New Insights into the Site and Mode of Antinociceptive Action of Flurbiprofen Enantiomers

Abstract

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.