The analgetic activity of inhibitors of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) was investigated using rat Randall-Selitto (RS) hyperalgesia and mouse phenylbenzoquinone (PBQ)-induced abdominal constriction assays. Using the RS assay, the CO inhibitors indomethacin, naproxen, and ibuprofen all effectively reduced hyperalgesia; whereas, the inhibitors of leukotriene production, MK886 and phenidone were inactive. SK&F 105809, a dual inhibitor of 5-LO/CO, significantly reduced hyperalgesia. In the PBQ assay, CO inhibitors were active, SK&F 105809 was nearly as potent as naproxen, and MK886 and phenidone were found to be active. Thus, improved analgetic activity appeared to result from inhibition of 5-LO and CO; whereas, in the RS assay, only CO inhibitors and SK&F 105809 were clearly effective. These results suggest that dual inhibitors, and in particular, SK&F 105809 may be more efficient analgesic agents than selective CO inhibitors in clinical situations in which 5-LO products play a significant role.