The effect of ketamine and methadon on healthy volunteers with special
focus on painscore, sedation, ventilatory depression and change of pupil
diameter.

In this double blinded, placebo-controlled crossover trial, the effect
of mu opioid receptor (MOR) versus N-methyl-D-aspartate (NMDAR) receptor
involvement in ketamine and methadone will be studied in healthy
volunteers. 48 Volunteers will receive either a ketamine or a methode
infusion and a concomitant placebo or naloxone infusion on two different
occasions. Volunteers will be in the respiratory leg or in the analgesia
leg of the study. Respiratory measurements by means of the dynamic
end-tidal forcing technique or VAS-score upon heatpain and pupil
diameter will be assessed regularly throughout the study in order to
obtain information on MOR- or NMDAR-involvement.

This study is therefore aimed at quantifying the relative contribution of the two major receptor systhems involved in S(+) ketamine and methadone induced analgesia and side effects( respiratory depression,sedation,miosis).

Respiratory measurements:

Respiratory measurements will be performed at the start of experiment (t=0) untill start of nalaxon/placebo background infusion (t=10).

Respiratory measurements will be resumed before start of test drug injection(methadone) or 90-min infusion (ketamine) up till t=130 min.

After this period respiration will be assessed every 20-30 minutes untill t=300.



At the analgesia leg we measure thermal pain, pupildiameter and sedation score just prior to naloxone/placebo bolus infusion t=10,just prior to test drug infusion t=40 and next at 10 min intervals(1st /2nd hours of the study),at 20 min intervals (3th hour of the study) at 30 min intervals,remainder of the study until t=300.

There are 2 separate studies.
Study A,in which the subject will receive a 80 min infusion of S(+) ketamine and
Study B in which the subject will receive iv methadone.
Each study has 2 legs, a respiratory leg and an analgesic leg. Per leg we will recruit 12 subjects.
The respiratory leg is identical for studies A and B. Twenty-four subjects (12 on ketamine and 12 on methadone) will participate.The subject will breath a fixed gas mixture such that his ventilation prior to any drug infusion is 20 L/min= 2L/min.
To that end the end-tidal carbon dioxide concentration will be clamped by 1 to 1,5 Kpa above the subjects resting PetCO2 using the dynamic end tidal forcing (DEF) technique.the inspired oxygen concentration is is normoxic (21%). Subjects will be randomly allocated to receive a background iv infusion of placebo.
The analgesia leg is identical for studies A and B.Twenty-four subjects (12 on ketamine and 12 on methadone ) will participate. thermal pain measurements will be performed just prior to the naloxone/placebo bolus infusion(10 min), just prior to the test drug infusion (40 min) and next at 10 min intervals (1st/2nd hoursof the study),20 min intervals (3th hour of the study),30 min intervals,remainder of the study (until t=300 min)
Pupillometry: pupil diameter will be assessed regularly during the analgesia studies by a pupillometry device.
Sedationscore will also be assessed regularly.