Association between NMDAR antagonists, drug abuse and dependence: A disproportionality analysis from the WHO pharmacovigilance database

Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N‐methyl‐d‐aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, “out of body” sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically‐related amino‐adamantane derivatives (e.g., amantadine and memantine). Using a quasi‐Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes &gt;21 million individual case safety reports collected from &gt;130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97–3.09]), ketamine (IC = 1.70 [1.57–1.83]), amantadine (IC = 0.21 [0.06–0.35]) and memantine (IC = 0.27 [0.13–0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current “opioid epidemic” context, due to their growing interest as non‐opioid antinociceptive drugs.</jats:p

Améliorer la balance bénéfices/risques de la méthadone en respectant ses spécificités pharmacologiques

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The opioid epidemic: A worldwide exploratory study using the WHO pharmacovigilance database.

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 [IC ; IC ], using a quasi-Bayesian confidence propagation neural network (BCPNN). A hierarchical cluster analysis (Ward's method) of the IC 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 (IC  > 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

Poisoning by lavandin extract in a 18-month-old boy

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