Abstract
Background and aim
Diclofenac is widely prescribed for the treatment of pain. Several network meta-analyses (NMA), largely of published trials have evaluated the efficacy, tolerability, and safety of nonsteroidal anti-inflammatory drugs (NSAIDs). The present NMA extends these analyses to unpublished older (legacy) diclofenac trials.
Methods
We identified randomised controlled trials (RCTs) of diclofenac with planned study duration of at least 4 weeks for the treatment of osteoarthritis (OA) from ‘legacy’ studies conducted by Novartis but not published in a peer reviewed journal or included in any previous pooled analyses. All studies reporting efficacy and/or safety of treatment with diclofenac or other active therapies or placebo were included. We used a Bayesian NMA model, and estimated relative treatment effects between pairwise treatments. Main outcomes included pain relief measured using visual analogue scale at 2, 4 and 12 weeks and patient global assessment (PGA) at 4 and 12 weeks for efficacy, all-cause withdrawals, and adverse events.
Results
A total of 19 RCTs (5030 patients) were included; 18 of which were double-blind and one singleblind. All studies were conducted before cyclooxygenase 2 inhibitors (COXIBs) became commercially available. Data permitted robust efficacy comparison between diclofenac and ibuprofen, but the amount of data for other comparators was limited. Diclofenac 150 mg/day was more efficacious than ibuprofen 1200 mg/day and had likely favourable outcomes for pain relief compared to ibuprofen 2400 mg/day. Diclofenac 100 mg/day had likely favourable outcomes compared to ibuprofen 1200 mg/day in alleviating pain. Based on PGA, diclofenac 150 mg/day was more efficacious and likely to be favourable than ibuprofen 1200 mg/day and 2400 mg/day, respectively. Risk of withdrawal due to all causes with diclofenac and ibuprofen were comparable. Diclofenac 150 mg/day was likely to have favourable efficacy and comparable tolerability with diclofenac 100 mg/day. Results comparing diclofenac and ibuprofen were similar to those from NMAs of published trials.
Conclusions
Results from these unpublished ‘legacy’ studies were similar to those from NMAs of published trials. The favourable efficacy results of diclofenac compared to ibuprofen expand the amount of available evidence comparing these two NSAIDs. The overall benefit-risk profile of diclofenac was comparable to that of ibuprofen in OA.
Implications
The present NMA results reassures that the older unpublished blinded trials have similar results compared to more recently published trials and also contributes to increase the transparency of clinical trials performed with diclofenac further back in the past.
Authors’ contributions: RMN conceptualised and designed the study.
The study was conducted and the data were analysed by RMN and PG.
PG was involved in data collection.
Interpretation of data was done by RMN, PG, RAM, SP and RLC. All the authors drafted the manuscript and revised the contents. They also approved the final version and were responsible for the integrity of data analysis.
Conflict of interest: This study was conducted by Mapi on behalf of Novartis Pharma AG (Basel, Switzerland) who funded the study. PG is an employee of Mapi and served as paid consultant to Novartis during the conduct of this study and the preparation of this manuscript. SP, RN, AI, and RLC are employees of Novartis and are thus eligible for Novartis stock and stock options. RAM has no competing interests to declare in this work.
Funding: The study was funded by Novartis Pharma AG.
Acknowledgements
Authors thank Andreas Karabis (Mapi Group, The Netherlands) for his help in study conduct and preparation of the manuscript. The authors also thank Jitendriya Mishra (Novartis Healthcare Pvt. Ltd., Hyderabad, India) for providing medical writing assistance on this manuscript. Funding for writing assistance was provided by Novartis Pharma AG.
This manuscript is dedicated to the memory of Richard M. Nixon.
References
[1] Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, AlMazroa MA, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basáñez M-G, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabé E, Bhalla K, Bhandari B, Bikbov B, Abdulhak AB, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braith-waite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT-A, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fèvre EM, Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FGR, Franklin R, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gosselin R, Grainger R, Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum N, Kawakami N, Keren A, Khoo J-P, King CH, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh J, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M, Ohno SL, Lyons R, Ma J, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGill N, McGrath J, Medina-Mora ME, Meltzer M, Memish ZA, Mensah GA, Merriman TR, Meyer A-C, Miglioli V, Miller M, Miller TR, Mitchell PB, Mocumbi AO, Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KMV, Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R, O’Donnell M, O’Hanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope Iii CA, Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Leòn FR, Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S, Shepard DS, Shin H, Shivakoti R, Silberberg D, Singh D, Singh GM, Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL, Stapelberg NJC, Steer A, Steiner T, Stolk WA, Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K, Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams SRM, Witt E, Wolfe F, Woolf AD, Wulf S, Yeh P-H, Zaidi AKM, Zheng Z-J, Zonies D, Lopez AD, Murray CJL. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163–96.10.1016/S0140-6736(12)61729-2Search in Google Scholar
[2] Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med 2015;162:46–54.10.7326/M14-1231Search in Google Scholar
[3] Conaghan PG, Peloso PM, Everett SV, Rajagopalan S, Black CM, Mavros P, Arden NK, Phillips CJ, Rannou F, van de Laar MA, Moore RA, Taylor SD. Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies. Rheumatology (Oxford, England) 2015;54:270–7.10.1093/rheumatology/keu332Search in Google Scholar
[4] Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, Citrome L, Gurr JA, Mooney LA, Moore BJ, Peña T, Sanes-Miller CH, Veitch K, Woolley KL, Yarker YE. Good Publication Practice for communicating company-sponsored medical research: GPP3Good Publication Practice for Company-Sponsored Research (GPP3). Ann Intern Med 2015;163:461–4.10.7326/M15-0288Search in Google Scholar
[5] https://www.novartis.com/sites/www.novartis.com/files/novartispublicationguidelinesposting.pdf.Search in Google Scholar
[6] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996;17:1–12.10.1016/0197-2456(95)00134-4Search in Google Scholar
[7] Caldwell DM, Ades AE, Higgins JPT. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. Br Med J 2005;331:897–900.10.1136/bmj.331.7521.897Search in Google Scholar
[8] Jansen JP, Fleurence R, Devine B, Itzler R, Barrett A, Hawkins N, Lee K, Boersma C, Annemans L, Cappelleri JC. Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. Value in Health 2011;14:417–28.10.1016/j.jval.2011.04.002Search in Google Scholar
[9] Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004;23:3105–24.10.1002/sim.1875Search in Google Scholar
[10] Dias S, Sutton AJ, Ades AE, Welton 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;33:607–17.10.1177/0272989X12458724Search in Google Scholar
[11] Spiegelhalter DJ, Best NG, Carlin BP, Van Der Linde A. Bayesian measures of model complexity and fit. J R Stat Soc Series B Stat Methodol 2002;64:583–639.10.1111/1467-9868.00353Search in Google Scholar
[12] van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, Moore RA. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis. Arthritis Res Ther 2015;17:66.10.1186/s13075-015-0554-0Search in Google Scholar
[13] Cope S, Donohue JF, Jansen JP, Kraemer M, Capkun-Niggli G, Baldwin M, Buckley F, Ellis A, Jones P. Comparative efficacy of long-acting bronchodilators for COPD – a network meta-analysis. Respir Res 2013;14:100.10.1186/1465-9921-14-100Search in Google Scholar
[14] Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382:769–79.10.1016/S0140-6736(13)60900-9Search in Google Scholar
[15] da Costa BR, Reichenbach S, Keller N, Nartey L, Wandel S, Juni P, Trelle S. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet 2016, http://dx.doi.org/10.1016/s0140-6736(16)30002-2.10.1016/S0140-6736(16)30002-2Search in Google Scholar
[16] Moore RA, Barden J. Systematic review of dexketoprofen in acute and chronic pain. BMC Clin Pharmacol 2008;8:11.10.1186/1472-6904-8-11Search in Google Scholar
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.sjpain.2017.03.006.
- Abbreviations
- AE
adverse event
- CFB
change from baseline
- CNT
Coxib and tNSAID Trialists’
- CrI
credible interval
- CSR
clinical study reports
- DIC
deviance information criterion
- IGA
investigator global assessment
- ITT
intention-to-treat
- NMA
network meta-analysis
- OA
osteoarthritis
- PGA
patient global assessment
- RCT
randomised controlled trials
- SAE
serious adverse event
- tNSAID
traditional non-steroidal anti-inflammatory drug
- VAS
visual analogue scale
© 2017 Scandinavian Association for the Study of Pain