Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats

The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethyltramadol [(+)-M1] and ( -)-O-desmethyltramadol [(-)-M1], main metabolites of tramadol, was studied in three groups of rats. (+)-M1 and (-)-M1, both with different pd properti es, were studied under steady-state and nonsteady-state conditions, dependi ng on the group. Plasma drug concentration and antinociception were simulta neously measured in each animal by using an enantioselective analytical ass ay and the tail-flick test, respectively. Respiratory depression also was e valuated in another series of experiments according to the same experimenta l conditions. The pk behavior was similar for both enantiomers and no signi ficant (P > .05) interaction between two compounds was found at this level. However, a significant (P < .01) potentiation in the antinociceptive effec t elicited by (+)-M1 was found during and after (-)-M1 administration. The pd model used to describe the time course of the antinociception in the pre sence of (+)-M1, (-)-M1, or both is based on previous knowledge of the comp ounds and includes the following: 1) an effect compartment model to account for the opioid effect of (+)-M1, and 2) an indirect response model account ing for the release of noradrenaline (NA) caused by (+)-M1, and the inhibit ion of the NA reuptake due to the action of (2)- M1. The model predicts a p ositive contribution to antinociception of the predicted increasing levels of NA. No significant (P > .05) respiratory effects were seen during or aft er (1)- M1 and (2)- M1 administration.