UNEXPECTED ANTINOCICEPTIVE EFFECT OF THE N-OXIDE (RWJ-38705) OF TRAMADOL HYDROCHLORIDE

N-Oxides of centrally acting analgesics generally have minimal analges ic activity. However, the N-oxide of tramadol produced dose-related, l ong-lasting antinociception in the mouse abdominal irritant, 48 degree s C hot-plate, 55 degrees C hot-plate, and tail-flick tests (ED(50) = 15.5, 84.7, 316.4 and 138.2 mg/kg, p.o., respectively). Tramadol N-oxi de (T-N-O) (RWJ 38705) was also antinociceptive in the 51 degrees C ho t-plate test in male (ED(50) = 63.2 mg/kg, i.p.) and female (ED(50) = 39.9 mg/kg, i.p.) rats. A characteristic feature of T-N-O was an exten ded duration of action in these tests (4-5 h). T-N-O had negligible af finity for opioid mu (K-i = 38.5 mu M) 6, or kappa receptors (K-i > 10 0 mu M) and, in contrast to tramadol, was essentially devoid of norepi nephrine or serotonin neuronal reuptake inhibitory activity (K-i > 100 mu M). 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 was not readily metabolized to tramadol in rat hepatic S9 fraction ( < 2%), implying that the conversion might occur in the gastrointestina l tract. Taken together, the results suggest that T-N-O acts as a prod rug for tramadol. T-N-O could offer the clinical benefits of an extend ed duration of action and a ''blunted'' plasma concentration spike, po ssibly leading to an enhanced side-effect profile.