Severe central sleep apnoea associated with nalmefene: a case report

Abstract

Nalmefene, an opioid antagonist, has recently been approved for the treatment of alcohol dependence. We describe here the first case of a 52‐year‐old woman who developed a severe central sleep apnoea (CSA) 5 months after initiation of nalmefene. Scoring of ventilation during sleep recording revealed an apnoea‐hypopnoea index of 67/h with 98.7% of central events and an apnoea index of 65/h. Nalmefene was withdrawn and a new polysomnography was performed which concluded that CSA has disappeared. Pathophysiology is still unclear but could involve the κ‐opioid receptors. Physicians should be aware that CSA might affect patients treated with nalmefene. Further investigations are required to determine the pathophysiology, frequency, and treatment of CSA associated with nalmefene and other therapy for alcohol disorders.

Nalmefene, an opioid antagonist, has recently been approved for the treatment of alcohol dependence. Data on its safety profile derived essentially from three major clinical trials which have included 1123 patients 1. No sleep‐disorder was described in such trials except a higher rate of insomnia (13.4% vs. 5.4% in placebo groups, P < 0.05) which could be mainly related to alcohol withdrawal 1. After informed consent obtained, we describe here the case of a 52‐year‐old woman who developed a severe central sleep apnoea (CSA) after initiation of nalmefene.

Nalmefene was initiated in June 2016, 18 mg/day for chronic alcoholic addiction in a context of depressive disorder and obesity (BMI = 35.6 kg m⁻²). An anxiolytic/antipsychotic (cyamemazine 25 mg day⁻¹) and two antidepressants (fluoxetine 20 mg/day and mianserine 30 mg/day) drugs were also prescribed.

In October 2016, she was referred to the sleep clinic for a recent onset of symptoms of sleep apnoea: snoring, nocturnal choking, and daytime sleepiness. Analysis of arterial blood gas measurements while breathing room air showed no abnormality. Scoring of ventilation during sleep recording revealed a severe CSA syndrome with an apnoea‐hypopnoea index (AHI) of 67/h with 98.7% of central events and an apnoea index of 65/h.

Nalmefene was withdrawn, and a new polysomnography was performed on December 2016 which concluded that CSA has disappeared but revealed an obstructive sleep apnoea syndrome with an AHI of 54/h and 13% of central events. The sleep and respiratory events scoring were performed by trained technician and validated by a senior sleep physician according to the 2012 AASM rules for sleep 2 and respiratory events 3. Because, differentiating obstructive from central events is a challenge and particularly for hypopnoeas, we used a recommended PSG‐based algorithm for obstructive versus central classification that was established against esophageal pressure measurements 4. Alcohol consumption was not interrupted during nalmefene introduction and after its withdrawal. Ventilatory response to CO₂ was performed only once nalmefene was withdrawn and both ventilatory response and drive were in the normal range.

This is the first case report of CSA associated with nalmefene use. After nalmefene was withdrawn, an obstructive sleep apnoea syndrome was unmasked when CSA disappeared. This has been reported using nonpressure supports treatment for CSA like acetazolamide 5. No sleep recording was performed in clinical trials with nalmefene albeit symptoms of sleep impairment were recorded. A clinical trial comparing the impact of nalmefene 40 mg day⁻¹, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1639 50 mg day⁻¹ or placebo on 125 alcohol‐dependent individuals showed that patients in the nalmefene group reported significantly higher levels of poor sleep, irritability, and impaired attention than those in either the naltrexone or the placebo group 6.

Opioids and opiates are well known to produce mixed sleep apnoeas increasing the upper airway collapse during sleep and depressing central respiratory drive through http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=319 activation 7. Contrariwise, opioid antagonists are assumed to improve such disorders 8. Nalmefene and naltrexone are both μ‐ and http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=317 antagonists, but nalmefene is a partial agonist of http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=318 whereas naltrexone is antagonist. κ‐opioid receptors are mainly involved in antinociceptive properties and have little effects on respiratory depression in animal models 9. Onset of CSA was described with baclofen, another treatment to help alcohol abstinence, and implication of the GABAergic system through depression of the central ventilatory drive was suggested 10. Recently, a study highlighted an interconnection and a modulation of GABA release through κ‐opioid receptors in rat suggesting the possibility of a common mechanism 11.

Furthermore, we cannot exclude that co‐prescription of nalmefene with an antidepressant and with alcohol consumption contributed to an increased risk of sleep apnoea. Indeed, an increased risk of central sleep apnoea has been reported in patients receiving methadone maintenance treatment associated with an antidepressant 12.

Physicians should be aware that central sleep apnoea might affect patients treated with nalmefene. Further investigations are required to determine the pathophysiology, frequency, and treatment of CSA with nalmefene and other therapy for alcohol disorders.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 13, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 14.

Competing Interests

There are no competing interests to declare.

Khouri, C. , Arbib, F. , Revol, B. , Pepin, J.‐L. , and Tamisier, R. (2018) Severe central sleep apnoea associated with nalmefene: a case report. Br J Clin Pharmacol, 84: 1075–1076. doi: 10.1111/bcp.13547.