In cats implanted chronically with catheters in the lumbar epidural space, the pharmacology of the analgesia of 4 opiates, which varied widely in their physicochemical properties, was studied. Results revealed the following order of epidural analgesic potency as indicated by suppression of the spinally mediate skin twitch reflex: lofentanyl greater than morphine greater than L-methadone greater than meperidine greater than D-methadone. With the doses used in these experiments the duration of action was: morphine greater than lofentanyl greater than L-methadone = meperidine. In addition, antagonism of these effects by systemic naloxone and the development of tolerance after daily epidural administration of morphine were demonstrated. These data, jointly, indicate a specific receptor mechanism of action. We suggest that this animal model may be useful for the evaluation of new opiates and non-opiates to be given via the epidural route.