Does Perioperative Use Of Ketorolac Adversely Affect Bone Healing And Fusion?
Researchers have shown that the perioperative use of single-dose ketorolac has numerous postoperative benefits including reduced pain, reduced sedation, decreased opioid consumption and reduced nausea and vomiting.1-3 However, surgeons often avoid the use of ketorolac in osteotomy and fusion surgery due to the concern of adverse effects on bone and fusion healing. Studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) can adversely affect osteogenic activity and fracture healing.4-6 Additionally, NSAIDs may negatively affect bone fusion rates.7-10
Nonsteroidal anti-inflammatory drugs reduce pain and inflammation by inhibiting cyclooxygenase (COX) isoenzymes. Multiple authors have demonstrated extensively in both human and animal studies that NSAIDs inhibit or delay bone healing.4-6 Several mechanisms theoretically contribute to the decreased osteogenic activity with NSAIDs. These mechanisms include the inhibition of COX-2 that is necessary for mesenchymal cell differentiation to osteoblasts; inhibition of prostaglandin synthesis, which promotes angiogenesis necessary for ossification; and the inhibition of COX, which prevents chondrocyte differentiation.11-14
Given the potential benefits of perioperative use of ketorolac, several authors have examined the limited use of ketorolac for postoperative analgesia. The majority of this research has focused on spinal arthrodesis, which is known to have a very high rate of non-union with reported pseudarthrosis rates ranging from 3 to 35 percent.15
Pradhan and colleagues evaluated postoperative use of ketorolac use on 1-3 level lumbar spine arthrodesis.16 In this study, 405 patients undergoing a primary lumbar posterolateral intertransverse process fusion received mandatory postoperative ketorolac (30 mg every six hours for 48 hours). Researchers compared the results of these fusions to a control group that did not receive ketorolac. There was no significant difference in the non-union rates between the two groups with pseudarthrosis occurring in 5.3 percent of patients who received ketorolac and 6.2 percent of patients who did not.
Sucato and coworkers similarly found that the administration of ketorolac less than 48 hours after posterior spinal fusion for adolescent idiopathic scoliosis did not result in higher pseudarthrosis rates in comparison to controls.17
Li, Reuben and their respective colleagues found that high-dose ketorolac increased the incidence of non-union following spinal fusion surgery but that short-term perioperative administration of lower-dose ketorolac did not increase the non-union rate.18,19
The results of these studies show that limited use of ketorolac for postoperative analgesia for spine fusion does not lead to increased rates of non-union. Researchers have shown a dose and time dependent effect with the use of ketorolac, noting increased non-union rates with higher doses (>120 mg/day) and longer (>48 hour) administration.16,18,19
With the intrinsically high rate of pseudarthrosis in spinal fusion, this procedure serves as a good model for arthrodesis and we may be able to extrapolate the results of these studies to other fusion procedures, including those of the foot and ankle.
References
1. De Oliveira GS, Jr., Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg. 2012;114(2):424-433.
2. Reuben SS, Connelly NR, Lurie S, Klatt M, Gibson CS. Dose-response of ketorolac as an adjunct to patient-controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg. 1998;87(1):98-102.
3. Kinsella J, Moffat AC, Patrick JA, Prentice JW, McArdle CS, Kenny GN. Ketorolac trometamol for postoperative analgesia after orthopaedic surgery. Br J Anaesth. 1992;69(1):19-22.
4. Cottrell JOC, P. Effect of Non-Steroidal Anti-Inflammatory Drugs on Bone Healing. Pharmaceuticals. 2010;3:1668-1693.
5. Beck A, Krischak G, Sorg T, et al. Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg. 2003;123(7):327-332.
6. Krischak GD, Augat P, Sorg T, et al. Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model. Arch Orthop Trauma Surg. 2007;127(1):3-9.
7. Dimar JR, 2nd, Ante WA, Zhang YP, Glassman SD. The effects of nonsteroidal anti-inflammatory drugs on posterior spinal fusions in the rat. Spine. 1996;21(16):1870-1876.
8. Riew KD, Long J, Rhee J, et al. Time-dependent inhibitory effects of indomethacin on spinal fusion. J Bone Joint Surg Am. 2003;85-A(4):632-634.
9. Maxy RJ, Glassman SD. The effect of nonsteroidal anti-inflammatory drugs on osteogenesis and spinal fusion. Reg Anesth Pain Med. 2001;26(2):156-158.
10. Deguchi M, Rapoff AJ, Zdeblick TA. Posterolateral fusion for isthmic spondylolisthesis in adults: analysis of fusion rate and clinical results. J Spinal Disord. 1998;11(6):459-464.
11. Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O'Keefe RJ. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest. 2002;109(11):1405-1415.
12. Hausman MR, Schaffler MB, Majeska RJ. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone. 2001;29(6):560-564.
13. Murnaghan M, Li G, Marsh DR. Nonsteroidal anti-inflammatory drug-induced fracture nonunion: an inhibition of angiogenesis? J Bone Joint Surg Am. 2006;88(Suppl 3):140-147.
14. Cottrell JA, O'Connor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture-healing. J Bone Joint Surg Am. 2009;91(11):2653-2665.
15. Steinmann JC, Herkowitz HN. Pseudarthrosis of the spine. Clin Orthop Rel Res. 1992; 284:80-90.
16. Pradhan BB, Tatsumi RL, Gallina J, Kuhns CA, Wang JC, Dawson EG. Ketorolac and spinal fusion: does the perioperative use of ketorolac really inhibit spinal fusion? Spine. 2008;33(19):2079-2082.
17. Sucato DJ, Lovejoy JF, Agrawal S, Elerson E, Nelson T, McClung A. Postoperative ketorolac does not predispose to pseudoarthrosis following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis. Spine. 2008;33(10):1119-1124.
18. Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine. 2011;36(7):E461-468.
19. Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth. 2005;52(5):506-512.
