Antinociceptive and neurotoxicologic screening of chronic intrathecal administration of ketorolac tromethamine in the rat.
Many drugs are tested intrathecally to investigate alternatives to opioids. We aimed to explore the analgesic and possible neurotoxic effects of chronic intrathecally-administered ketorolac tromethamine in rats. Catheters were placed via atlantoaxial interval in 28 Wistar rats under anesthesia of intraperitoneally-injected thiopental 30 mg/kg. Rats were randomized into 4 groups and administered 4 repeated intrathecal doses of therapy with 5-day intervals. The control group received 10 microL of saline, and the other groups received 50, 150, and 400 microg of ketorolac tromethamine respectively. The formalin test, behavioral test, and histopathological examination of four different spinal cord levels were performed. Neither behavioral testing nor histopathological examination revealed abnormalities that would suggest neurotoxicity. Formalin tests showed that both phase I and phase II responses of ketorolac tromethamine groups were significantly less than those of the control group. Although phase I responses did not differ during comparisons among ketorolac tromethamine-administered groups, phase II responses decreased significantly in groups that received 150 and 400 microg of ketorolac tromethamine. Intrathecally administered ketorolac tromethamine reduced nociceptive responses and exhibited no untoward neurological effect even at large doses. However, its intrathecal use as a safe alternative drug for chronic pain remains to be investigated in other species.


CONCLUSIONS
The present study is unique because it has demonstrated that chronic intrathecal administration of ketorolac tromethamine in rats, even at considerably large doses, showed a potent analgesic effect during the formalin test without exhibiting any neurotoxic side effect.
Korkmaz
H Ayben
HA
Departments of *Anesthesiology and Reanimation, †Neurosurgery,the ‡Animal Research Center, and the §Department of Pathology, Dokuz Eylül University, School of Medicine, İzmir, Turkey.
Maltepe
Fikret
F
Erbayraktar
Serhat
S
Yilmaz
Osman
O
Güray
Merih
M
Canda
M Şerefettin
MŞ
Günerli
Ali
A
Gökmen
Necati
N
D000700:Analgesics; D000768:Anesthesia, General; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D007278:Injections, Spinal; D020911:Ketorolac Tromethamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009474:Neurons / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000473:pathology
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005557:Formaldehyde; D020911:Ketorolac Tromethamine