Among the 34 high-quality, 23 moderate-quality, and 1 low-quality studies that met the inclusion criteria, non-selective and selective clyclooxygenase-2 (COX-2) oral nonsteroidal anti-inflammatory drugs (NSAID) consistently improved pain and function compared to controls in the treatment of osteoarthritis of the knee (Reginster 2017; Lee 2017; Gordo 2017; Strand 2017; Essex 2014; Kongtharvonskul 2016; Altman 2015; Gibofsky 2014; Ishijima 2014; Conaghan 2013; Essex 2012; Singh 2012; Elsaman 2016; Schnitzer 2011; Kivitz 2004; Fleischmann 1997; Lee 1986; Davies 1999; Sandelin 1997; Puopolo 2007; Gibofsky 2003; Bensen 1999; Kivits 2002; Clegg 2006; Sangdee 2002; Sheldon 2005; Tannenbaum 2004; Lehmann 2005; Rother 2007; Simon 2009; Svensson 2006; Schnitzer 2010; Doherty 2011; McKenna 2001 (a); Paul 2009; Bolten 2015; Essex 2016; Ekman 2014; Ohtori 2013; Selvan 2012; Pavelka 2007; Ehrich 1999; Lee 1985; Dwicandra 2018; Asmus 2014; Smugar 2006; Bingham 2007; Altman 1998; Schnitzer 1999; Birbara 2006; Williams 2001; Miceli 2004; Mckenna 2001 (b); Pincus 2004; Lohmander 2005; Schnitzer 2005b; Williams 2000; Fleischmann 2006). Although meta-analysis of non-selective oral NSAIDs compared to controls demonstrated a meaningful reduction in pain, the results need to be interpreted with caution due to the relatively high degree of heterogeneity. The meta-analysis of non-selective oral NSAIDs compared to controls demonstrated a meaningful improvement in function with an acceptable degree of heterogeneity. In terms of selective COX-2 oral NSAIDs, the meta-analysis of celecoxib, the only available selective COX-2 oral NSAID on the United States market, demonstrated a meaningful reduction in pain and improved function with an acceptable degree of heterogeneity. The comparison of non-selective and selective COX-2 oral NSAIDs shows no significant difference in the effectiveness between the types of oral NSAIDs (Gordo 2017; Essex 2014; Essex 2016; Essex 2012; Bensen 1999; Kivits 2002; Kivitz 2004; Puopolo 2007; Hochberg 2011; Mckenna 2001 (b); Schnitzer 2005b; Malik 2017). Although NSAIDs effectively reduce pain and improve function in the treatment of osteoarthritis of the knee, providers should consider patient comorbidities, the type of NSAID administered, dose, and duration of administration. In fact, the United States Food and Drug Administration (FDA) has a black-box warning for NSAIDs citing an increased risk of serious cardiovascular thrombotic events and serious gastrointestinal events. Therefore, we recommend the lowest effective dose for the shortest duration possible for the patient. Although selective COX-2 oral NSAIDs were developed to reduce gastrointestinal adverse events compared to non-selective oral NSAIDs, meta-analysis did not reveal a significant reduction in gastrointestinal adverse events.
Benefits/Harms of Implementation
Although oral NSAIDs are widely used to treat osteoarthritis of the knee, providers must recognize the specific risks associated with each medication. Specific patient contraindications need to be assessed on an individual basis (Example: patient with cardiac conditions have an increased risk of myocardial infarction).
Outcome Importance
The most important consideration will be removal of oral narcotics from the medications prescribed in the treatment of osteoarthritis of the knee. This becomes particularly significant due to the rise of the opioid epidemic in the United States.
Cost Effectiveness/Resource Utilization
Evidence based decision making in selecting the optimal systemic treatment for the treatment of symptomatic knee osteoarthritis should result in improved pain and function. For a given systematic treatments as effectiveness increases without raising the risk of adverse events so will its cost-effectiveness. To date, the most cost-effective systemic treatment is still to be determined.
Acceptability
Currently oral NSAIDs are commonly utilized approach in treating symptomatic knee osteoarthritis, hence there should be no issues implementing this recommendation as it does not influence a major change in clinical practice, and it provides further evidence to support and guide these practices.
Feasibility
This recommendation may be implemented immediately having a potential positive impact in clinical practice.
Future Research
Most important future research will provide high quality investigation through either prospective randomized trials or prospective cohort studies to establish efficacy within specific subgroups and populations to tailor systemic medications increasing efficacy and decreasing risk of adverse effects
- Reginster, J. Y., Dudler, J., Blicharski, T., Pavelka, K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT). Annals of the Rheumatic Diseases 2017; 9: 1537-1543
- Rother, M., Lavins, B. J., Kneer, W., Lehnhardt, K., Seidel, E. J., Mazgareanu, 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. Annals of the Rheumatic Diseases 2007; 9: 1178-1183
- Sandelin, J., Harilainen, A., Crone, H., Hamberg, P., Forsskåhl, B., Tamelander, 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. Scandinavian Journal of Rheumatology 1997; 4: 287- 292
- Sangdee, C., Teekachunhatean, S., Sananpanich, K., Sugandhavesa, N., Chiewchantanakit, S., Pojchamarnwiputh, S., Jayasvasti, S. Electroacupuncture versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. BMC Complementary and Alternative Medicine 2002; 0: 3
- Schnitzer, T. J., Hochberg, M. C., Marrero, C. E., Duquesroix, B., Frayssinet, H., Beekman, M. Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. Seminars in Arthritis & Rheumatism 2011; 4: 285-97
- Schnitzer, T. J., Kamin, M., Olson, W. H. Tramadol allows reduction of naproxen dose among patients with naproxen-responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled study. Arthritis and Rheumatism 1999; 7: 1370-1377
- Schnitzer, T. J., Kivitz, A., Frayssinet, H., Duquesroix, B. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter study. Osteoarthritis and Cartilage 2010; 5: 629-639
- Schnitzer, T.J., Kivitz, A.J., Lipetz, R.S., Sanders, N. and Hee, A. (2005), Comparison of the COX?inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of Osteoarthritis of the knee. Arthritis & Rheumatism, 53: 827-837. https://doi.org/10.1002/art.21586
- Selvan, T., Rajiah, K., Nainar, M. S., Mathew, E. M. A clinical study on glucosamine sulfate versus combination of glucosamine sulfate and NSAIDs in mild to moderate knee osteoarthritis. Thescientificworldjournal 2012; 0: 902676
- Sheldon, E., Beaulieu, A., Paster, Z., Dutta, D., Yu, S., Sloan, V. S. Efficacy and tolerability of lumiracoxib in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind comparison with celecoxib and placebo. Clinical Therapeutics 2005; 1: 64-77
- Simon, L. S., Grierson, L. M., Naseer, Z., Bookman, A. A., Zev 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; 3: 238-245
- Singh, K., Sharma, R., Rai, J. Diacerein as adjuvant to diclofenac sodium in osteoarthritis knee. International Journal of Rheumatic Diseases 2012; 1: 69-77
- Smugar, S. S., Schnitzer, T. J., Weaver, A. L., Rubin, B. R., Polis, A. B., Tershakovec, A. M. Rofecoxib 12.5 mg, rofecoxib 25 mg, and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies. Current Medical Research and Opinion 2006; 7: 1353-1367
- Strand, V., Bergman, M., Singh, J. A., Gibofsky, A., Kivitz, A., Young, C. Low-dose SoluMatrix diclofenac in patients with osteoarthritis pain: impact on quality of life in a controlled trial. Clinical Rheumatology 2017; 6: 1357-1367
- Svensson, O., MalmenÃs, M., Fajutrao, L., Roos, E. M., Lohmander, L. S. Greater reduction of knee than hip pain in osteoarthritis treated with naproxen, as evaluated by WOMAC and SF-36. Annals of the Rheumatic Diseases 2006; 6: 781-784
- Tannenbaum, H., Berenbaum, F., Reginster, J. Y., Zacher, J., Robinson, J., Poor, G., Bliddal, H., Uebelhart, D., Adami, S., Navarro, F., et al., Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Annals of the Rheumatic Diseases 2004; 11: 1419-1426
- Williams, G. W., Ettlinger, R. E., Ruderman, E. M., Hubbard, R. C., Lonien, M. E., Yu, S. S., Zhao, W., Geis, G. S. Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib: a randomized, controlled trial. 2000; 2: 65-74
- Altman, R. D., Moskowitz, R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. Journal of Rheumatology 1998; 11: 2203-2212
- Altman, R., Hochberg, M., Gibofsky, A., Jaros, M., Young, C. Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week, phase 3 study. Current Medical Research & Opinion 2015; 12: 2331-43
- Asmus, M. J., Essex, M. N., Brown, P. B., Mallen, S. R. Efficacy and tolerability of celecoxib in osteoarthritis patients who previously failed naproxen and ibuprofen: Results from two trials. International Journal of Clinical Rheumatology 2014; 6: 551-558
- Bensen, W. G., Fiechtner, J. J., McMillen, J. I., Zhao, W. W., Yu, S. S., Woods, E. M., Hubbard, R. C., Isakson, P. C., Verburg, K. M., Geis, G. S. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clinic Proceedings 1999; 11: 1095â?1105
- Bingham, C. O., Sebba, A. I., Rubin, B. R., Ruoff, G. E., Kremer, J., Bird, S., Smugar, S. S., Fitzgerald, B. J., O'Brien, K., Tershakovec, A. M. 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, England) 2007; 3: 496â? 507
- Birbara, C., Ruoff, G., Sheldon, E., Valenzuela, C., Rodgers, A., Petruschke, R. A., Chang, D. J., Tershakovec, A. M. Efficacy and safety of rofecoxib 12.5 mg and celecoxib 200 mg in two similarly designed osteoarthritis studies. Current Medical Research and Opinion 2006; 1: 199â?210
- Bolten, W. W., Glade, M. J., Raum, S., Ritz, B. W. The safety and efficacy of an enzyme combination in managing knee osteoarthritis pain in adults: a randomized, double-blind, placebo-controlled trial. Arthritis 2015; 0: 251521
- Conaghan, P. G., Dickson, J., Bolten, W., Cevc, G., Rother, 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 2013; 7: 1303-12
- Davies, G. M., Watson, D. J., Bellamy, 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 and Research 1999; 3: 172â?179
- Doherty, M., Hawkey, C., Goulder, M., Gibb, I., Hill, N., Aspley, S., Reader, S. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Annals of the Rheumatic Diseases 2011; 9: 1534-1541
- Dwicandra, N. M. O., Jaya, M. K. A. The effect of diacerein and meloxicam combination versus meloxicam alone on physical function in patients with knee osteoarthritis. Asian Journal of Pharmaceutical and Clinical Research 2018; 10: 325-329
- Ehrich, E. W., Schnitzer, T. J., McIlwain, H., Levy, R., Wolfe, F., Weisman, M., Zeng, Q., Morrison, B., Bolognese, J., Seidenberg, B., Gertz, B. J. Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group. Journal of Rheumatology 1999; 11: 2438-47
- Ekman, E. F., Gimbel, J. S., Bello, A. E., Smith, M. D., Keller, D. S., Annis, K. M., Brown, M. T., West, C. R., Verburg, K. M. Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen. Journal of Rheumatology 2014; 11: 2249-59
- Elsaman, A. M., Radwan, A. R., Mohammed, W. I., Ohrndorf, S. Low-dose Spironolactone: Treatment for Osteoarthritis-related Knee Effusion. A Prospective Clinical and Sonographic-based Study. Journal of Rheumatology 2016; 6: 1114-20
- Essex, M. N., Behar, R., O'Connell, M. A., Brown, P. B. Efficacy and tolerability of celecoxib and naproxen versus placebo in Hispanic patients with knee osteoarthritis. International journal of general medicine 2014; 0: 227-35
- Essex, M. N., Bhadra, P., Sands, G. H. Efficacy and tolerability of celecoxib versus naproxen in patients with osteoarthritis of the knee: a randomized, double-blind, double-dummy trial. Journal of International Medical Research 2012; 4: 1357-70
- Essex, M. N., O'Connell, M. A., Behar, R., Bao, W. Efficacy and safety of nonsteroidal anti-inflammatory drugs in Asian patients with knee osteoarthritis: summary of a randomized, placebo-controlled study. International Journal of Rheumatic Diseases 2016; 3: 262-70
- Fleischmann, R. M., Flint, K., Constantine, G., Kolecki, B. A double-masked comparison of Naprelan and nabumetone in osteoarthritis of the knee. Naprelan Study Group. Clinical Therapeutics 1997; 4: 642-55
- Fleischmann, R., Sheldon, E., Maldonado-Cocco, J., Dutta, D., Yu, S., Sloan, V. S. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib. Clinical Rheumatology 2006; 1: 42-53
- Gibofsky, A., Hochberg, M. C., Jaros, M. J., Young, C. L. Efficacy and safety of low-dose submicron diclofenac for the treatment of osteoarthritis pain: a 12 week, phase 3 study. Current Medical Research & Opinion 2014; 9: 1883-93
- Gibofsky, A., Williams, G. W., McKenna, F., Fort, J. G. Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial. Arthritis and Rheumatism 2003; 11: 3102-3111
- Gordo, A. C., Walker, C., Armada, B., Zhou, D. Efficacy of celecoxib versus ibuprofen for the treatment of patients with osteoarthritis of the knee: A randomized double-blind, non-inferiority trial. Journal of International Medical Research 2017; 1: 59-74
- Ishijima, M., Nakamura, T., Shimizu, K., Hayashi, K., Kikuchi, H., Soen, S., Omori, G., Yamashita, T., Uchio, Y., Chiba, J., Ideno, Y., Kubota, M., Kurosawa, H., Kaneko, K., Research 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 Research & Therapy 2014; 1: R18
- Kivitz, A. J., Greenwald, M. W., Cohen, S. B., Polis, A. B., Najarian, D. K., Dixon, M. E., Moidel, R. A., Green, J. A., Baraf, H. S., Petruschke, R. A., Matsumoto, A. K., Geba, G. P. Efficacy and safety of rofecoxib 12.5 mg versus nabumetone 1,000 mg in patients with osteoarthritis of the knee: a randomized controlled trial. 2004; 5: 666-74
- Kivitz, A. J., Greenwald, M. W., Cohen, S. B., Polis, A. B., Najarian, D. K., Dixon, M. E., Moidel, R. A., Green, J. A., Baraf, H. S., Petruschke, R. A., Matsumoto, A. K., Geba, G. P. Efficacy and safety of rofecoxib 12.5 mg versus nabumetone 1,000 mg in patients with osteoarthritis of the knee: a randomized controlled trial. 2004; 5: 666-74
- Kongtharvonskul, J., Woratanarat, P., McEvoy, M., Attia, J., Wongsak, S., Kawinwonggowit, V., Thakkinstian, A. Efficacy of glucosamine plus diacerein versus monotherapy of glucosamine: a double-blind, parallel randomized clinical trial. Arthritis Research & Therapy 2016; 1: 233
- Lee, M., Yoo, J., Kim, J. G., Kyung, H. S., Bin, S. I., Kang, S. B., Choi, C. H., Moon, Y. W., Kim, Y. M., Han, S. B., In, Y., Choi, C. H., Kim, J., Lee, B. K., Cho, S. A Randomized, Multicenter, Phase III Trial to Evaluate the Efficacy and Safety of Polmacoxib Compared with Celecoxib and Placebo for Patients with Osteoarthritis. Clinics in Orthopedic Surgery 2017; 4: 439-457
- Lee, P., Davis, P., Prat, A. The efficacy of diflunisal in osteoarthritis of the knee. A Canadian Multicenter Study. Journal of Rheumatology 1985; 3: 544-8
- Lee, P., Davis, P., Prat, A. The efficacy of diflunisal in osteoarthritis of the knee: an extended study. Journal of Rheumatology 1986; 3: 666-7
- Lehmann, R., Brzosko, M., Kopsa, P., Nischik, R., Kreisse, A., Thurston, H., Litschig, S., Sloan, V. S. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib. Current Medical Research and Opinion 2005; 4: 517-526
- Lohmander LS, McKeith D, Svensson O, et alA randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritisAnnals of the Rheumatic Diseases 2005;64:449-456.
- Lohmander LS, McKeith D, Svensson O, et alA randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritisAnnals of the Rheumatic Diseases 2005;64:449-456.
- McKenna, F., Borenstein, D., Wendt, H., Wallemark, C., Lefkowith, J. B., Geis, G. S. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scandinavian Journal of Rheumatology 2001; 1: 11â?18
- McKenna, F., Borenstein, D., Wendt, H., Wallemark, C., Lefkowith, J. B., Geis, G. S. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scandinavian Journal of Rheumatology 2001; 1: 11â?18
- Miceli-Richard, C., Le Bars, M., Schmidely, N., Dougados, M. Paracetamol in osteoarthritis of the knee. Annals of the Rheumatic Diseases 2004; 8: 923-930
- Ohtori, S., Inoue, G., Orita, S., Takaso, M., Eguchi, Y., Ochiai, N., Kishida, S., Kuniyoshi, K., Aoki, Y., Ishikawa, T., Miyagi, M., Kamoda, H., Suzkuki, M., Nakamura, J., Kubota, G., Sakuma, Y., Oikawa, Y., Toyone, T., Inage, K., Sainoh, T., Yamauchi, K., Takahashi, K. Efficacy of combination of meloxicam and pregabalin for pain in knee osteoarthritis. 2013; 5: 1253-8
- Pavelka, K., Trc, T., Karpas, K., Vitek, P., Sedlackova, M., Vlasakova, V., Bohmova, J., Rovensky, J. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled study with primary end points at two months after the end of a three-month treatment period. Arthritis & Rheumatism 2007; 12: 4055-64
- Pincus T, Koch G, Lei H, et alPatient 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. Annals of the Rheumatic Diseases 2004;63:931-939
- Puopolo, A., Boice, J. A., Fidelholtz, J. L., Littlejohn, T. W., Miranda, P., Berrocal, A., Ko, A., Cichanowitz, N., Reicin, A. S. A randomized placebo-controlled trial comparing the efficacy of etoricoxib 30 mg and ibuprofen 2400 mg for the treatment of patients with osteoarthritis. Osteoarthritis and Cartilage 2007; 12: 1348-1356
- Williams, H. J., Ward, J. R., Egger, M. J., Neuner, R., Brooks, R. H., Clegg, D. O., Field, E. H., Skosey, J. L., AlarcÃn, G. S., Willkens, R. F. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis and Rheumatism 1993; 9: 119-1206
- Williams, H. J., Ward, J. R., Egger, M. J., Neuner, R., Brooks, R. H., Clegg, D. O., Field, E. H., Skosey, J. L., AlarcÃn, G. S., Willkens, R. F. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis and Rheumatism 1993; 9: 119-1206
- Paul S,Das N,Ghosh S. The effects of Aceclofenac and nabumetone in osteoarthritis. JNMA J Nepal Med Assoc 2009;48(174):121-125.