Fig. 6.  Simulation study for an acute pain paradigm. Simulation studies enable the systematic exploration of inferences made in our study with respect to anticipated norketamine effect size. We performed simulations to estimate the effect of the large change in norketamine concentration and relatively modest change in ketamine concentration that we observed after rifampicin treatment on acute pain relief induced by the 2-h, 40-mg/h ketamine infusion (gray bar ). We made a priori  assumptions with respect to the norketamine contributions to ketamine effect: simulations with 0, 10, and 25% norketamine contribution were made. The difference in effect observed in the simulated pain relief with and without rifampicin treatment will give an indication of the norketamine contribution to effect. The top diagram shows the difference in VAS between placebo and rifampicin data for the three norketamine contributions to effect: 0, 10, and 25%. VAS = visual analog score.