New insights into the site and mode of antinociceptive action of flurbiprofen enantiomers.
The S-enantiomer of flurbiprofen has been shown to have both antiinflammatory and antinociceptive effects, whereas R-flurbiprofen is antinociceptive but not antiinflammatory. Importantly, only S-flurbiprofen inhibited prostaglandin biosynthesis in vitro at therapeutic concentrations. R-flurbiprofen did not undergo significant chiral inversion to S-flurbiprofen in rats and humans. A study was conducted to gain new insight into the possible sites and modes of action of flurbiprofen enantiomers. In a modified Randall Selitto assay, both enantiomers were antinociceptive in a dose-dependent manner after systemic administration. After local administration into the inflamed paw, only S-flurbiprofen produced significant dose-related antinociception. In a physiologic study, we recorded extracellularly from nociceptive spinal cord neurons that were rendered hyperexcitable. Intravenous administration of R- and S-flurbiprofen reduced responses of neurons to pressure applied to the inflamed knee and the noninflamed ankle and paw in a dose-dependent manner. When injected directly into the knee joint, only S-flurbiprofen but not R-flurbiprofen reduced responses to pressure. These results suggest a central site of antinociceptive action for R- and S-flurbiprofen and an additional peripheral site for S-flurbiprofen. The findings may be of clinical relevance, as it was demonstrated that both enantiomers also were antinociceptive in humans. Because R-flurbiprofen caused less toxicity in rats than the S-enantiomer or the racemic compound, a reduction in the quantitatively most important side effects in the gastrointestinal tract might be achieved with the use of R-flurbiprofen for pain therapy.
Geisslinger
G
G
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
Schaible
H G
HG
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000494:pharmacology*; D006801:Humans; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects*; D013237:Stereoisomerism
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D005480:Flurbiprofen