Results Twenty subjects participated in the study to receive, in random order, a single OTF (50 mg) or, on a second occasion, two OTFs applied simultaneously (100 mg) sublingually (n = 15) or on the buccal mucosa (n = 5). One subject participated only once (receiving 100 mg S-ketamine), due to side effects experienced from the intravenous S-ketamine infusion. Since no differences were observed in the sublingual and mucosal application regarding pharmacokinetics and pharmacodynamics of S-ketamine and its metabolites, we combined the two in the pharmacokinetic and pharmacodynamic model analyses. The mean age of the volunteers was 24 years (with range 19-32 years), mean weight 73 kg (53-93 kg), and mean body mass index 23 kg/m2 (19-27 g/m2) with an equal number of men and women participating (10/10). To summarize the pharmacokinetic data that stands at the basis of the pharmacodynamic analyses, we give the average plasma concentrations for S-ketamine, S-norketamine and S-hydroxynorketamine following 50 and 100 mg S-ketamine OTF in Figure 3.1 on page 49. It shows the large first-pass effect, with relatively high concentrations of the S-ketamine metabolites. No serious adverse events occurred during the study (see chapter 2 for a description of adverse events). The effects of the 50 and 100 mg S-ketamine OTF on pain responses are given in Figure 3.2 on page 49 for the three assays: electrical pain, heat pain and pain pressure. The data indicate that the OTF produces antinociception in all three assays, but irrespective of the pain assay a clear dose-response relationship was absent. Among subjects, pain relief was most variable in the pain pressure test compared to the other pain test with pain relief lasting two hours (heat pain test) or longer (electrical pain test). Comparing Figures 3.1 and 3.2, gives rise to the suggestion that the S-ketamine effect is pharmacokinetically-driven, i.e. that the pain responses closely follow the S-ketamine concentration profile, without any effect of the metabolites. In Figure 3.4, panels A and B, the individual median drug high visual analogueue scores are given in gray and red, respectively. The peak median effect is higher for the 100 mg S-ketamine OTF compared to the lower dose OTF. 48
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