We have reported that subanalgesic doses of new generation non-steroidal anti-inflammatory drugs (
NSAIDs) enhance the antinociceptive activity of the mu-
opiate fentanyl, and the duration of its effect, in acute nociception. Since this
therapy is intended for situations of
hyperalgesia, we have compared the antinociceptive activity of
fentanyl in the absence and in the presence of subeffective doses of
NCX-701 (
nitroparacetamol) in normal animals and in animals with
carrageenan-induced monoarthritis. Subanalgesic dose of
NCX-701 did not modify any of the nociceptive responses on its own but reduced the ID50 of
fentanyl more than two-fold in both the normal and sensitized states. When administered alone, full recovery from
fentanyl was always observed within 15 to 20 minutes, however, full recovery was not observed in the presence of
NCX-701.
Naloxone was unable to reverse the effect, suggesting a possible reduction of other
opiate-mediated secondary effects. We therefore studied the possibility that combining administration of
fentanyl and
nitroparacetamol (NCX-701) would reduce the development of acute tolerance to
fentanyl in behavioral experiments. Acute tolerance to
fentanyl in behavioral nociceptive reflexes was developed within 72 h after the constant infusion of the
drug, whereas in animals treated with small doses of
NCX-701 tolerance was not observed. In summary, our results, both in normal animals and in animals with
hyperalgesia, show that
fentanyl antinociception can be strongly potentiated with subanalgesic doses of the
NSAID NCX-701 and that the development of acute tolerance to
fentanyl in normal animals is prevented by this combination of drugs.