Discussion The main findings from our population pharmacodynamic modeling study of an S-ketamine OTF are summarized as follows: (i) the sublingual and buccal 50 and 100 mg S-ketamine OTFs are antinociceptive with effects lasting at least 2 h; (ii) the onset of effect is rapid with peak effects within 30 to 45 min; (iii) drug high had a peak effect at 30 min and lasted at least 2 h; (iv) S-ketamine potency was lower for antinociception than for drug high by a factor of 3 to 5; (v) there were no contributions of S-norketamine and S-hydroxynorketamine to the antinociceptive or drug high S-ketamine effects detected in our model. A clear dose-response relationship was not observed in the nociceptive data. For all three pain assays, the effect of doubling the dose of the OTF did not produce a significant increase in antinociception. Several mechanisms may be involved: (i) this may be related to a 20% lower S-ketamine bioavailability for 100 mg OTF compared to 50 mg OTF (bioavailability 50 mg = 29%vs. 100mg 23%);2 (ii) as observed in Figure 3.6, for electrical and heat pain, the effect-site concentration-effect curve becomes ultimately flat at high concentrations; for pressure pain, the slope of the response is initially not particularly steep and some overlap in the response data may be expected; (iii) The high concentrations of the measured and non-measured metabolites may have an antagonistic effect on the antinociceptive response.5 High concentrations of S-norketamine and S-hydroxynorketamine were observed after the 50 and 100 mg S-ketamine OTFs due to the high first-pass effect. We earlier showed that S-norketamine counteracts the effects of S-ketamine,5 but see below; (iv) possibly some noise in the data and variability in the day-to-day analgesic drug efficacy may have caused the overlap of antinociceptive response; (v) since we applied several noxious stimuli in a relatively short period of time to the volunteers, this may have altered the discriminatory ability of the nociception signaling pathways. Such an effect was earlier observed for volunteers treated with an opioid;13 (vi) and finally, theoretically, there may be a ceiling in the ability of the nociceptive assays at higher drug doses. In a post hoc analysis, we observed that the separately estimatedC50s following the two S-ketamine OTFs did not differ, indicative that the absence of a dose-dependency of antinociceptive effect is probably related to the following items (i) reduced bioavailability for the higher dose OTF, (ii) flat concentration-effect relationship, and (iii) lesser discriminatory ability of the pain signaling pathways when multiple stimuli are administered. An effect of metabolites on the antinociceptive and drug high responses is further discussed below. 56
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