Table 4.

Characteristics of the Included Studies I: Effects of NSAIDs on Chondrocytes.

Year of the Study	Study	In Vitro	In Vivo	Species	N	Follow-up, Min-Max	Outcome Measures	NSAIDs	NSAIDs Administration	Frequency of Administration	Source of Cells	Effects
2017	Abrams et al.	1	0	Human chondrocytes	16	Duration dose equivalent to 2 half-lives plus additional 2 weeks in selected cases	Live/dead assay	Ketorolac	Chondrocytes were cultured in a bioreactor and the medication was constantly delivered	Constantly delivered—single dose injection	Human knee joint—intercondylar notch	Dose-dependent cytotoxic effect of ketorolac on human articular chondrocytes. Specifically, 0.6% ketorolac resulted in increased cell death versus 0.3% ketorolac (P = 0.046); 0.5% meperidine was significantly less chondrotoxic versus 1.0% meperidine (P = 0.001) and 1.5% meperidine (P = 0.001). There was no significant difference in chondrotoxicity for 1.0% meperidine versus 1.5% meperidine (P = 0.665)
2013	Beitzel et al.	1	0	Human chondrocytes		24 and 120 hours	Proliferation and viability (luminescence) assay	Keterolac	1-hour in vitro exposure		Lonza (Hopkinton, MA)	The mean number of viable cells after 24 hours was 1488 ± 203 cells for the no-treatment 2% FBS control and 2748 ± 133 cells for the 10% FBS control (P < 0.002 compared with 2% FBS). After 120 hours, the mean viable cell number of the no-treatment 2% FBS control was 7397 ± 470 cells and 13152 ± 990 cells for the 10% FBS control treatment (P < 0.021 compared with 2% FBS).
2004	Dogan et al.	0	1	New Zealand male rabbits	30	24 hours, 48 hours, and 10 days	Histopathological analysis	Ketorolac	Intra-articular (knee)	Single dose		Significant neutrophil and macrophage invasion and accumulation of the articular cartilage and synovial membrane, in conjunction with synovial hypertrophy, and hyperplasia following ketorolac or morphine injection into the knee.
1998	Irwin et al.	0	1	Sprague-Dawley rats	30	24 hours, 48 hours, 5 days, and 10 days	Histopathological analysis	Keterolac	Intra-articular (knee)	Single dose		At 24 hours and 5 days postinjection, the inflammation of the joint was significantly higher (P < 0.05) in ketorolac group compared with control
2015	Orak et al.	0	1	Wistar albino rats	100	48 hours, 1 week, 2 weeks, 4 weeks, and 8 weeks	Histopathological analysis	Tenoxicam and diclofenac	Intra-articular (knee)	Single dose		Increased fibroblast numbers and fibrosis levels (P < 0.05) were observed in knee joint following tenoxicam and diclofenac treatment
2004	Ozyuvaci et al.	0	1	Sprague-Dawley rats	50	24 hours, 48 hours, 7 days, 14 days, and 21 days	Histopathological analysis	Tenoxicam	Intra-articular (knee)	Single dose		Erosion of the joint surfaces and edema in the histological specimens was were observed at 24 and 48 hours after intra-articular tenoxicam injection. However, no histopathological changes were found at 7, 14, and 21-days after injection.
2014	Ekici et al.	0	1	Sprague-Dawley rats	40	1, 2, 7, 14, and 21 days	Histopathological analysis	Dexketoprofen	Intra-articular (knee)	Single dose		No significant histopathological damage up to 21 days after intraarticular administration
2014	Riggin et al.	0	1	Sprague-Dawley rats	64	2, 7, 28, and 84 days	Knee kinematics, mechanics, cartilage mechanical and histological evaluation	Ketorolac	Intra-articular (knee)	Single dose		No difference between the intervention and control groups in knee kinematics, mechanics and cartilage mechanical and histological evaluation.
2007	Shapiro et al.	0	1	New Zealand white rabbits	30	6 and 15 weeks	Histopathological analysis	Ketorolac	Intra-articular (knee)	Single dose		No significant degenerative changes were found after ketorolac administration
2008	Saricaoglu et al.	0	1	Sprague-Dawley rats	25	1, 2, 7, 14, and 21 days	Histopathological analysis	Lornoxicam	Intra-articular (knee)	Single dose		No significant differences in joint inflammation and cartilage degeneration were found, between saline and lornoxicam applied knees with histological evaluation.
2011	Schroeder et al.	0	1	New Zealand white rabbits	45	72 hours, 2 weeks, and 6 weeks	Histopathological analysis	Lornoxicam	Intra-articular (knee)	1, 2, or 3 injections		Repeated intra-articular administration of lornoxicam was well tolerated. Mechanical irritation of the injection and to adaptive responses of the synoviocytes were demonstrated; however, no signs of toxicity to bone or chondrotoxicity was found.

FBS = fetal bovine serum; NSAID = nonsteroidal anti-inflammatory drugs.