Chondrotoxicity of Injectable NSAIDs and Narcotics

OBJECTIVES: The administration of intra-articular NSAIDs and narcotics has been frequently performed to augment pain control and to decrease inflammation. The chondrotoxicity of these medications have not been evaluated. METHODS: Normal human cartilage was arthroscopically harvested from the intercondylar notch in patients undergoing routine ACL reconstruction (N =16 patients). Medication and treatment duration used in this study includes one NSAID, ketorolac at 0.3% and 0.6% for 10 hours, and three narcotics, fentanyl at 0.0005% and 0.001% for 7 hours, meperidine at 0.5%, 1%, and 1.5% for 6 hours, and morphine at 0.01%, 0.02%, and 0.04% for 4 hours. Each medication was delivered in a custom bioreactor over its clinical duration of action. To validate the chondrogenic characteristics of cultured cells, RT-qPCR was applied for the expression of cartilage-specific proteoglycan, aggrecan, the chondrogenic transcription factor, SOX9, the major collagen in cartilage, type II collagen, and the chondrocyte differentiation index, collagen II/I ratio. Undifferentiated human chondrocytes were used as the control. The acute cytotoxicity was determined by fluorescent vital dye staining, followed by flow cytometric analysis, and presented as percentage of dead cells from the total population. The proliferation/AlamarBlue assay was applied, and the growth curves were generated with a two-day interval for up to two weeks. RESULTS: The treatment of a single dose of 0.3% or 0.6% ketorolac demonstrated a significant increase of cell death (0.3% concentration = 16.28% ± 1.26 loss of viability, p < .0001; 0.6% concentration= 41.88 ± 13.42, p < .05) compared to saline control (4.71% ± 1.21). All tested concentrations of meperidine exhibited significant chondrotoxicity (0.5% concentration = 13.61% ± 1.80 loss of viability, p < .01; 1% concentration= 80.53% ± 10.26, p = .001; 1.5% concentration= 89.53% ± 11.00, p < .001). Additionally, ketorolac exhibited a significant dose-response on cell death between 0.3% and 0.6% (p < .05), and higher ranges of meperidine had significant impact on survival (1%, p < .005; 1.5%, p < .005) compared to 0.5% concentration. Treatment with any concentration of fentanyl (0.0005% concentration= 6.13% ± 2.85; 0.001% concentration= 6.02% ± 3.03) or morphine (0.01% concentration= 6.40% ± 1.00; 0.02% concentration= 7.51% ± 2.08; 0.04% concentration= 8.37% ± 2.33) had no significant effect on cell death compared to saline controls. The fentanyl treatments showed no significant difference compared to saline controls up to 8 days with correlation coefficient at 0.1 for concentration = 0.01%, 0.3 for concentration = 0.02%, and -0.5 for concentration = 0.04%. The treatment of morphine exhibited a similar result with no significant difference between the experimental group and saline with correlation coefficient at 0.9 for concentration = 0.0005%, and 0.6 for concentration = 0.001%. CONCLUSION: A single-dose exposure of 0.3% or 0.6% ketorolac or 0.5-1.5% meperidine resulted in a significant increase in chondrotoxicity and, therefore, should not be used for intra-articular injection. Fentanyl and morphine did not exhibit either acute or delayed chondrotoxicity.