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Department of Pharmacology, The Ohio State University, College of Medicine and Public Health, Columbus, Ohio
Address correspondence and reprint requests to Gopi A. Tejwani, PhD, The Ohio State University, Department of Pharmacology, College of Medicine and Public Health, 5197 Graves Hall, 333 West 10th Ave., Columbus, OH 43210-1239. Address e-mail to Tejwani.1{at}osu.edu
The management of severe pain may require "balanced analgesia," involving the use of analgesics with different modes of action. Clonidine, an 
2-adrenoreceptor agonist produces analgesia by itself as well as when given with morphine and local anesthetics. Ketorolac is indicated for the management of moderately severe acute pain and causes analgesia equivalent to morphine. This study was designed to investigate whether the addition of ketorolac promotes antinociception produced by intrathecal administration of clonidine in male Sprague-Dawley rats. Intrathecal injection of clonidine (1–30 µg) induced a dose-dependent increase in antinociception as measured by the tail flick (TF) and hot plate tests. Ketorolac alone (150–600 µg) increased the antinociception by 50%–60% only in the TF test. Ketorolac (10 µg) decreased clonidine (10 µg)-induced antinociception from 69.1% ± 7.8% to 23.5% ± 1.6% (P < 0.05) in the TF test and 35.7% ± 4.7% to 4.5% ± 0.1% (P < 0.05) maximum possible effect in the hot plate test. Ketorolac also antagonized the effect of 30 µg of clonidine. The opioid receptor antagonist naloxone antagonized the antinociceptive effect of clonidine and ketorolac, indicating the involvement of the opioid system in the antinociception produced by clonidine or ketorolac. However, neither clonidine nor ketorolac (10-8 to 10-3 M) inhibited the binding of specific ligands to µ-, 
-, and 
-opioid receptors, indicating a lack of direct interaction of clonidine and ketorolac with opioid receptors. These results suggest that intrathecal injection of ketorolac antagonizes the antinociception produced by clonidine.
Implications: Clonidine and ketorolac are two important drugs used to give pain relief to patients. We observed that ketorolac inhibits clonidine-induced analgesia in the rat. We recommend that this drug interaction should be taken into account when both clonidine and ketorolac are used together to alleviate pain in patients.
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