Ketorolaco intratecal

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Intrathecal Ketorolac Enhances Antinociception from Clonidine
Dawn R. Conklin,
BA,

and James C. Eisenach,

MD

From the Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Although both 2-adrenergic agonists and cyclooxygenase inhibitors produce analgesia,their exact sites of action and interaction remain unclear. A previous report demonstrated a surprising inhibition of antinociception in rats from intrathecal clonidine by coadministered ketorolac. There are no other reports of interaction between these two classes of analgesics. We therefore reexamined this interaction, determining the effect of intrathecal clonidine and ketorolac alone and incombination in normal rats. Clonidine, but not ketorolac, produced antinociception to noxious hind paw

thermal stimulation. The addition of ketorolac significantly enhanced the effect of clonidine, indicating a synergistic interaction for analgesia. Although the reasons for the discrepancy between this and the previous report are unclear, these results are consistent with previous studies thatindicate an antinociceptive action of intrathecal 2-adrenergic agonists in the normal condition, a lack of such effect for cyclooxygenase inhibitors, and positive reinforcing effects of these two systems when co-stimulated. (Anesth Analg 2003;96:191–4)

he study of intrathecal application of drugs for the treatment of pain is important for two reasons. First, it is directly relevant to anesthesiapractice in that the intrathecal space is often instrumented as part of perioperative, peripartum, or chronic pain care, and currently available intrathecal analgesics have significant shortcomings. Second, it provides important fundamental information regarding mechanisms of analgesic action and of pain transmission, which could guide pharmaceutical development of both intrathecal and systemic drugdevelopment. A good example of these rationales is examination of cyclooxygenase (COX) enzyme expression and inhibition in the spinal cord as it relates to pain treatment. COX is expressed in the normal spinal cord in small amounts, both isoforms COX-1 and COX-2, with the latter predominating (1). Indeed, the constitutive presence of COX-2 in the spinal cord has been suggested to underlie theearly analgesic effect of COX inhibitors after surgery or other peripheral injury and at times before peripheral COX-2 expression is

T

Supported, in part, by NIH grants GM35523 and NS41386. Accepted for publication September 10, 2002. Address correspondence and reprint requests to James C. Eisenach, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical CenterBlvd., Winston-Salem, NC 27157–1009. Address e-mail to eisenach@wfubmc.edu. DOI: 10.1213/01.ANE.0000039319.43540.73
©2003 by the International Anesthesia Research Society 0003-2999/03

increased. After peripheral injury, spinal COX-2 expression is greatly enhanced, leading to increased spinal release of prostaglandins with resultant increased substance P release and central sensitization (2). Forthis reason, spinally administered COX inhibitors produce analgesia after injury. We have recently completed preclinical toxicity screening of a COX inhibitor for intrathecal administration (JC Eisenach, unpublished observations) and, with the Food and Drug Administration, have begun clinical trials with this therapy. It is becoming increasingly apparent that single drugs are unlikely to produceeffective analgesia with minimal side effects, especially in the setting of chronic pain. For this reason, the study of drug interactions is relevant. Intrathecally administered COX inhibitors have been demonstrated to enhance analgesic effects of intrathecal opioids (3). Surprisingly, however, the other class of approved intraspinal analgesics, 2-adrenergic agonists, has been reported to be...
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