3 S-ketamine oral thin film pharmacodynamics Norketamine and hydroxynorketamine Due to the large first-pass effect, plasma concentrations of S-norketamine and S-hydroxynorketamine were relatively high compared to intravenous ketamine administration ( chapter 2 and Figure 3.1). Our modeling approach detected no contribution of these two S-ketamine metabolites to the antinociceptive and drug high effects of the S-ketamine OTF. Animal studies do show an antinociceptive effect from both ketamine and norketamine,14,15 while we earlier observed a small negative contribution of S-norketamine to the antinociceptive and hemodynamic effects of S-ketamine in healthy volunteers.5 We argued that this is one of the main reasons for the observation of pain facilitation after ketamine treatment, when norketamine concentrations exceed ketamine concentrations in plasma. Such observations are sometimes observed both clinically and in experimental studies.16,17,18 The absence of a negative S-norketamine contribution to the antinociception from the OTF, suggests that S-norketamine has either no antinociceptive effect in humans, or the effect is small and was not detected from the noise in the data in our current study. Still, the absence of treatment arms that received S-norketamine precludes a definite conclusion regarding the effect of either metabolite on the pharmacodynamic responses in our study. For now, we cautiously infer from our modeling approach that S-norketamine has no or just little effect on either analgesia or drug high in human volunteers. The excitatory phenomena observed after ketamine infusion in other studies may then be related to the rebound activation of N-methyl-D-aspartate receptor and non-N-methyl-D-aspartate receptor glutamate receptors from accumulated excitatory amino acids in the synaptic cleft.18 In an animal study, Kroin et al.7 showed earlier that (2R,6R)- hydroxynorketamine is an efficacious analgesic in mice. In three pain models, nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome, and plantar incision postoperative pain, (2R,6R)-hydroxynorketamine was effective and superior to ketamine in terms of efficacy and side effect profile. Hence, we anticipated a long-term analgesic effect fromS-hydroxynorketamine in our model with sustained and relatively high S-hydroxynorketamine concentrations in plasma. While after intravenous S-ketamine the ratio peak concentration S-hydroxynorketamine to S-ketamine equals 0.3,3 this ratio ≈ 1 after application of the S-ketamine OTF, irrespective of dose (Figure 3.1). The absence of an S-hydroxynorketamine contribution may be dose-related (i.e. at higher concentration an effect may become visible), related to the stereoselectivity in the effect of hydroxynorketamine (S-hydroxynorketamine in our study vs. R-hydroxynorketamine in the study of Kroin et al.,7 and finally it may be due to the cancellation of an antinociceptive effect from Shydroxynorketamine by a pronociceptive rebound effect from the accumulated excitatory amino acids following the decline inS-ketamine plasma concentration 57
RkJQdWJsaXNoZXIy MTk4NDMw