analysis to determine the S-ketamine bioavailability. Here we only present the pharmacodynamic data obtained during the OTF test phase. Noxious assays Three independent pain assays, namely thermal noxious pain, electrical noxious pain and pressure pain, were randomly applied around predefined time intervals: t = 0, 10, 20, 30, 40, 60, 80, 100, 120, 150, 180, 240, 300 and 360 min after placement of the OTF(s) with 3-5 min in between tests. Electrical pain was induced by an in-house manufactured transcutaneous electrical current stimulator.9 A constant current electrical stimulus train (stimulation at 20 Hz, pulse duration 0.2 ms) was applied on the skin over the tibial bone on the non-dominant side of the body through two surface electrodes. The location of the electrodes was such that muscle contractions did not occur. The current that it induced a numerical pain rating score (NRS) of 8 on a pain scale from 0 (no pain) to 10 (worst pain imaginable) at baseline was used in the remainder of the study. The search for the correct current was performed three times before any drug administration at 5-10 min intervals in steps of 0.5 mA. Thermal noxious stimulation was applied on the volar side of the nondominant forearm using a 3 cm2 Peltier element or thermal probe of the Pathway device (Medoc Ltd., Israel) that allows computer-controlled changes in contact heat changes in steps of ±0.5 oC.9 In the current study a heat level was chosen that at baseline caused an NRS of 8 on the above-mentioned 11-point pain scale. The correct heat level was derived from three tests at 5-10 min intervals. Pressure pain was induced using an Algometer (FDN 200 series, Wagner Instruments Inc., Greenwich, CT).10 Pressure pain was delivered on a 1 cm2 skin area between the thumb and index finger of the non-dominant hand. The device has a force capacity (± accuracy) of 200 ± 2 N (= 20 ± 0.2 kgf) and graduation of 1 N (100 gf), respectively. A gradually increasing pressure was applied and the subjects indicated when the pressure became painful (pressure pain threshold). Three tests were applied at baseline; the obtained pressure values were averaged and served as the baseline value. A researcher well trained in this assay performed the pressure pain tests throughout the study visit days. Questionnaire The Bowdle questionnaire was taken at regular intervals to determine the effect of treatment on mental and psychotomimetic side effects.11 The timing of the questionnaires was at baseline (prior to any drug administration) and at 30 min intervals until 6 h after thin film application. In case the querying coincided with pain testing, the questionnaires were taken prior to pain testing. The Bowdle questionnaire allows the derivation of three factors of psychedelic ketamine effects: drug high and changes in internal and external perception. All 44
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