@article {Raffa1098, author = {R B Raffa and M L Haslego and C A Maryanoff and F J Villani and E E Codd and C D Connelly and R P Martinez and J J Schupsky and J A Buben and W N Wu and A N Takacs and L A Mckown}, title = {Unexpected antinociceptive effect of the N-oxide (RWJ 38705) of tramadol hydrochloride.}, volume = {278}, number = {3}, pages = {1098--1104}, year = {1996}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {N-Oxides of centrally acting analgesics generally have minimal analgesic activity. However, the N-oxide of tramadol produced dose-related, long-lasting antinociception in the mouse abdominal irritant, 48 degrees C hot-plate, 55 degrees C hot-plate, and tail-flick tests (ED50 = 15.5, 84.7, 316.4 and 138.2 mg/kg, p.o., respectively). Tramadol N-oxide (T-N-O) (RWJ 38705) was also antinociceptive in the 51 degrees C hot-plate test in male (ED50 = 63.2 mg/kg, i.p.) and female (ED50 = 39.9 mg/kg, i.p.) rats. A characteristic feature of T-N-O was an extended duration of action in these tests (4-5 h). T-N-O had negligible affinity for opioid mu (Ki = 38.5 microM) delta. or kappa receptors (Ki \> 100 microM) and, in contrast to tramadol, was essentially devoid of norepinephrine or serotonin neuronal reuptake inhibitory activity (Ki \> 100 microM). However, T-N-O displayed tramadol-like characteristics in vivo. There were also significant amounts of tramadol in plasma after T-N-O administration, and the levels resulting from equal oral doses of T-N-O and tramadol were the same, suggesting that the conversion of T-N-O to tramadol was rapid and essentially quantitative. T-N-O was not readily metabolized to tramadol in rat hepatic S9 fraction (\< 2\%), implying that the conversion might occur in the gastrointestinal tract. Taken together, the results suggest that T-N-O acts as a prodrug for tramadol. T-N-O could offer the clinical benefits of an extended duration of action and a "blunted" plasma concentration spike, possibly leading to an enhanced side-effect profile.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/278/3/1098}, eprint = {https://jpet.aspetjournals.org/content/278/3/1098.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }