Letter to the Editor: In Response
We appreciate the opportunity to respond to the issues raised by Dr. Cook et al. They expressed concern that the intraarticular administration of ketorolac should demonstrate a clinically proven effect in a placebo-controlled trial prior to investigations comparing it with a combination of drugs. In our previous study , we showed that when intraarticular ketorolac is administered with intraarticular bupivacaine, analgesia is enhanced compared with either intravenous ketorolac or placebo. Although there are a few studies [2,3] that have revealed no clinical benefit of intraarticular bupivacaine, our experience and other recent placebo-controlled studies [4,5] reveal a significant beneficial effect. Intraarticular bupivacaine has thus become our standard of care. We therefore use intraarticular bupivacaine as the "control" in our clinical studies, similar to the protocol reported in the literature by other investigators.
After the completion of our clinical study, the drug manufacturer recommended using smaller doses of ketorolac in the management of pain (package insert). (Roche/Syntex, Nutley, NJ) We are thus currently using smaller doses of intraarticular ketorolac (15 mg) with equally effective analgesia (unpublished data). We, however, still believe that a single 60-mg intraarticular dose of ketorolac is safe. Although there is concern about the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on cartilage when given parenterally, this appears to be a dose-dependent effect with ketorolac. Biomechanical studies on rabbit bone have shown that when 2 mg [center dot] kg-1 [centered dot] d-1 ketorolac was used after surgery for six weeks, no clinical effect on bone repair or metabolism was noted. Increasing the dose to 4 mg [center dot] kg-1 [center dot] d-1 produced a deterioration in the mechanical properties of the bone matrix . We agree that it is prudent to select those NSAIDs least likely to damage cartilage in studies involving intraarticular administration. At the time of this investigation, ketorolac was the only intraarticular NSAID that had been evaluated . This study involving in vitro bovine cartilage revealed that ketorolac had no effect on the degradation of cartilage matrix. In fact, ketorolac appears to have a protective effect on articular cartilage by preventing the release of cytokines, including interleukin-1, which has been shown to play a pivotal role in triggering excessive cartilage degradation under inflammatory conditions.
Because we demonstrated [in the study referenced by Dr. Cook et al. ] that intraarticular ketorolac is as effective as intraarticular morphine, we do not recommend the widespread use of the former drug. Because morphine is less expensive, we recommend its use over ketorolac; however, we do believe that intraarticular ketorolac can be safely administered in those patients in whom morphine is medically contraindicated.
Scott S. Reuben, MD,
Neil Roy Connelly, MD
Department of Anesthesiology; Baystate Medical College; Tufts University; School of Medicine; Springfield, MA 01199
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