Evaluation of interaction between gabapentin and ibuprofen on the formalin test in rats.
BACKGROUND
Gabapentin is active in the regulation of facilitated pain states evoked by tissue injury. The mechanism of this action is believed to be through a specific binding site, likely at the spinal level. Nonsteroidal antiinflammatory drugs have a comparable behavioral profile, although their actions are believed to be mediated by cyclooxygenase inhibition at the spinal level. This study was undertaken to determine the nature of the interaction of these two mechanistically distinct antihyperalgesic agents in rats in a model of facilitated processing, the formalin test.


METHODS
The effects of intraperitoneal gabapentin and ibuprofen were examined on flinching behavior and cardiovascular response (mean arterial blood pressure [MABP] and heart rate measured in the tail artery) evoked by the injection of formalin (5%; 50 microl). Their interaction was characterized using an isobolographic analysis.


RESULTS
Injection of formalin into the hind paw caused a biphasic flinching and parallel increases in MABP. Gabapentin and ibuprofen produced a limited effect on the flinching in phase 1, but both drugs produced dose-dependent suppression of the flinching observed during phase 2 (gabapentin ED50 = 88 mg/kg; ibuprofen ED50 = 19 mg/kg). Gabapentin similarly showed a dose-dependent suppression of the MABP and heart rate response only during phase 2; ibuprofen showed dose-dependent reduction of MABP response in both phases. The isobolographic analysis carried out using equipotent dose ratios in phase 2 revealed an additive interaction between the two drugs. Neither gabapentin nor ibuprofen affected the baseline cardiovascular measures.


CONCLUSIONS
Gabapentin and ibuprofen independently alter the facilitated state as measured by somatomotor and autonomic response. Together these agents interact in an additive fashion if delivered concurrently. This combination may prove useful in managing postinjury pain states in humans.
Yoon
M H
MH
Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Yaksh
T L
TL
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000700:Analgesics / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000077206:Gabapentin; D006339:Heart Rate / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D007052:Ibuprofen