbaum DFuchs-Winkelmann S. Gait patterns after intraarticular treatment of patients with osteoarthritis of the knee—hyaluronan versus triamcinolone: a prospective, randomized, doubleblind, monocentric study. Eur J Med Res. 2009;14:157-64. [PMID: 19380288]
98.
Skwara APeterlein CDTibesku CORosenbaum DFuchs-Winkelmann S. Changes of gait patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the knee: a prospective, randomised, doubleblind study. Knee. 2009;16:466-72. [PMID: 19362003]  doi: 10.1016/j.knee.2009.03.003
99.
Shimizu MHiguchi HTakagishi KShinozaki TKobayashi T. Clinical and biochemical characteristics after intra-articular injection for the treatment of osteoarthritis of the knee: prospective randomized study of sodium hyaluronate and corticosteroid. J Orthop Sci. 2010;15:51-6. [PMID: 20151251]  doi: 10.1007/s00776-009-1421-0
100.
Housman LArden NSchnitzer TJet al. Intra-articular hylastan versus steroid for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2014;22:1684-92.
101.
Leighton RAkermark CTherrien RRichardson JBAndersson MTodman MGet alDUROLANE Study Group. NASHA hyaluronic acid vs. methylprednisolone for knee osteoarthritis: a prospective, multi-centre, randomized, non-inferiority trial. Osteoarthritis Cartilage. 2014;22:17-25. [PMID: 24185114]  doi: 10.1016/j.joca.2013.10.009
102.
Shichikawa KIgarashi MSugawara SIwasaki Y. Clinical evaluation of high molecular weight sodium hyaluronate (SPH) on osteoarthritis of the knee—a multi-center well controlled comparative study. Jpn J Clin Pharmacol Therapeut. 1983;14:545-58.
103.
Shichikawa KMaeda AOgawa N. [Clinical evaluation of sodium hyaluronate in the treatment of osteoarthritis of the knee]. Ryumachi. 1983;23:280-90. [PMID: 6364389]
104.
Bragantini ACassini MDe Bastiani GPerbellini A. Controlled single-blind trial of intra-articulary injected hyaluronic acid (Hyalgan®) in osteoarthritis of the knee. Clin Trials J. 1987;24:333-40.
105.
Grecomoro GMartorana UDi Marco C. Intra-articular treatment with sodium hyaluronate in gonarthrosis: a controlled clinical trial versus placebo. Pharmatherapeutica. 1987;5:137-41. [PMID: 3310017]
106.
Dixon ASJacoby RKBerry HHamilton EB. Clinical trial of intra-articular injection of sodium hyaluronate in patients with osteoarthritis of the knee. Curr Med Res Opin. 1988;11:205-13. [PMID: 3063436]
107.
Russell IJ MJLawrence VALessard JABriggs BTMay GS. A randomized placebo (PL) and no-intervention (NI) controlled, trial of intra-articular (IA) 1% sodium hyaluronate (HA) in the treatment of knee osteoarthritis (OA). Arthritis Rheum. 1992;(35 Suppl):S132.
108.
Dougados MNguyen MListrat VAmor B. High molecular weight sodium hyaluronate (hyalectin) in osteoarthritis of the knee: a 1 year placebo-controlled trial. Osteoarthritis Cartilage. 1993;1:97-103. [PMID: 8886085]
109.
Moreland LWArnold WJSaway ASavory CSikes D. Efficacy and safety of intra-articular Hylan G-F20 (Synvisc®), a viscoelastic derivative of hyaluronan, in patients with osteoarthritis of the knee. Arthritis Rheum. 1993;36:S165.
110.
Puhl WBernau AGreiling HKöpcke WPförringer WSteck KJet al. Intra-articular sodium hyaluronate in osteoarthritis of the knee: a multicenter, double-blind study. Osteoarthritis Cartilage. 1993;1:233-41. [PMID: 15449510]
111.
Cohen MAShiroky JBBallachey MLNeville CEsdaile JM. Double-blind randomized trial of intra-articular (I/A) hyaluronate in the treatment of osteoarthritis of the knee. Arthritis Rheum. 1994;37(Suppl):R31.
112.
Creamer PSharif MGeorge EMeadows KCushnaghan JShinmei Met al. Intra-articular hyaluronic acid in osteoarthritis of the knee: an investigation into mechanisms of action. Osteoarthritis Cartilage. 1994;2:133-40. [PMID: 11548229]
113.
Dahlberg LLohmander LSRyd L. Intraarticular injections of hyaluronan in patients with cartilage abnormalities and knee pain. A one-year double-blind, placebo-controlled study. Arthritis Rheum. 1994;37:521-8. [PMID: 8147929]
114.
Henderson EBSmith ECPegley FBlake DR. Intra-articular injections of 750 kD hyaluronan in the treatment of osteoarthritis: a randomised single centre double-blind placebo-controlled trial of 91 patients demonstrating lack of efficacy. Ann Rheum Dis. 1994;53:529-34. [PMID: 7944639]
115.
Scale DWobig MWolpert W. Viscosupplementation of osteoarthritic knees with hylan: A treatment schedule study. Curr Therap Res Clin Exp. 1994;55:220-32.
116.
Carrabba MParesce EAngelini MRe KATorchiana EEMPerbellini A. The safety and efficacy of different dose schedules of hyaluronic acid in the treatment of painful osteoarthritis of the knee with joint effusion. Eur J Rheumatol Inflamm. 1995;15:25-31.
117.
Corrado EMPeluso GFGigliotti Set al. The effects of intra-articular administration of hyaluronic acid on osteoarthritis of the knee: a clinical study with immunological and biochemical evaluations. Eur J Rheumatol Inflamm. 1995;15:47-56.
118.
Sodium Hyaluronate (SUPARTZ) PMA P980044: Summary of Safety and Effectiveness Data. 24 January 2001. Accessed at www.accessdata.fda.gov/cdrh_docs/pdf/P980044b.pdf on 20 September 2013.
119.
Formiguera Sala SEsteve de Miguel R. Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: a short term study. Eur J Rheumatol Inflamm. 1995;15:33-8.
120.
Lohmander LSDalén NEnglund GHämäläinen MJensen EMKarlsson Ket al. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Hyaluronan Multicentre Trial Group. Ann Rheum Dis. 1996;55:424-31. [PMID: 8774159]
121.
Wu JJShih LYHsu HCChen TH. The double-blind test of sodium hyaluronate (ARTZ) on osteoarthritis knee. Zhonghua Yi Xue Za Zhi (Taipei). 1997;59:99-106. [PMID: 9175299]
122.
Wobig MDickhut AMaier RVetter G. Viscosupplementation with hylan G-F 20: a 26-week controlled trial of efficacy and safety in the osteoarthritic knee. Clin Ther. 1998;20:410-23. [PMID: 9663358]
123.
Huskisson ECDonnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford). 1999;38:602-7. [PMID: 10461471]
124.
Brandt KDBlock JAMichalski JPMoreland LWCaldwell JRLavin PT. Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. ORTHOVISC Study Group. Clin Orthop Relat Res. 2001:130-43. [PMID: 11302304]
125.
Bunyaratavej NChan KMSubramanian N. Treatment of painful osteoarthritis of the knee with hyaluronic acid. Results of a multicenter Asian study. J Med Assoc Thai. 2001;84 Suppl 2:S576-81. [PMID: 11853284]
126.
Tamir ERobinson DKoren RAgar GHalperin N. Intra-articular hyaluronan injections for the treatment of osteoarthritis of the knee: a randomized, double blind, placebo controlled study. Clin Exp Rheumatol. 2001;19:265-70. [PMID: 11407078]
127.
Karlsson JSjögren LSLohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology (Oxford). 2002;41:1240-8. [PMID: 12421996]
128.
Saravanan VMTStobbs DDaymond TJ. Inflammatory effusion after viscosupplementation with Hylan G-F 20 [Abstract 336]. Rheumatology. 2002;41 Suppl 1 121.
129.
Jubb RWPiva SBeinat LDacre JGishen P. A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee. Int J Clin Pract. 2003;57:467-74. [PMID: 12918884]
130.
Tsai CLChang CCChen SCBeinat LPiva S. Treatment of knee osteoarthritis in Asian population with an intra-articular hyaluronan of MW 500-730 KDa [Abstract P333]. Osteoarthritis Cartilage. 2003;11 Suppl A 119.
131.
Altman RDAkermark CBeaulieu ADSchnitzer TDurolane International Study Group. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2004;12:642-9. [PMID: 15262244]
132.
Day RBrooks PConaghan PGPetersen MMulticenter Trial Group. A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. J Rheumatol. 2004;31:775-82.
133.
Pham TLe Henanff ARavaud PDieppe PPaolozzi LDougados M. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis. 2004;63:1611-7. [PMID: 15331394]
134.
Cubukçu DArdiç FKarabulut NTopuz O. Hylan G-F 20 efficacy on articular cartilage quality in patients with knee osteoarthritis: clinical and MRI assessment. Clin Rheumatol. 2005;24:336-41. [PMID: 15599642]
135.
Neustadt DCaldwell JBell MWade JGimbel J. Clinical effects of intraarticular injection of high molecular weight hyaluronan (Orthovisc) in osteoarthritis of the knee: a randomized, controlled, multicenter trial. J Rheumatol. 2005;32:1928-36. [PMID: 16206349]
136.
Rolf CGEngstrom BOhrvik JValentin ALilja BLevine DW. A comparative study of the efficacy and safety of hyaluronan viscosupplements and placebo in patients with symptomatic and arthroscopy-verified cartilage pathology. J Drug Assess. 2005;8:183-200.
137.
Sezgin MDemirel ACKaraca COrtancil OUlkar GBKanik Aet al. Does hyaluronan affect inflammatory cytokines in knee osteoarthritis? Rheumatol Int. 2005;25:264-9. [PMID: 14999424]
138.
Kotevoglu NIyibozkurt PCHiz OToktas HKuran B. A prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis. Rheumatol Int. 2006;26:325-30. [PMID: 15959784]
139.
Petrella RJPetrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol. 2006;33:951-6. [PMID: 16652426]
140.
Blanco FJFernández-Sueiro JLPinto-Tasende JAet al. Intra-articular hyaluronan treatment of patients with knee osteoarthritis waiting for replacement surgery. Open Arthritis J. 2008;1:1-7.
141.
Lundsgaard CDufour NFallentin EWinkel PGluud C. Intra-articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis: a randomized clinical trial. Scand J Rheumatol. 2008;37:142-50. [PMID: 18415773]  doi: 10.1080/03009740701813103
142.
Petrella RJCogliano ADecaria J. Combining two hyaluronic acids in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Clin Rheumatol. 2008;27:975-81. [PMID: 18204873]  doi: 10.1007/s10067-007-0834-4
143.
Sanofi-Aventis. A double blind, randomized trial of intra-articular injections of 20 mg of HYALGAN for the treatment of knee pain due to osteoarthritis [NCT00130468]. 2008. Accessed at http://en.sanofi.com/img/content/study/L_9385_summary.pdf on 8 July 2015.
144.
Altman RDRosen JEBloch DAHatoum HTKorner P. A double-blind, randomized, saline-controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis of the knee, with an open-label safety extension (the FLEXX trial). Semin Arthritis Rheum. 2009;39:1-9. [PMID: 19539353]  doi: 10.1016/j.semarthrit.2009.04.001
145.
Baltzer AWMoser CJansen SAKrauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17:152-60. [PMID: 18674932]  doi: 10.1016/j.joca.2008.06.014
146.
Diracoglu DVural MBaskent ADikici FAksoy C. The effect of viscosupplementation on neuromuscular control of the knee in patients with osteoarthritis. J Back Musculoskelet Rehabil. 2009;22:1-9. [PMID: 20023357]  doi: 10.3233/BMR-2009-0207
147.
Chevalier XJerosch JGoupille Pvan Dijk NLuyten FPScott DLet al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis. 2010;69:113-9. [PMID: 19304567]  doi: 10.1136/ard.2008.094623
148.
Jørgensen AStengaard-Pedersen KSimonsen OPfeiffer-Jensen MEriksen CBliddal Het al. Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Ann Rheum Dis. 2010;69:1097-102. [PMID: 20447955]  doi: 10.1136/ard.2009.118042
149.
Kul-Panza EBerker N. Is hyaluronate sodium effective in the management of knee osteoarthritis? A placebo-controlled double-blind study. Minerva Med. 2010;101:63-72. [PMID: 20467406]
150.
Huang TLChang CCLee CHChen SCLai CHTsai CL. Intra-articular injections of sodium hyaluronate (Hyalgan®) in osteoarthritis of the knee. a randomized, controlled, double-blind, multicenter trial in the Asian population. BMC Musculoskelet Disord. 2011;12:221. [PMID: 21978211]  doi: 10.1186/1471-2474-12-221
151.
Navarro-Sarabia FCoronel PCollantes ENavarro FJde la Serna ARNaranjo Aet alAMELIA study group. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011;70:1957-62. [PMID: 21852252]  doi: 10.1136/ard.2011.152017
152.
DeCaria JEMontero-Odasso MWolfe DChesworth BMPetrella RJ. The effect of intra-articular hyaluronic acid treatment on gait velocity in older knee osteoarthritis patients: a randomized, controlled study. Arch Gerontol Geriatr. 2012;55:310-5. [PMID: 22169699]  doi: 10.1016/j.archger.2011.11.007
153.
Ferring Pharmaceuticals. A 26 week, double-blind, randomized, placebo-controlled study of the efficacy and safety of single intra-articular injection 1.2% sodium hyaluronate for treatment of painful osteoarthritis of the knee, with optional 26-week open-label safety extension (NCT00988091) Last updated 13 June 2012 Accessed at https://clinicaltrials.gov/ct2/show/NCT00988091?term=NCT00988091&rank=1 on 12 May 2015.
154.
Kosuwon WSirichatiwapee WVisanuyotin TJeeravipoolvarn PLaupattarakasem W. Determination of cartilage volume using MRI in patients with knee osteoarthritis: efficacy study of 25 milligrams of sodium hyaluronate (2.5 Ml) versus placebo. Clin Exp Pharmacol. 2012;2 2 1.
155.
Strand VBaraf HSLavin PTLim SHosokawa H. A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 2012;20:350-6. [PMID: 22342928]  doi: 10.1016/j.joca.2012.01.013
156.
Arden NKÅkermark CAndersson MTodman MGAltman RD. A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin. 2014;30:279-86. [PMID: 24168077]  doi: 10.1185/03007995.2013.855631
157.
van der Weegen WWullems JABos ENoten Hvan Drumpt RA. No difference between intra-articular injection of hyaluronic Acid and placebo for mild to moderate knee osteoarthritis: a randomized, controlled, double-blind trial. J Arthroplasty. 2015;30:754-7. [PMID: 25548079]  doi: 10.1016/j.arth.2014.12.012
158.
Friedman DMMoore ME. The efficacy of intraarticular steroids in osteoarthritis: a double-blind study. J Rheumatol. 1980;7:850-6. [PMID: 7009857]
159.
Gaffney KLedingham JPerry JD. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response. Ann Rheum Dis. 1995;54:379-81. [PMID: 7794044]
160.
Jones ADoherty M. Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Ann Rheum Dis. 1996;55:829-32. [PMID: 8976640]
161.
Ravaud PMoulinier LGiraudeau BAyral XGuerin CNoel Eet al. Effects of joint lavage and steroid injection in patients with osteoarthritis of the knee: results of a multicenter, randomized, controlled trial. Arthritis Rheum. 1999;42:475-82. [PMID: 10088770]
162.
Raynauld JPBuckland-Wright CWard RChoquette DHaraoui BMartel-Pelletier Jet al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2003;48:370-7. [PMID: 12571845]
163.
Chao JWu CSun BHose MKQuan AHughes THet al. Inflammatory characteristics on ultrasound predict poorer long-term response to intraarticular corticosteroid injections in knee osteoarthritis. J Rheumatol. 2010;37:650-5. [PMID: 20080918]  doi: 10.3899/jrheum.090575
164.
Yavuz USökücü SAlbayrak AOztürk K. Efficacy comparisons of the intraarticular steroidal agents in the patients with knee osteoarthritis. Rheumatol Int. 2012;32:3391-6. [PMID: 22057944]  doi: 10.1007/s00296-011-2188-0
165.
Ottillinger BGömör BMichel BAPavelka KBeck WElsasser U. Efficacy and safety of eltenac gel in the treatment of knee osteoarthritis. Osteoarthritis Cartilage. 2001;9:273-80. [PMID: 11300751]
166.
Bookman AAWilliams KSShainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ. 2004;171:333-8. [PMID: 15313991]
167.
Roth SHShainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164:2017-23. [PMID: 15477437]
168.
Tugwell PSWells GAShainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002-12. [PMID: 15468367]
169.
Baer PAThomas LMShainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskelet Disord. 2005;6:44. [PMID: 16086839]
170.
Baraf HSGloth FMBarthel HRGold MSAltman RD. Safety and efficacy of topical diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: pooled data from three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials. Drugs Aging. 2011;28:27-40. [PMID: 21174485]  doi: 10.2165/11584880-000000000-00000
171.
Baraf HSGold MSClark MBAltman RD. Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: a randomized controlled trial. Phys Sportsmed. 2010;38:19-28. [PMID: 20631460]  doi: 10.3810/psm.2010.06.1779
172.
Barthel HRHaselwood DLongley S 3rdGold MSAltman RD. Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009;39:203-12. [PMID: 19932833]  doi: 10.1016/j.semarthrit.2009.09.002
173.
Conaghan PGDickson JBolten WCevc GRother M. A multicentre, randomized, placebo- and active-controlled trial comparing the efficacy and safety of topical ketoprofen in Transfersome gel (IDEA-033) with ketoprofen-free vehicle (TDT 064) and oral celecoxib for knee pain associated with osteoarthritis. Rheumatology (Oxford). 2013;52:1303-12. [PMID: 23542612]  doi: 10.1093/rheumatology/ket133
174.
Kneer WRother MMazgareanu SSeidel EJEuropean IDEA-033 study group. A 12-week randomized study of topical therapy with three dosages of ketoprofen in Transfersome gel (IDEA-033) compared with the ketoprofen-free vehicle (TDT 064), in patients with osteoarthritis of the knee. J Pain Res. 2013;6:743-53. [PMID: 24187510]  doi: 10.2147/JPR.S51054
175.
Rother MConaghan PG. A randomized, double-blind, phase III trial in moderate osteoarthritis knee pain comparing topical ketoprofen gel with ketoprofen-free gel. J Rheumatol. 2013;40:1742-8. [PMID: 23996292]  doi: 10.3899/jrheum.130192
176.
Sandelin JHarilainen ACrone HHamberg PForsskåhl BTamelander G. Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel. Scand J Rheumatol. 1997;26:287-92. [PMID: 9310109]
177.
Rother MLavins BJKneer WLehnhardt KSeidel EJMazgareanu S. Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial. Ann Rheum Dis. 2007;66:1178-83. [PMID: 17363401]
178.
Simon LSGrierson LMNaseer ZBookman AAZev Shainhouse J. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143:238-45. [PMID: 19380203]  doi: 10.1016/j.pain.2009.03.008

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 163Number 51 September 2015
Pages: 365 - 372

History

Published online: 1 September 2015
Published in issue: 1 September 2015

Keywords

Authors

Affiliations

Raveendhara R. Bannuru, MD, PhD
From Tufts Medical Center, Sackler School of Graduate Biomedical Sciences of Tufts University, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.
Timothy E. McAlindon, MD
From Tufts Medical Center, Sackler School of Graduate Biomedical Sciences of Tufts University, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.
Matthew C. Sullivan, BA
From Tufts Medical Center, Sackler School of Graduate Biomedical Sciences of Tufts University, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.
John B. Wong, MD
From Tufts Medical Center, Sackler School of Graduate Biomedical Sciences of Tufts University, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.
David M. Kent, MD
From Tufts Medical Center, Sackler School of Graduate Biomedical Sciences of Tufts University, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.
Christopher H. Schmid, PhD
From Tufts Medical Center, Sackler School of Graduate Biomedical Sciences of Tufts University, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.
Grant Support: By the Agency for Healthcare Research and Quality.
Disclosures: Dr. Bannuru reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and grants and personal fees from the American College of Rheumatology and Sanofi outside the submitted work. Dr. McAlindon reports grants from Croma, Flexion Therapeutics, the National Institutes of Health, the Agency for Healthcare Research and Quality, Fidia, Sanofi-Aventis, Samumed, and AbbVie and personal fees from Novartis, McNeil, Bioventus, and the Federal Trade Commission outside the submitted work. Dr. Wong reports grants from the Patient-Centered Outcomes Research Institute and National Institutes of Health National Center for Complementary and Alternative Medicine and nonfinancial support from the European League Against Rheumatism outside the submitted work. Dr. Kent reports grants from the National Institutes of Health during the conduct of the study. Dr. Schmid reports grants from Brown University during the conduct of the study and personal fees from Pfizer outside the submitted work. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0623.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Corresponding Author: Raveendhara R. Bannuru, MD, PhD, Center for Treatment Comparison and Integrative Analysis (CTCIA), Tufts Medical Center, 800 Washington Street, Box #406, Boston, MA 02111; e-mail, [email protected].
Current Author Addresses: Drs. Bannuru and McAlindon and Mr. Sullivan: Division of Rheumatology, Tufts Medical Center, 800 Washington Street, Box 406, Boston, MA 02111.
Dr. Kent: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.
Dr. Wong: Division of Clinical Decision Making, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.
Dr. Schmid: Brown University School of Public Health, 121 South Main Street, Providence, RI 02912.
Author Contributions: Conception and design: R.R. Bannuru, T.E. McAlindon, D.M. Kent, C.H. Schmid.
Analysis and interpretation of the data: R.R. Bannuru, T.E. McAlindon, J.B. Wong, D.M. Kent, C.H. Schmid.
Drafting of the article: R.R. Bannuru, M.C. Sullivan, J.B. Wong, D.M. Kent, C.H. Schmid.
Critical revision of the article for important intellectual content: R.R. Bannuru, T.E. McAlindon, M.C. Sullivan, J.B. Wong, D.M. Kent, C.H. Schmid.
Final approval of the article: R.R. Bannuru, T.E. McAlindon, M.C. Sullivan, J.B. Wong, D.M. Kent, C.H. Schmid.
Provision of study materials or patients: R.R. Bannuru, D.M. Kent.
Statistical expertise: R.R. Bannuru, C.H. Schmid.
Obtaining of funding: R.R. Bannuru, D.M. Kent.
Administrative, technical, or logistic support: R.R. Bannuru.
Collection and assembly of data: R.R. Bannuru, M.C. Sullivan, D.M. Kent.
This article was published online first at www.annals.org on 28 July 2015.

Metrics & Citations

Metrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format





Download article citation data for:
Raveendhara R. Bannuru, Timothy E. McAlindon, Matthew C. Sullivan, et al. Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials. Ann Intern Med.2015;163:365-372. [Epub 1 September 2015]. doi:10.7326/M15-0623

View More

Get Access

Login Options:
Purchase

You will be redirected to acponline.org to sign-in to Annals to complete your purchase.

Create your Free Account

You will be redirected to acponline.org to create an account that will provide access to Annals.

View options

PDF/ePub

View PDF/ePub

Related in ACP Journals

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media