◊ OBJECTIVE:
Our aim was to study local synovial metabolism, inflammation, and subjective pain scoring after intra-articular injection of morphine, ketorolac, or placebo in knee arthroscopy.
◊ METHODS:
Sixty patients undergoing knee arthroscopy were randomized into 3 groups receiving morphine, ketorolac, or placebo before surgery. Microdialysis of the synovial membrane was performed in 10 patients in each group 4 hrs postoperatively. Lactate, glucose, glycerol, glutamate, and prostaglandin E2 (PGE2) were monitored regarding biochemical compounds and visual analog scale regarding perceived postoperative pain.
◊ RESULTS:
Ketorolac effectively attenuated postoperative PGE2 levels. Glycerol increased over time in the ketorolac group. Glutamate showed a decrease over time in both the morphine and ketorolac groups. Differences in PGE2 in the reference tissue indicated a systemic effect of ketorolac. There were no effects on subjective pain scoring (visual analog scale).
◊ CONCLUSIONS:
To our knowledge, this is the first study on the local metabolic and inflammatory effect of intra-articularly administered morphine or ketorolac. For the first time, glutamate was studied in synovial tissue, and our results suggest that local release of glutamate may be important for nociception and inflammation. The effects of ketorolac on PGE2 implicates a local effect on inflammation and possibly, also nociception, but it should be remembered that 60 mg of ketorolac given intra-articularly also has a systemic effect. Release of glycerol after administration of ketorolac may indicate a toxicity of nonsteroidal anti-inflammatory drugs that must be further evaluated.
◊ Reviewed by C. Stein, MD, PhD
Chairman, Dept. of Anesthesiology and Critical Care Medicine
Freie Universität and Charité Campus Benjamin Franklin, Berlin, Germany.
AND
R. Moshourab, MD
Research associate
Freie Universität and Charité Campus Benjamin Franklin, Berlin, Germany.
This well designed randomized double-blind prospective study addressed the issue of locally applied analgesics and inflammation using the microdialysis technique. Microdialysis is a powerful tool for measuring even small fluctuations of inflammatory compounds. The study examines the early (up to 4 hours) changes in inflammatory mediators at the site of injury and correlates them with locally administered analgesics (NSAIDs and opioids).
The authors analysed their data in a “static” (absolute concentrations) and in a “dynamic” (change of concentrations over time) manner. Compared to the reference tissue, the subcutaneous fat of the contralateral thigh, the synovial tissue displayed increased levels of lactate, glutamate, and PGE2 (except in the ketorolac group). In the morphine and placebo group, the PGE2 concentrations decreased over time. Synovial lactate concentrations increased and glucose concentrations decreased over time. The synovial glycerol concentration increased only in the ketorolac group. Importantly, all three groups received IA bupivacaine postoperatively. There is extensive animal research showing modulation of hyperalgesia and inflammation by local anaesthetics. Thus, the effect of bupivacaine may likely have superseded effects of the drugs given prior to surgery and should have been controlled for by comparison with patients not receiving bupivacaine.
According to the results, there is a distinct pattern of effects of morphine and ketorolac on local inflammatory mediators. While ketorolac had a specific unquestionable effect on PGE2 levels compared to morphine and placebo both morphine and ketorolac decreased synovial glutamate levels over time. ketorolac has systemic and probably unspecific actions that may result in side effects. in contrast, the effect on glutamate, although small in magnitude, was specific and localized.
There was no difference in rescue medication used during the postoperative period which is most likely due to the IA injection of bupivacaine. It is impossible to draw any meaningful conclusions from this on the effects of morphine and ketorolac. As expected in minor surgery, pain dissipated in all groups during several hours post-surgery. Ketorolac inhibited PGE2 production, but did not significantly influence the subjective pain rating up to 14 days after surgery. Lower doses of ketorolac should be investigated to inhibit PGE2 only locally.
Ketorolac and morphine altered measurements of inflammatory and metabolic mediators. However, these alterations did not influence subjective pain ratings. The authors have clearly mentioned the limitations of their study, IA ketorolac in such dosages might still exhibit systemic side effects and might be damaging to the synovial tissue. In the future, they should extend their investigations to chronic inflammatory conditions such as rheumatoid arthritis and use lower ketorolac dosages.
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