Alcohol and Oxycodone - The influence of the combination of alcohol and an opioid on ventilation in healthy young and elderly volunteers - the 'A&O' study

Opioid use and abuse has increased over the past decades. An associated
increase of opioid related mortality has been observed of which opioid induced
respiratory depression is thought to be the most important cause. With
increasing use of opioids the adverse events caused by concomitant use of
substances influencing the pharmacokinetic and pharmacodynamic properties of
opioids becomes more prevalent. In forensic literature in cases of opioid
related mortality concomitant use of alcohol is described most often. In
previous studies focusing on the respiratory effects of alcohol by itself no
major effects on ventilation were observed. We hypothesize that the concomitant
administration of an opioid and alcohol will result in a synergistic effect on
ventilation. We will measure carbon dioxide ventilatory response curves in
young and elderly healthy volunteers during an alcohol clamping method to
induce a pseudo steady state in blood alcohol level and after administration of
one of the most prescribed opioid analgesics. The results of this study will
provide further insight into opioid induced respiratory depression and the
influence of concomitant alcohol use.

In the current study we will measure ventilatory response, as assessed by
ventilatory carbon dioxide responses to the administration of oxycodone during
three conditions: a *low alcohol condition*, a *high alcohol condition* and a
*no alcohol condition*. Furthermore the influence of alcohol on analgesia and
sedation induced by oxycodone will be assessed. In order to achieve the two
steady state alcohol conditions we will use a clamping method developed at the
Centre for Human Drug Research (CHDR) by Zoethout et al. (33-36). The study
will take place in two phases and will consist of a phase with 40 young
volunteers and a phase with 40 elderly volunteers.

A single blind crossover study. The three conditions/study days will be defined
as follows:
1 a high dose alcohol steady state with oral oxycodone (1.0 g L-1)
2 a low dose alcohol steady state with oral oxycodone (0.5 g L-1)
3 a placebo condition with oral oxycodone. (no alcohol infusion)

During the first phase young healthy volunteers will be included followed by
the second fase in which elderly healthy volunteers will be included.

Intravenous administration of ethanol inducing a steady state BrAC-level (at
0.5 g L-1 or at 1.0 g L-1)
Oral administration of Oxycodone 20mg IRS

The study will be conducted in the anesthesiology department of a hospital,
where all necessary emergency
procedures are in place. The study will be conducted by researchers with
experience of treating respiratory depression. Naloxone
injections will be available to treat urgent, severe respiratory depression.
Other support measures for breathing and hemodynamics will also be available,
such as maintenance of fluid, oxygen and vasopressors. Cardiovascular emergency
measures such as defibrillation, magnesium sulfate (IV) and antiarrhythmic
drugs will also be available.

The overall risk / benefit assessment is considered acceptable under the
conditions described above.