Reversal of opioid-induced respiratory depression with opioid antagonists - a study in opioid naïve individuals and chronic opioid users under real-life conditions

The opioid crisis has a significant socioeconomic impact worldwide but
particularly in the US the number of opioid-related deaths is soaring. Opioid
deaths are due to respiratory depression which is caused by the activation of µ-
opioid receptors expressed on the surface of neurons in brainstem respiratory
centers. Activation of these opioid receptors by both illicit opioids and
prescription opioids may initiate respiratory compromise, which in many
individuals is short-lived or reverts to normal breathing activity. In some
individuals, often due to underlying disease, an opioid overdose or the
combination of opioid use with other centrally depressant drugs (such as sleep
medication or alcohol), diminished breathing progresses into irregular (or
cyclic) breathing and eventually into apnea (the complete cessation of
breathing). This may lead to cardiorespiratory collapse and ultimately death.3
The most effective treatment of opioid-induced respiratory depression is
treatment with opioid receptor antagonists, most importantly naloxone.3,6
Naloxone is a competitive opioid receptor antagonist that is able to reactivate
rhythmic respiratory activity although the optimal conditions of its effective
use in real-life (or street) conditions remain unknown.3 We previously studied
the ability of intravenous naloxone to reverse opioid-induced respiratory
conditions in healthy volunteers under experimental conditions, i.e. during
inhalation of carbon dioxide.4,7 This was done to maximize the effect of
naloxone and does lead to relevant and useful pharmacokinetic (PK) and
pharmacodynamic (PD) data but is far off from real-life conditions of opioid
overdoses in chronic opioid abusers and the use of other administration routes
than intravenous, e.g. intranasal and nalmefene as opposed to naloxone.or
intramuscular routes. As presented at research meetings, the FDA, under the
supervision of David Strauss, has been using our prior experimental data in
simulation studies to model naloxone doses to reverse the phenylpiperidines
fentanyl and derivatives, however these simulations were based on (intravenous)
experimental data and not on real-life conditions and were not performed in
chronic opioid users.

Since it is important to study the ability of naloxone and nalmefene to reverse
opioid-induced respiratory depression under real-life conditions induced by
potent opioids, we designed a set of experiments to study the ability of
intranasal and intramuscular naloxone and intravenous nalmefene to reverse
respiratory depression induced by two potent opioids, fentanyl and sufentanil
reverseved by intranasal naloxone (in Year 1) and fentanyl and sufentanil
reversed by intramuscular intravenous naloxone and nalmefene (in Year 2).
Studies are performed in volunteers without underlying disease and chronic
opioid users. We will measure ventilation, end-tidal expired CO2, pupil
diameter and drug concentrations in plasma under real-life conditions, i.e.
without supplemental inhalation of carbon dioxide. In this study we mimic an
opioid overdose under stable and highly monitored conditions by titrating the
opioid to 40-60% depression of ventilation. Next, naloxone is administered at
multiple times to characterize its effect on opioid affected ventilation.
Importantly, we will measure the respiratory variables continuously on a
breath-to-breath basis, while pupil diameter and plasma concentration are
measured regularly allowing the precise matching of effects (ventilation and
pupil diameter) and effects to plasma concentration.

The studies in the two populations (healthy subjects and chronic opioid users)
will have a 2-arm cross-over and randomized design:

- In the first study (Year 1), all subjects will be tested twice with at least
one week in between visits. On visit 1, the effect of 4 mg intranasal naloxone
will be tested during fentanyl- or sufentanil induced respiratory depression
with 2 administrations over time (4-5 h); on visit 2 the effect of 4 mg
intranasal naloxone will be tested during fentanyl- or sufentanil-induced
respiratory depression with 2 administrations over time (4-5 h). If the first
visit is fentanyl, the second visit will be sufentanil and vice versa. 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.

- In the second study (Year 2), all subjects will be tested twice with at least
one week in between visits. On visit 1, the effect of an escalating intravenous
dose of nalmefene or intravenous naloxone2 mg intramuscular naloxone will be
tested during sufentanilfentanyl-induced respiratory depression with up to 4 or
513 administrations over time (2-31 h); on visit 2 the effect of 2 mgan
escalating dose of intravenous nalmefene or intravenous naloxone intramuscular
naloxone will be tested during fentanyl-induced respiratory depression with up
to 4 or 513 administrations over time (2-31 h). The sequence of visits is
sequential with first the fentanyl study and subsequently the sufentanil study.
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.

The choice of the two opioids is based on their pharmacokinetic properties.
While fentanyl has a t*koff of 2 min, sufentanil*s t*koff equals 10 min. The
koff determines the affinity of the opioid for the receptor; the longer t*koff
the more difficult reversal by naloxone is. Apart from buprenorphine, fentanyl
and sufentanil are the opioids with the greatest difference in t*koff for all
clinically available opioids.

The collected data (ventilation, end-tidal PCO2, pupil dimeter, concentration
opioid and concentration naloxone and nalmefene) will be analyzed using a
population modeling approach to obtain reliable pharmacokinetic-pharmacodynamic
data that allow precise description of opioid-induced respiratory depression
and naloxone/nalmefene-induced respiratory stimulation, opioid- and
naloxone/nalmefene-induced changes in pupil diameter , and opioid- and
naloxone/nalmefene-induced changes in withdrawal. .

This study has been transitioned to CTIS with ID 2024-518041-16-00 check the CTIS register for the current data.

The goal of the studies is multiple:
1. To describe the pharmacokinetics of intravenously administered fentanyl and
sufentanil;
2. To describe the pharmacodynamics of intravenously administered fentanyl and
sufentanil (important model parameters include receptor equilibration constants
kon and koff and t*ke0, the blood-effect-site equilibration half-life of the
opioid) for respiratory depression and miosis (reduction of pupil size).
3. To describe the pharmacokinetics of intranasal and intravenous naloxone and
intravenous nalmefene;
4. To describe the pharmacodynamics of intranasal and intramuscular naloxone in
its ability to reverse respiratory depression and miosis (important model
parameters include C50, a measure of potency and t*ke0).
5. Finally, 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 fentanyl and sufentanil, with
respiratory depression ranging from moderate to severe. See quad chart.
6. Additionally, we will determine whether the dynamics of the surrogate
biomarker, pupil diameter, mimics respiratory depression and hence may be used
in the development of new opioid antagonists and study other routes of
administration of current and new reversal agents.

Open label randomized crossover study

Administration of an opioid and an opioid antagonist

In this pharmacokinetic-pharmacodynamic modeling study, the effect of IM and IN
and IV 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
(beyond the stopping rules) 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.