Efficacy of Naloxone in Reducing Postictal Central Respiratory Dysfunction in Patients With Epilepsy
Status:
Completed
Trial end date:
2020-07-01
Target enrollment:
Participant gender:
Summary
Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults with
drug-resistant epilepsy, with an incidence of about 0.4%/year. The diagnosis of SUDEP
requires that anamnestic data and post-mortem examination do not reveal a structural or
toxicological cause for death. Generalized tonic-clonic seizures (GTCS) are the main risk
factor for SUDEP, which they appear to trigger in most instances. Indeed, experimental and
clinical data strongly suggest that most SUDEP result from a postictal respiratory
dysfunction progressing to terminal apnea, later followed by cardiac arrest.
Postictal apnea could partly derive from a seizure-induced massive release of endogenous
opioids. Animal studies suggest that such seizure-related release of endogenous opioid
peptides participate to termination of seizures. In patients with epilepsy, functional
imaging studies have confirmed that seizures induce release of endogenous opioids. The
brainstem respiratory centers contain the highest density in opioid receptors, accounting for
respiratory depression being one of the cardinal symptoms of opioid overdose.
The investigators hypothesis is that SUDEP partly results from a post-ictal apnea promoted by
a GTCS-induced massive release of endogenous opioids, and that an opioid antagonist could
represent an effective preventive treatment of SUDEP. This could be achieved by chronic
administration of Naltrexone, an opioid antagonist that has been used in a large population
of patients with chronic alcoholism at high risk of seizures, without showing any
pro-convulsant effect. This is a crucial feasibility issue since antagonising a mechanism
thought to participate to seizure termination could theoretically aggravate seizures.
Before evaluating the efficacy of chronic administration of naltrexone, it is legitimate to
perform a proof of concept study by testing the acute effect of an equivalent injectable
treatment (Naloxone) in the immediate aftermath of GTCS recorded inhospital during video-EEG
monitoring of patients with refractory epilepsy. One third of these patients develop
postictal respiratory dysfunction and hypoxemia, which should be reduced by the investigators
intervention if the investigators hypothesis is correct.
The main objective of the study is to evaluate the efficacy of 0.4 mg intravenous naloxone,
versus placebo, administered in the immediate aftermath of a GTCS, in reducing the severity
of the postictal central respiratory dysfunction occurring after the end of the seizure, as
measured by pulse oximetry.
About 25% of patients with drug-resistant partial epilepsy who undergo long-term video-EEG
monitoring develop at least one partial secondary generalized tonic-clonic seizure. However,
these patients cannot be individualized a priori. Therefore, all adult patients with
drug-resistant epilepsy who will undergo long-term video-EEG monitoring in one of the
participating centres, will lack all exclusion criteria, and will give their written informed
consent to participate to the study if they develop GTCS, will be included in the study. They
will all benefit from continuous monitoring of pulse oximetry (together with video, EEG, and
respiration recordings), and will be equipped with a peripheral venous catheter throughout
the video-EEG. The modalities of the video-EEG monitoring will be consistent with the current
practices and similar across the 8 centres (apart from the venous catheter which is not
standard practice).
In case of occurrence of a generalized tonic-clonic seizure, patients will be randomized
(1:1) to receive intravenous naloxone (0.4 mg) or placebo. Placebo will be isotonic sodium
chloride which preparation and packaging will be centralized to ensure its
indistinguishability from naloxone. Randomization will be centralized and stratified by
centre. The evolution from a partial seizure to a GTCS being gradual, and the total duration
of the seizure ranging from 2 to 3 minutes, the injection will be prepared during the course
of the seizure. Given the assumptions about the role of endogenous opioids release in the
spontaneous termination of seizures, naloxone will be administrated immediately after the end
of the GTCS and not before.
All digital data (video, EEG, respiration, SpO2) will be centralized and evaluated blind to
other data by the PI of the study who will not be involved in the video-EEG monitoring of the
included patients. The same automatic and objective analysis of SpO2 data than the one
already developed in the PHRC REPOMSE will be performed.