Non-opioid antinociceptive drugs : risk of respiratory depression and death related to concomitant use of gabapentinoids in addition to opioids.

INTRODUCTION: Respiratory depression and opioid-related death are reported when opioids are associated with gabapentinoids. Meta-analyses of randomized clinical trials investigating efficacy and safety of such association failed to assess these risks because of the lack of data. The aim of this systematic review was to investigate the risk of respiratory depression or death during this combination in the scientific literature, including case reports or series, observational studies, and clinical trials. AREAS COVERED: PubMed®, Web of Science®, Embase®, and Google Scholar® were searched from their inception to December 2021, for original articles in English, French, and German. Data synthesis was done on a narrative approach by type of articles. EXPERT OPINION: The review included 25 articles (4 case reports, 2 cross-sectional, 3 case-control, 14 cohort studies, and 2 clinical trials). Respiratory depression or opioid-related death and co-exposure to gabapentinoids were associated in perioperative setting/chronic pain (odds ratios around 1.3) and in opioid maintenance treatment (hazard ratio 3.4). These findings are in agreement with experimental studies showing that a single dose of gabapentinoid may reverse opioid respiratory tolerance. Because the combination gabapentinoids-opioids is highly prevalent in all clinical context, all health care professionals and patients must be aware of this risk.

Safety concerns on the abuse potential of esketamine: Multidimensional analysis of a new anti-depressive drug on the market.

Prominent features of esketamine (e.g., similar mechanism of action as ketamine and target population) require to be vigilant regarding its benefits/risks balance and its risks of abuse in real-life settings. The aim of this study was to review all available pharmacological and clinical data to assess the abuse potential of esketamine shortly after its marketing. This multidimensional study is a quantitative and qualitative analysis of complementary data sources, ranging from preauthorization data (i.e., fundamental pharmacology and clinical trials) to real-life settings data (i.e., pharmacovigilance databases and web forums). According to esketamine pharmacology, its psychoactive effects play a role both in its therapeutic effect and its abuse potential. Only one out of the three short-term efficacy trials found a significant difference between esketamine and placebo in treatment-resistant depression. Beside adverse events that may be sought for abuse purpose (e.g., dissociation, sedation, euphoric mood, hallucination, feeling drunk, and derealization), clinical signs related to substance use disorder (e.g., tolerance, withdrawal syndrome, and drug dependence) and misuse (e.g., off-label use) were also identified in pharmacovigilance databases. Analysis of pharmacovigilance narratives and web forums showed that esketamine psychoactive effects are appreciated by some patients, while they are badly experienced by others. Strict compliance with the market authorization, close monitoring of patients by psychiatrists, and surveillance of any signs of misuse, abuse, or dependence must be part of any treatment course.

Gabapentinoid Abuse in France: Evidence on Health Consequences and New Points of Vigilance.

Introduction: Gabapentinoid drugs (gabapentin and pregabalin) are widely used worldwide for epileptic and pain disorders. First signals of gabapentinoid abuse occurred in the last decade. This study aims to describe clinical characteristics of gabapentinoid use related disorders and health consequences in France. Materials and Methods: We designed a multisource investigation reviewing data reported to the French Addictovigilance Network (FAN) with pregabalin and gabapentin from 2010 to 2019. Information was obtained through the analysis of Spontaneous Reports (SRs) notified by health professionals and the pharmacoepidemiological surveys OSIAP (suspicious prescriptions forms indicators of potential abuse), OPPIDUM (observation of illicit drugs and misuse of psychotropic medications), DRAMES (death related to prescription drugs and other substances), and DTA (toxic deaths due to analgesics). Results: Over 2010-2019 period, were collected: (i) 265 SRs (258 pregabalin; 7 gabapentin); (ii) 816 forged prescription forms (805 pregabalin, 10 gabapentin, 1 involving both drugs); (iii) 145 cases of gabapentinoid use in people who use drugs (121 pregabalin; 24 gabapentin) and (iv) 31 cases of gabapentinoid-related deaths (25 pregabalin; 6 gabapentin). Risk factors of gabapentinoid abuse were opioid use disorders or psychiatric history, but cases of primary abuse in subjects without any substance abuse history were observed. Adverse outcomes concern almost exclusively pregabalin, with coma, dyspnea, convulsion, and conduction disorders. Treatment demands increased from 10.6% in 2018 to 23.1% in 2019, with pregabalin cited as the first substance leading to addictological care in the 2019 OPPIDUM survey. Gabapentinoid-related deaths increased over time. Pregabalin has become the first drug mentioned in forged prescriptions in 2019 (23.8% of OSIAP), while it ranked at the 15th position in 2017 (2.6%). Discussion: This study shows the importance of addictovigilance monitoring for gabapentinoids. Addictovigilance data helped to make visible the gabapentinoid-abuse related health harms (hospitalization for serious neurologic, psychiatric or cardiac effects, requests for addictological support and deaths) and to confirm the intrinsic abuse potential of pregabalin. These data highlight new points of vigilance considering observed primary abuse. At this point in France, the risk of abuse and related complications is very apparent with pregabalin. Still, it is identical to that observed elsewhere with gabapentin.