TRPV1 antagonists have been considered as potential treatments for pain associated with inflammatory diseases and cancer. During Phase I clinical trials
with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicits marked, but reversible, and generally plasma concentration-dependent
hyperthermia. Furthermore, in a Phase Ib study, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long-lasting hyperthermia with
maximal body temperature surpassing 40 ºC, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals.
Since TRPV1 blockade elicited hyperthermia is a major hurdle, we investigated the possibility of eliminating hyperthermia while maintaining antihyperalgesia by two
approaches: i) peripheral restriction of TRPV1 antagonists, ii) characterization of TRPV1 modulators that exhibit differential pharmacology. Results from the
preclinical studies of both approaches will be discussed.