title: Unexpected antinociceptive effect of the N-oxide (RWJ 38705) of tramadol hydrochloride.
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.
authors.affiliation: R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Raffa
authors.forename: M L
authors.initials: ML
authors.lastname: Haslego
authors.forename: C A
authors.initials: CA
authors.lastname: Maryanoff
authors.forename: F J
authors.initials: FJ
authors.lastname: Villani
authors.forename: E E
authors.initials: EE
authors.lastname: Codd
authors.forename: C D
authors.initials: CD
authors.lastname: Connelly
authors.forename: R P
authors.initials: RP
authors.lastname: Martinez
authors.forename: J J
authors.initials: JJ
authors.lastname: Schupsky
authors.forename: J A
authors.initials: JA
authors.lastname: Buben
authors.forename: W N
authors.initials: WN
authors.lastname: Wu
authors.forename: A N
authors.initials: AN
authors.lastname: Takacs
authors.forename: L A
authors.initials: LA
authors.lastname: Mckown
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D017450:Receptors, Opioid, mu; C101588:tramadol N-oxide; D009270:Naloxone; D014147:Tramadol