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Randomized Controlled Trial
. 2025 Jun;10(3):880-893.
doi: 10.1002/epi4.70046. Epub 2025 Apr 28.

Efficacy of naloxone in reducing hypoxemia and duration of immobility following focal to bilateral tonic-clonic seizures

Sylvain Rheims  1   2 , Fatima Chorfa  3 , Véronique Michel  4 , Edouard Hirsch  5 , Louis Maillard  6 , Luc Valton  7   8 , Fabrice Bartolomei  9 , Philippe Derambure  10 , Vincent Navarro  11   12 , Julien Biberon  13 , Arielle Crespel  14 , Anca Nica  15 , Martine Lemesle Martin  16 , Laure Mazzola  17 , Jerome Petit  18 , Vincent Rossero  2 , Sébastien Boulogne  1   2 , Mathilde Leclercq  1 , Laurent Bezin  2 , Catherine Mercier  3 , Pascal Roy  3 , Philippe Ryvlin  19 ; ENALEPSY Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Efficacy of naloxone in reducing hypoxemia and duration of immobility following focal to bilateral tonic-clonic seizures

Sylvain Rheims et al. Epilepsia Open. 2025 Jun.

Abstract

Objective: Evaluating the efficacy of an opioid antagonist, naloxone (NLX), to reduce the severity of post-ictal hypoxemia and immobility after focal to bilateral tonic-clonic seizures (FBTCS).

Methods: ENALEPSY is a double-blind placebo (PCB)-controlled trial conducted in patients with focal epilepsy undergoing long-term video-EEG monitoring (LTM). Patients with a FBTCS during LTM were randomized 1:1 to receive intravenous NLX or PCB within the 2 min following the end of FBTCS. After database lock, a discrepancy between the allocated arm and the received treatment was detected, resulting in a 4:1 NLX:PCB ratio. To further explore the efficacy of NLX, we used historical control (HC) data collected in patients included in the REPO2MSE study whose characteristics matched those of patients randomized in ENALEPSY. The efficacy of NLX was then assessed versus PCB and versus HC. The primary endpoint was the delay between the end of the seizure and recovery of SpO2 ≥ 90%. Secondary efficacy outcomes included desaturation nadir and duration of the post-ictal immobility.

Results: 33 patients contributed to the NLX group, 7 to the PCB group, and 43 to the HC group. The proportion of FBTCS type 1 or 3 was 84% in NLX, 100% in PCB, and 84% in HC. NLX did not improve the delay of recovery of SpO2 ≥ 90% or the desaturation nadir. By contrast, the duration of the post-ictal immobility differed across groups. The time to mobility recovery within the first 5 min post-ictal was very similar in the PCB (200.3 ± 215.8 s) and HC (194.4 ± 192.0 s) groups, and significantly shorter in the NLX group (128.9 ± 151.1 s) when compared to HC (Hazard Ratio, 1.84; 95% CI, 1.11-3.05; p = 0.021).

Significance: NLX did not prevent post-ictal respiratory dysfunction but might reduce the duration of post-ictal immobility. Confirmation of this effect and its impact on SUDEP risk will require additional studies.

Plain language summary: Release of endogenous opioids might participate in the severity of post-ictal hypoxemia and immobility after focal to bilateral tonic-clonic seizures (FBTCS). We conducted a multicenter double-blind randomized placebo-controlled trial evaluating the efficacy of an opioid antagonist, naloxone (NLX), administered within 2 min following the end of FBTCS. The efficacy of NLX was further explored with a comparison with historical control. NLX did not improve the delay of recovery or the severity of post-ictal hypoxemia. Post-ictal immobility was significantly shorter in the NLX group when compared to historical control. The impact of these results on SUDEP prevention will require additional studies.

Keywords: SUDEP; epilepsy; generalized convulsive seizures; naloxone; post‐ictal EEG hypoxemia; post‐ictal immobility.

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Conflict of interest statement

No author has a conflict of interest related to this study. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
Flowchart of the study.
FIGURE 2
FIGURE 2
Time to recovery of SpO2 ≥ 90% from the end of the seizure to 5 min post‐ictal.
FIGURE 3
FIGURE 3
Time to first voluntary movement and to the patient's ability to handshake was analyzed from the end of the seizure to 5 min post‐ictal.
See this image and copyright information in PMC

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