• James C Eisenach, Regina Curry, David D Hood, and Tony L Yaksh.
• Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA. eisenach@wfubmc.edu
• Pain. 2002 Oct 1;99(3):599-604.

AbstractSpinal prostaglandin synthesis has been implicated in acute pain processes and in generation and maintenance of central sensitization, and intrathecal injection of cyclo-oxygenase (COX) inhibitors produce antinociception and reduce hypersensitivity in animals. We herein report a Phase I safety assessment of intrathecal injection of the COX inhibitor, ketorolac, in healthy volunteers, and demonstrate no serious side effects. Preclinical studies suggest a major site of action of COX inhibitors for analgesia lies in the central nervous system, especially the spinal cord. For example, COX isoenzymes are expressed in the spinal cord, acute noxious stimuli and inflammation increase spinal prostaglandin production, and spinally administered prostaglandins excite dorsal horn projection neurons, induce release of excitatory neurotransmitters, and cause nociceptive behavior. Intrathecal injection of COX inhibitors increases thermal and mechanical withdrawal threshold in animals with inflammation or nerve injury at doses several 100-fold less than those required systemically. Following pre-clinical neurotoxicity screening and regulatory agency approval, we examined the safety of intrathecal injection of a preservative-free formulation of the COX inhibitor, ketorolac. In an open label, dose-escalating design, 20 healthy volunteers received intrathecal ketorolac, 0.25, 0.5, 1, or 2mg (n=5 per group). Ketorolac did not alter blood pressure, although there was small (10-12%), dose-independent reduction in heart rate for the first hour after injection when data from all subjects were pooled. Ketorolac did not affect sensory or motor function or deep tendon reflexes, and there were no subjective sensations, neurologic or otherwise, reported by the volunteers. Ketorolac did not reduce pain report to heat stimuli applied to the lateral calf. One subject had a mild headache 24h after study, resolving the next day. There were no long-term side effects 6 months after study. These data suggest that intrathecal ketorolac does not produce a high incidence of serious adverse events, and they support further investigation for analgesia.

18 keywords...

hide…