Enhancement of fentanyl antinociception by subeffective doses of nitroparacetamol (NCX-701) in acute nociception and in carrageenan-induced monoarthritis.

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.

Comparison of the antinociceptive activity of two new NO-releasing derivatives of the NSAID S-ketoprofen in rats.

1 Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes inducing analgesic, anti-inflammatory and antipyretic actions. They are not devoid of severe side effects and so, the search for new compounds with similar or higher effectiveness and a lower incidence of undesired actions is important. Nitric oxide (NO)-releasing NSAIDs resulted from this search. 2 We have compared the antinociceptive effectiveness of cumulative doses of two new NO-releasing derivatives of S-ketoprofen, HCT-2037 and HCT-2040, using the recording of spinal cord nociceptive reflexes in anesthetized and awake rats and after intravenous and oral administration. 3 S-ketoprofen and HCT-2040 were equieffective in reducing responses to noxious mechanical stimulation after i.v. administration in anesthetized animals (ID50s: 1.3+/-0.1 and 1.6+/-0.2 micromol kg(-1) respectively), but did not modify wind-up. HCT-2037 was two-fold more potent (ID50 of 0.75+/-0.1 micromol kg(-1)) in responses to mechanical stimuli and very effective in reducing wind-up (63+/-17% of control; P<0.01; MED: 0.4 micromol kg(-1)), indicating a greater activity than the parent compound. 4 In awake animals with inflammation, HCT-2037 p.o. fully inhibited mechanical allodynia, 91+/-12% reduction, and hyperalgesia, 94+/-8% reduction. Equivalent doses of S-ketoprofen only partially reduced either allodynia (50+/-11%) or hyperalgesia (40+/-4%). The effect on responses to noxious thermal stimulation was similar for the two compounds. 5 We conclude that the molecular changes made in the structure of S-ketoprofen including an NO moiety in its structure, improve the antinociceptive profile of the compound opening new perspectives in a safer use of NSAIDs as analgesic drugs.