Background and Aims: The current opioid epidemic in the United States began 20 years ago and has become the leading cause of accidental deaths in the country. This crisis prompted us to explore trends in opioid abuse and dependence worldwide. We sought to identify other countries at high‐risk of opioid use disorders, using the World Health Organization's (WHO) pharmacovigilance database.Methods: We performed a disproportionality analysis using VigiBase, the WHO Global Individual Case Safety Report (ICSR) database. Five opioids used worldwide were included: oxycodone, fentanyl, morphine, tramadol, and codeine. We extracted all ICSRs associated with the drugs of interest, considered as suspect medication and recorded up until 5 June 2021, using the narrow Standardised MedDRA Query (SMQ) for drug abuse and dependence. Countries with at least one ICSR for each of the five opioids were retained. The relationship between the use of a drug (i.e. an opioid) and the occurrence of an adverse drug reaction (i.e. drug abuse and dependence) for each country was assessed by calculating the information component (IC) and its 99.9% CI [IC₀₀₀₅; IC₉₉₉₅], using a quasi‐Bayesian confidence propagation neural network (BCPNN). A hierarchical cluster analysis (Ward's method) of the IC₀₀₀₅ value for each of the five opioids was performed to identify subgroups of countries with similar reported risks of opioid abuse and dependence.Results: Among 21 countries, the optimal number of clusters was calculated to be four, each with a Jaccard index >0.5 (0.95, 0.78, 0.65 and 0.75, respectively). Six countries with the highest signals of drug abuse and dependence were identified in cluster 1, with significant CIs for the five opioids of interest (IC₀₀₀₅ > 0), ranging from 0.9 to 5.8 for the lower endpoint.Conclusions: There appear to be four distinct clusters of countries with similar opioid abuse and dependence profiles. The group with the highest reported risk for the opioids oxycodone, fentanyl, morphine, tramadol and codeine includes Australia, Canada, France, Germans, the United Kingdom and the United States.

Introduction: Central sleep apnea (CSA) syndrome has gained a considerable interest in the sleep field within the last 10 years. It is overrepresented in particular subpopulations such as patients with stroke or heart failure. Early detection and diagnosis, as well as appropriate treatment of central breathing disturbances during sleep remain challenging. Areas covered: Based on a systematic review of CSA in adults the clinical evidence and polysomnographic patterns useful for discerning central from obstructive events are discussed. Current therapeutic indications of CSA and perspectives are presented, according to the type of respiratory disturbances during sleep, alterations in blood gases and ventilatory control. Expert opinion: The precise identification of central events during polysomnographic recording is mandatory. Therapeutic choices for CSA depend on the typology of respiratory disturbances observed by polysomnography, changes in blood gases and ventilatory control. In CSA with normocapnia and ventilatory instability, adaptive servo-ventilation is recommended. In CSA with hypercapnia and/or rapid-eye movement sleep hypoventilation, non-invasive ventilation is required. Further studies are required as strong evidence is lacking regarding the long-term consequences of CSA and the long-term impact of current treatment strategies.

The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies.