Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists — ROAR  

Chronic Opioid Use Clinical Trial

Official title: Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions

Status Recruiting

Clinical Trial Summary

In this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intramuscular naloxone to reverse opioid (fentanyl and sufentanil)- induced respiratory depression in healthy volunteers and chronic opioid users to develop dosing recommendations in case of opioid-induced respiratory depression from an opioid overdose in clinical practice and in the out-of-hospital overdose.

Clinical Trial Description

Primary objective:

To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation and intranasal and intramuscular naloxone in its ability to reverse respiratory depression (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to perform simulation studies aimed at optimizing dosing regimens for intranasal and intramuscular naloxone in individuals that overdosed on potent opioids, with respiratory depression ranging from moderate to severe.

Secondary objectives:

To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on pupil diameter and intranasal and intramuscular naloxone in its ability to reverse miosis (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to compare the ventilatory and pupil effects of the opioids and of naloxone.

Study design:

This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.

Study population:

We will study 12 healthy individuals of either sex aged 18-55 years and 12 individuals that are chronic opioids users (> 60 daily oral morphine equivalents; 18-55 years).

Intervention:

Study 1: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intranasal naloxone (IN, 4 mg) will be administered at 30 min intervals. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intranasal bioavailability.

Study 2: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intramuscular (IM, 2 mg) will be administered at 30 min intervals. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intramuscular bioavailability. At regular intervals blood will be drawn for measurement of drug concentration; at regular intervals pupil diameter will be measured.

Main study parameters:

The main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone), ventilation is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively. See Data analysis below.

The secondary study measurement is pupil diameter. Together with the plasma concentration of the opioid and naloxone), the pupil diameter is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively. See Data analysis below. Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

In this pharmacokinetic-pharmacodynamic modeling study, the effect of intramuscular and intranasal naloxone is studied during infusion of two opioids, fentanyl and sufentanil, in mixed population of healthy volunteers and chronic opioid users. The PK/PD analysis will yield important information regarding dosing regimens of IM and IN naloxone at fentanyl and sufentanil doses much higher than we will administer here, but that may represent doses in case of an overdose both in clinical patients and opioid abusers. Side effects related to the medication will be mild to moderate with most common side effects: nausea, vomiting, dizziness, somnolence, dry mouth and respiratory depression (from the opioids), and possibly mild withdrawal symptoms from naloxone. Side effects will dissipate over time while severe occurrences of nausea and vomiting will be treated with an antiemetic; severe occurrence of withdrawal symptoms will be treated with clonidine.

Respiratory depression is the topic of the current study; severe occurrences may be treated with intravenous naloxone. The participants will have no benefit from this trial in terms of disease burden reduction or disease alleviation. The gained knowledge from the study is large as this is the first study to systematically study IM and IN naloxone dosing in chronic opioid users. ;

Related Conditions & MeSH terms

• Chronic Opioid Use
• Depression
• Depressive Disorder
• Opioid Induced Respiratory Depression
• Respiratory Insufficiency

• NCT number: NCT05338632
• Study type: Interventional
• Source: Leiden University Medical Center
• Contact: Rutger van der Schrier, MD
• Phone: +31 (0)71 5299893
• Email: r.m.van_der_schrier@lumc.nl
• Status: Recruiting
• Phase: Phase 1
• Start date: June 24, 2022
• Completion date: May 30, 2024