Is Ketorolac (Toradol) a Safe and Effective Intra-Articular Injection?
Ketorolac Tromethamine, often referred by its trade name toradol, is an injectable non-steroidal anti-inflammatory drug (NSAID). Like all NSAIDS, it has anti-inflammatory, analgesic and antipyretic properties and is a non-selective COX inhibitor. It is frequently used to treat pain in a variety of clinical settings. Although there are oral formulations, it is more commonly used as an intravenous or intramuscular injection, or as ophthalmologic drops. A growing utilization among orthopedists and sports medicine physicians is to use it for intra-articular analgesia and anti-inflammatory. Although generally not well studied, this article seeks to review the evidence of that indication.
Intra-articular ketorolac appears to be safe. Previous studies have identified no detrimental effects of intra-articular NSAID injections on articular cartilage, ligaments or kinematic function of native knees in animal models [5, 9]. Interestingly, plasma concentrations of intra-articular ketorolac given intra-articularly were similar to intramuscular concentrations when given prior to total hip arthroplasty [13].
Ketorolac has been considered as either an adjunct or replacement for corticosteroid injections. Park et al compared ultrasound guided intra-articular ketorolac versus corticosteroid injection in osteoarthritis of the hip and found ketorolac to be as effective as corticosteroid injection at 1, 3 and 6 months [4]. Although not ketorolac specifically, Unlu at al found that intra-articular tenoxicam was safe and effective for reducing pain and functional disability in patients with knee OA until the 6-month follow-up [7]. Bellamy et al found similar pain relief between ketorolac and corticosteroids for knee osteoarthritis, and noted that ketorolac presented a cost savings of 143% when compared to corticosteroids [14]. These studies provide the first data that intra-articular ketorolac are likely non-inferior to corticosteroids, and potentially superior and less expensive.
It is worth noting that in in vitro studies, ketorolac (and PRP) were inferior to methylprednisolone when measuring inflammatory markers in the lab [12]. The clinical significance of this is not known.
In patients with adhesive capsulitis, intra-articular ketorolac was as effective as steroid injections alone in pain relief and functional improvement in patients with frozen shoulder and more improvement in passive abduction and external rotation were observed than steroid injection alone at 3 and 6 months [10]. Lee et al found that when ketorolac was added to hyaluronic acid injection, patients showed more rapid analgesic onset than intra-articular HA alone and did not induce any serious complications [1].
Ketorolac has a role in postoperative management as well. Intra-articular ketorolac status post knee arthroplasty resulted in reduced morphine consumption, reduced pain intensity, increased mobility and earlier readiness for hospital discharge [2]. In patients undergoing arthroscopy, ropivacaine plus morphine and ketorolac immediately post op had a significant reduction in visual analog score up to 24 hours post op [3]. In fact, when measuring post-arthroscopy analgesia, ketorolac was superior to morphine and bupivacaine up to 24 hours [6]. Another study showed no benefit with repeat boluses after the first initial injection [11].
Summary. Overall, I was surprised by the lack of data and research surrounding intra-articular ketorolac. This may stem, in part, that it is off label use, although the best available research states that it is safe in patients who can otherwise tolerate NSAIDS. In patients with hip and knee osteoarthritis, ketorolac was as effective or superior to corticosteroids. Whether it can be included as an adjunct to corticosteroids is unknown. It appears to help with adhesive capsulitis and perhaps as an adjunct to hyaluronic acid injections. On the surgical side, there appears to be a role for postoperative analgesia. Overall, the data is weak due to a lack of robust, blinded, randomized clinical trials and there are several studies ongoing attempting to investigate these questions. In the interim, it is reasonable to consider intra-articular ketorolac in the above context where corticosteroids may be contraindicated.
References
1. Lee, Sang Chul, Dong-Wook Rha, and Won Hyuk Chang. “Rapid analgesic onset of intra-articular hyaluronic acid with ketorolac in osteoarthritis of the knee.” Journal of back and musculoskeletal rehabilitation 24.1 (2011): 31-38.
2. Andersen, Karen Vestergård, et al. “Local infiltration analgesia for total knee arthroplasty: should ketorolac be added?.” British journal of anaesthesia 111.2 (2013): 242-248.
3. Ng SH, Chick SE. Reducing parameter uncertainty for stochastic systems. ACM Trans Model Comput Simul. 2006;16(1):26–51. doi:10.1145/1122012.1122014.
4. Park, Ki Deok, et al. “Ultrasound guided intra-articular ketorolac versus corticosteroid injection in osteoarthritis of the hip: a retrospective comparative study.” Skeletal radiology44.9 (2015): 1333-1340.
5. Shapiro PS, Rohde RS, Froimson MI, et al. The effect of local corticosteroid or ketorolac exposure on histologic and biomechanical properties of rabbit tendon and cartilage. Hand (New York). 2007;2:165–72.
6. Calmet J, Esteve C, Boada S, Giné J. Analgesic effect of intraarticular ketorolac in knee arthroscopy: comparison of morphine and bupivacaine. Knee Surg Sports Traumatol Arthrosc. 2004;12:552–5.
7. Unlu Z, Ay K, Tuzun C. Comparison of intra-articular tenoxicam and oral tenoxicam for pain and physical functioning in osteoarthritis of the knee. Clin Rheumatol. 2006;25(1):54–61.
8. Fajardo, Marc, et al. “Effect of a perioperative intra-articular injection on pain control and early range of motion following bilateral TKA.” Orthopedics 34.5 (2011): e33-e36.
9. Riggin, Corinne N., et al. “Intra‐articular tibiofemoral injection of a nonsteroidal anti‐inflammatory drug has no detrimental effects on joint mechanics in a rat model.” Journal of Orthopaedic Research 32.11 (2014): 1512-1519.
10. Ahn, Jae Ki, et al. “Effects of Ultrasound-guided intra-articular ketorolac injection with capsular distension.” Journal of back and musculoskeletal rehabilitation 28.3 (2015): 497-503.
11. Andersen, Karen V., et al. “Local infiltration analgesia is not improved by postoperative intra-articular bolus injections for pain after total hip arthroplasty: A randomized, double-blind, placebo-controlled study with 80 patients.” Acta orthopaedica86.6 (2015): 647-653.
12. Mazzocca, Augustus D., et al. “An in vitro evaluation of the anti-inflammatory effects of platelet-rich plasma, ketorolac, and methylprednisolone.” Arthroscopy: The Journal of Arthroscopic & Related Surgery 29.4 (2013): 675-683.
13. Affas, F., et al. “Plasma concentration of ketorolac after local infiltration analgesia in hip arthroplasty.” Acta Anaesthesiologica Scandinavica 58.9 (2014): 1140-1145.
14. Bellamy, Jaime L., Brandon J. Goff, and Siraj A. Sayeed. “Economic impact of ketorolac vs corticosteroid intra-articular knee injections for osteoarthritis: a randomized, double-blind, prospective study.” The Journal of arthroplasty 31.9 (2016): 293-297.
