Systemically administered loperamide–oxymorphindole synergistically reverses mechanical hypersensitivity in inflamed animals. (A) Peripherally-mediated mechanical nociceptive responses in the von Frey assay were assessed. Following complete Freund’s adjuvant–induced inflammation in the left hind paw, subjects were given a subcutaneous injection of loperamide, oxymorphindole or combination and postdrug mechanical sensitivity responses were analyzed as % antihyperalgesia, which was used to generate dose–response curves. (B) Isobolographic analysis of the data from A, showing a synergistic interaction compared to the theoretical additive ED₅₀ value. ***P < 0.001.