An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions

Abstract

Background Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone (“Z-drugs”) clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. Methods Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. Results An overall number of 33 240 (e.g., 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. Conclusion Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications.

Focus on Clozapine Withdrawal- and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database

“…Such listings showed all information related to the ADR, the patient, the drug, the reporter, and the diagnosis. In line with previous studies from our group [36][37][38][39], the ADRs considered here were, per se, voluntary and unsolicited communications [34] reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorization Holders for those ADRs occurring outside the EEA. Individual Case Safety Reports, such as voluntary reports, refer to the format and content for the reporting of one or several suspected ADRs in relation to a medicinal product that occur in a single patient at a specific point of time [40].…”

“…Patients' data were analyzed using a range of parameters, including: socio-demographic characteristics (age and gender); source/reporter country (EEA or non-EEA) and reporter qualification (i.e., pharmacist, physician); outcomes (fatal, recovered, resolved); clozapine dosage; possible concomitant drug(s); and diagnosis/reporter's comments, if recorded [37]. The analysis included cases of overdoses, suicides, and fatalities.…”

“…Within the standardized MedDRA Query (SMQ) 'drug abuse, dependence and withdrawal' section, we identified the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug diversion, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, product use issue, substance abuse, and withdrawal syndrome. For the definition of 'abuse'; 'addiction'; 'dependence'; and 'misuse' please refer to references [35][36][37][38][39][40]. Moreover, in accordance with MedDRA, 'withdrawal' is identified in association with the abrupt cessation or reduction in intake of a drug in a habituated person.…”

New/emerging psychoactive substances and associated psychopathological consequences

“…The Z-drugs' (zolpidem, zopiclone and zaleplon) addictive potential has already been highlighted (Kapil et al, 2014;Schifano et al, 2019). Zolpidem and zopiclone seem to be the most involved in the diversion and abuse phenomena ([ACMD], 2013), and it is likely that the misusing phenomenon is currently underestimated (Hajak et al, 2003).…”

Pregabalin Abuse in Combination With Other Drugs: Monitoring Among Methadone Patients

“…Sedatives and hypnotics are commonly misused prescription drugs. These include barbiturates, benzodiazepines (BZDs) and BZD-like drugs such as z-hypnotics, opioids, and opioid substitution medications which are used for pain relief, and stimulants to treat attention deficit and hyperactivity disorder (ADHD) (3). Other medications such as antidepressants, anti-Parkinson drugs, cough and cold medicines, and stimulants such as methylphenidate are also misused (2,4,5).…”