Gabapentinoids and sleep apnea syndrome: a safety signal from the WHO pharmacovigilance database

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Dear Editor, Gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system. Loss of GABA inhibition has been shown to be implicated in epileptogenesis. Gabapentin (a GABA analog enhancing GABA synthesis) and structurally related pregabalin, known as gabapentinoids, are both used in the treatment of epilepsy and neuropathic pain. The main adverse effects reported with gabapentinoids are sleepiness, dizziness, headache, nausea, and vomiting. Due to the structural similarity between gabapentin and baclofen (a centrally acting GABA-B agonist), gabapentin was reported to produce “baclofen-like” effects [1] (Figure 1A). Like baclofen, some studies have shown that gabapentin might be of interest in alcohol dependence management [2]. In this context, baclofen is linked to sleep apnea syndrome [3, 4], aggravating sleep-disordered breathing by depressing central ventilatory drive and/or increasing upper airway obstruction. – (A) Schematic diagram of the synthesis, transport, activity of GABA at synapses, and potential drug mechanisms. GABA is synthesized in inhibitory neurons from glutamate by the enzyme glutamic acid decarboxylase (GAD). Reuptake of GABA occurs through the activity of GABA transporters (GAT). GABA-A and GABA-B receptors achieve postsynaptic inhibition by activating chloride and potassium currents that hyperpolarize the cell. (B) Reporting odds ratio of sleep apnea syndrome associated with antiepileptic drugs (with 95% confidence intervals). Drugs with <5 cases are not presented. We hypothesized that gabapentinoids might be associated with sleep apnea syndrome. A recent pilot study reported a higher apnea–hypopnea index with gabapentin, supporting our hypothesis [5]. To further address this issue, we performed a disproportionality analysis using VigiBase, the WHO Global Individual Case Safety Reports (ICSRs) database, developed and maintained since 1978 by the Uppsala Monitoring Center. Up to July 2018, more than 17 million ICSRs have been collected from 131 countries. Most reports came from North America and Europe and were declared by health professionals, pharmaceutical companies, or patients. They usually contain reporter information, patient characteristics (age, gender, and medical history), a clinical description of the adverse drug reaction (ADR), its seriousness and evolution, and drug exposures with dates, dosages, and indications. Drugs are classified according to the Anatomical Therapeutic Chemical (ATC) classification system. ADR coding uses the Medical Dictionary for Regulatory Activities (MedDRA). Our objective was to compare the reporting of sleep apnea associated with every antiepileptic drug. Benzodiazepines (ATC N03AE), known to induce respiratory depression due to their affinity for the GABA-A receptor [6] (Figure 1A), were used as positive controls. We extracted all the ICSRs from VigiBase with the MedDRA (version 21.0) preferred terms “sleep apnea syndrome” associated with antiepileptic drugs, recorded from December 9, 1970 to July 1, 2018. The preferred terms “sleep apnea syndrome” included all the following terms: “apnea syndrome,” “central sleep apnea syndrome,” “hypopnea syndrome,” “obstructive sleep apnea hypopnea syndrome,” “obstructive sleep apnea syndrome,” “sleep apnea,” and “sleep apnea syndrome.” A de-duplicated dataset was used. The relationship between the use of each antiepileptic drug and the occurrence of ADR (i.e. sleep apnea syndrome) was assessed by calculating the reporting odds ratio associated with its 95% confidence interval [CI] in a case–noncase model compared with other drugs. Reporting odds ratio was calculated using the following formula [7]: Reporting odds ratio = (a/b)/(c/d) with (a) the number of reported sleep apnea (cases) with the antiepileptic drug, (b) the number of ADRs other than sleep apnea with the antiepileptic drug, (c) the number of sleep apnea with all other drugs in VigiBase, and (d) the number of ADRs with all other drugs in VigiBase excepting sleep apnea. A reporting odds ratio with a 95% CI lower boundary of >2 and ≥5 cases was considered to be significant [8]. Of the 17 519 277 ICSRs reported to Vigibase between December 1970 and July 2018, 8915 (0.05%) were reported sleep apnea (cases). Up to July 2018, Vigibase contained 76 reported sleep apnea (cases) for gabapentin and 123 for pregabalin. The majority of reported sleep apnea (cases) attributed to exposure to gabapentinoids originated from the United States (87%) and was reported after 2013 (58%). The reporting odds ratio for both drugs were significant: 2.61 [2.08 to 3.27] for gabapentin and 2.42 [2.02 to 2.89] for pregabalin, whereas no other antiepileptic drugs had a reporting odds ratio with a lower boundary of >2. The reporting odds ratio was also significant for benzodiazepines: 3.07 [2.58 to 3.66] (Figure 1B). We used a case–noncase design to evaluate the association between the use of antiepileptic drugs and the reporting of sleep apnea in the WHO drug adverse event database. Reports of sleep apnea syndrome appear to be rare and probably underestimated. Despite the well-known problem of underreporting in pharmacovigilance, a significant disproportionality signal was found for gabapentinoids. Our result should be understood as a safety signal, confirming previous observations of sleep apnea with GABA agonists, such as baclofen. Benzodiazepines were used as positive control to support the robustness of disproportionality. However, our analysis has limitations: a small number of reports and possible selective reporting bias. An important issue is insufficient information in VigiBase to allow appropriate adjustment for potential confounders. A prospective database of systematic sleep studies is needed to determine the prevalence and severity of pregabalin- or gabapentin-related sleep apnea. Physicians need to be aware that sleep apnea might affect patients treated with pregabalin or gabapentin. Rates of gabapentinoids use in the United States tripled between 2002 and 2015 and raise concern [9], especially in the opioid crisis context leading to the emergence of pregabalin and gabapentin misuse and abuse [10]. Importantly, Johansen showed that the use of gabapentinoids was not evenly distributed through the population but concentrated among individuals who were older with numerous comorbidities and/or had numerous opioid and/or benzodiazepine prescriptions [9], which are all risk factors for sleep apnea. Although pharmacovigilance analyses show associations and not causation, this study has to raise physicians’ awareness about the possible emergence or exacerbation of sleep apnea with gabapentinoids, particularly in patients with sleep-disordered breathing, a history of substance use disorder, or associated with opioids and benzodiazepines. This work was supported by the French National Research Agency in the framework of the “Investissements d’avenir” program (ANR-15-IDEX-02) and the ‘‘e-health and integrated care” Chair of excellence from the Grenoble Alpes University Foundation. Conflict of interest statement. None declared. We thank Alison Foote (Grenoble Alpes University Hospital) for critically editing the manuscript. The authors would like to thank the Uppsala Monitoring Center that provided and gave permission to use the data analyzed in the present study. Results and conclusions are those of the authors and not those of the National Centres, Uppsala Monitoring Centre, or WHO.