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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.