Effect of µ-opioid receptor (MOR) versus N-methyl-D-aspartate receptor (NMDAR) involvement in ketamine and methadone effects in healthy volunteers with special focus on antinociception, sedation, respiratory depression and pupil constriction

Analgesic agents act via activation or blockade of specific protein effector
systems or receptors. The most important analgesics used in contemporary
medicine are drugs belonging to the opioid-family that act via the opioid
receptor system, most importantly the µ-opioid receptor system. However, some
agents attain their effects via more than one receptor system. The µ-opioid
methadone is an example of such an agent, acting also via blockade of the
N-methyl-D-aspartate receptor (NMDAR). Some agents that act via multiple
receptor systems are advantageous as the dual receptor activation and/or
blockade may enhance efficacy. Again methadone is an example of such action:
prolonged µ-opioid receptor activation may at one point cause reduced analgesic
efficacy related to development of hyperalgesia and tolerance; NMDAR blockade
prevents or at least slows down such action, enhancing the analgesic efficacy
of methadone. An agent from a different class is S(+)-ketamine, which
predominantly acts via blockade of the NMDAR. Studies from our laboratory in
mice lacking the µ-opioid receptor indicate that a large part of ketamine*s
analgesic effect is related to an effect via the µ-opioid receptor.

Little is know on the relative contribution of NMDAR and µ-opioid receptor
systems in the analgesic and side effect profile of methadone and ketamine,
despite their use for over 4 decades. Detailed knowledge about the complete
pharmacodynamics of an analgesic drug is a prerequisite for optimizing pain
therapy. Elucidating the full receptor mechanisms of these two important
analgesics will serve as a major step in improvement of pharmacotherapy of
pain. Apart form increasing our knowledge on these two agents, it will, for
example, allow the development of drug combinations of existing agents with
single receptor mechanisms. Or, it will allow appropriate choices of drugs
under certain specific pain circumstances (for example, use an analgesic acting
at just the µ-opioid receptor or one that has a dual receptor mechanism in a
patient with a neuropathic component to his pain).

In the current approach we will block the µ-opioid receptor in healthy
volunteers using a high-dose naloxone background infusion. Naloxone is a
non-specific opioid-receptor antagonist that is used frequently in clinical
practice to reverse opioid overdose. Studies from our laboratory indicate that
naloxone is a safe drug with little or no side effects, even at high dose
(doses up to 8 mg have been tested by us). In the current study approach we
will compare the effect of the two agents during background infusions of either
naloxone or placebo. Placebo and naloxone will be given as bolus + continuous
infusion allowing for the complete blockade of the opioid receptors during the
study. The study design is randomized, double-blind and cross over.

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

Randomized, double-blind and cross-over

Study A
Twenty-four subjects will receive a 80-min continuous infusion of
S(+)-ketamine. The dose (per 70 kg) is 40 mg.h-1. The subjects will be randomly
allocated to receive a background iv infusion of placebo (NaCl 0.9%) or
naloxone. The background infusion will start 30-min prior to the start of the
ketamine infusion. The naloxone/placebo dose is bolus 0.04 mg.kg-1 (given over
120-s), followed by 0.04 mg.kg-1.h-1. The background infusion will continue
until the end of study (t = 220 min).

Study B
Twenty-four subjects will receive an iv methadone dose of 0.15 mg.kg-1. The
subjects will be randomaly allocated to receive a background iv infusion of
placebo (NaCl 0.9%) or naloxone. The background infusion will start 30-min
prior to the metahdone infusion. The naloxone/placebo dose is bolus 0.04
mg.kg-1 (given over 120-s), followed by 0.04 mg.kg-1.h-1. The background
infusion will continue until the end of study (t = 220 min).

The risk of the subjects is minimal. benefit to the subjects is absent.

nature of risks/discomfort:

1. Nausea (well treatable);
2. vivid dreams (will stop immediately upon termination of the ketamine
infusion)
3. bruising from iv.