Efficacy of naloxone in reducing postictal central respiratory dysfunction in patients with epilepsy: study protocol for a double-blind, randomized, placebo-controlled trial.
Generalized tonic-clonic seizures (GTCSs) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). Experimental and clinical data strongly suggest that the majority of SUDEP results from a postictal respiratory dysfunction progressing to terminal apnea. Postictal apnea could partly derive from a seizure-induced massive release of endogenous opioids. The main objective of this study is to evaluate the efficacy of an opioid antagonist, naloxone, administered in the immediate aftermath of a GTCS, in reducing the severity of the postictal central respiratory dysfunction.



The Efficacy of Naloxone in Reducing Postictal Central Respiratory Dysfunction in Patients with Epilepsy (ENALEPSY) study is a multicenter, double-blind, randomized, placebo-controlled trial conducted in patients with drug-resistant focal epilepsy who are undergoing long-term video-electroencephalogram (EEG) monitoring (LTM) in an epilepsy monitoring unit (EMU). We plan to randomize 166 patients (1:1) to receive intravenous naloxone (0.4 mg) or placebo in the immediate aftermath of a GTCS. Because inclusion in the study needs to take place prior to the occurrence of the GTCS, and because such occurrence is observed in about one-fourth of patients undergoing LTM, we plan to include a maximum of 700 patients upon admission in the EMU. The primary endpoint will be the proportion of patients whose oxygen saturation is <90 % between 1 and 3 min after the end of a GTCS. Secondary outcomes will include the following: the proportion of patients who show postictal apnea, the occurrence and duration of postictal generalized EEG suppression, the total duration of the postictal coma, postictal pain, and the number of patients who have a second GTCS within 120 min after the intravenous injection.



The demonstration of naloxone's efficacy on the severity of postictal hypoxemia will have two primary consequences. First, naloxone would be the first and only therapeutic approach that could be delivered immediately to reverse postictal apnea. Second, demonstration that an opioid antagonist can effectively reduce postictal apnea would pave the way for an assessment of a preventive therapy for SUDEP targeting the same pathophysiological pathway using oral administration of naltrexone.



ClinicalTrials.gov identifier: NCT02332447 . Registered on 5 January 2015.
Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, France. sylvain.rheims@chu-lyon.fr.|Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, Lyon, France. sylvain.rheims@chu-lyon.fr.|Epilepsy Institute (IDEE), Lyon, France. sylvain.rheims@chu-lyon.fr.
Sylvain
S
Rheims
Department of Neurology, University Hospital of Toulouse, Toulouse, France.
Luc
L
Valton
Department of Clinical Neurophysiology, University Hospital of Bordeaux, Bordeaux, France.
Véronique
V
Michel
Department of Neurology, University Hospital of Nancy, Nancy, France.
Louis
L
Maillard
Epileptology Unit, Assistance Publique-Hôpitaux de Paris - Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|Brain and Spine Institute (ICM; INSERM UMRS1127, CNRS UMR7225), Pierre and Marie Curie University, Paris, France.
Vincent
V
Navarro
Department of Clinical Neurophysiology, University Hospital, Saint-Etienne, France.
Philippe
P
Convers
Department of Clinical Neurophysiology and Epileptology, Timone Hospital, Marseille, France.
Fabrice
F
Bartolomei
Department of Neurology, University Hospital of Rennes, Rennes, France.
Arnaud
A
Biraben
Epilepsy Unit, University Hospital of Montpellier, Montpellier, France.
Arielle
A
Crespel
Department of Clinical Neurophysiology, Lille University Medical Center, EA 1046, Lille 2 University of Health and Law, Lille, France.
Philippe
P
Derambure
Department of Clinical Neurophysiology, INSERM U930, University Hospital of Tours, Tours, France.
Bertrand
B
de Toffol
Department of Neurology, University Hospital of Strasbourg, Strasbourg, France.
Edouard
E
Hirsch
Department of Neurology, Michallon Hospital, Grenoble, France.|Institute of Neurosciences, INSERM U836, Grenoble Alpes University, Grenoble, France.
Philippe
P
Kahane
Department of Clinical Neurophysiology, University Hospital of Dijon, Dijon, France.
Martine Lemesle
ML
Martin
La Teppe Epilepsy Center, Tain l'Hermitage, France.
Didier
D
Tourniaire
Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, France.|Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, Lyon, France.
Sébastien
S
Boulogne
Department of Biostatistics, Hospices Civils de Lyon, Lyon, France.
Catherine
C
Mercier
Department of Biostatistics, Hospices Civils de Lyon, Lyon, France.
Pascal
P
Roy
Epilepsy Institute (IDEE), Lyon, France.|Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Philippe
P
Ryvlin
D002985:Clinical Protocols; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004569:Electroencephalography / Q000379:methods; D005602:France; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D007275:Injections, Intravenous; D009270:Naloxone / Q000008:administration & dosage* / Q000009:adverse effects; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D012107:Research Design; D012125:Respiratory Center / Q000187:drug effects* / Q000503:physiopathology; D012131:Respiratory Insufficiency / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D012640:Seizures / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014741:Video Recording
D009292:Narcotic Antagonists; D009270:Naloxone
Epilepsy; Naloxone; Opioids; SUDEP