Antinociceptive effects of morphine, fentanyl, tramadol and their combination, in morphine-tolerant mice

The development of morphine-tolerance after chronic administration, reduces analgesic efficacy and is a significant clinical problem in some patients; may be managed clinically by increasing the doses of morphine and/or the administration of a second mu-opioid agonist. In morphine-tolerant mice, we investigated the presence of an interaction when two opioids are administered simultaneously. We determined the antinociceptive effects of morphine (M), fentanyl (FEN), and tramadol (TRM) individually and combined in a 1:1 proportion, based on their potency. Nociceptive thresholds were evaluated in CD1 mice using the hot plate test. Morphine tolerance was induced by the subcutaneous implantation of a 75 mg morphine pellet, whereas control animals received a placebo pellet; the experiments were performed three days later. In both (placebo and morphine pellets), dose–response curves for M, FEN and TRM, individually and combined were obtained, and the doses that produced 50% inhibition (ED50) were determined. Sustained exposure to morphine induced a significant decrease in antinociceptive potency to acute M or FEN administration (tolerance), which was of a lesser magnitude after acute TRM; in these experiments the analysis of the interaction between chronic morphine and each opioid, demonstrated functional antagonism. The simultaneous administration of two opioids in morphine-tolerant mice, demonstrated antagonism for the M:FEN combination, whereas the effects of TRM combined with M or FEN, remained additive. The results suggest that during morphine-tolerance, TRM could be a useful drug to induce effective analgesia when combined with FEN or M.

Research Highlights
► In morphine-tolerant mice, the co-administration of morphine and fentanyl shows antagonism when antinociceptive effects are evaluated.
► No interaction is present when tramadol is combined either with morphine or fentanyl.
► The presence of tolerance modifies the type of interaction between morphine and fentanyl that changes from additive (in naïve) to antagonism (in tolerant mice).
► A lesser magnitude of cross-tolerance to chronic morphine is showed when tramadol is administered individually or combined with a strong agonist (such as morphine or fentanyl).