Primary Objective:
To determine the effect of low-dose (10 mg) oxycodone versus placebo in individuals that use paroxetine on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg at 1 week (4-10 days) of SSRI treatment.
Secondary objectives:
To determine the effect of low-dose (10 mg) oxycodone versus placebo in individuals that either use sertraline, citalopram or escitalopram on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg at 1 week (4-10 days) of SSRI treatment.
To determine the effect of low dose (10 mg) oxycodone versus placebo in individuals that either use paroxetine, sertraline, citalopram or escitalopram on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg following at 1 month (25- 45 days) following initiation of SSRI treatment.
To determine whether the effects of SSRI on opioid induced respiratory depression alter during the course of treatment.
To determine the effect of low-dose oxycodone versus placebo in individuals that use and SSRI on pupil diameter.
To determine the effect of paroxetine on the pharmacokinetics of oxycodone.
Study design:
The design of the study is double-blind, placebo-controlled and cross over.
two groups will be studied: Time 1: individuals that use an SSRI for 1 week (day 4-10 after initiation of treatment); Time 2: (the same) individuals that use an SSRI for 1 month (day 25-45 after initiation of treatment); Subjects from Time 1 may transition to time 2 (preferably).
This is a crossover study. Subjects will be randomized (placebo vs oxycodone) with at least 2days in-between study days.
Subjects will be asked to take their antidepressant on t = 0 h, and will then dose the oxycodone on t = 2 h. Primary endpoint is ventilation measured at an extrapolated end-tidal PCO2 of 55 mmHg (VE55) at t = 4 h.
Prior to any antidepressant intake (t = 0) and at 1 h intervals following drug intake, the ventilatory response to hypercapnia will be measured for 6 hours. If VE55 is below 20% of baseline a further 1 or 2 measurements will be obtained
In between respiratory measurements, pupil diameter will be measured the using a handheld pupilometer. Additionally, subjects will be queried the at 1 h intervals for sedation,lightheadedness, nausea/vomiting using 11-point Likert scale from 0 (no effect) to 10 (max. possible effect).
In all subjects, a blood sample will be draw to determine the state of the CYP 2C8/3A4/2D6 gene to determine the metabolic state of the antidepressant among the subjects and relate this as covariate to our results. Additionally, 10 venous blood samples will be drawn for pharmacokinetic oxycodon analysis by Ardena (Assen). Blood will be drawn for a venipuncture in the arm or via an access line in the cubital vein. Blood sampling will be at t = 0 (blank), t = 15 min, 30 min, t = 45 min, t = 60 min, t = 120 min, t = 180 min, t = 240 min en t = 300 min.
SSRIs: the following SSRIs are planned to be studied :
* Paroxetine, dose at least 20 mg (Primary endpoint)
* Citalopram , dose at least 20 mg
* Escilatopram, dose at least 10 mg,
* Sertraline, dose at least 50 mg
