Fatalities in relation to buprenorphine snorting and ethanol co-ingestion: mechanisms of toxicity.

Wereadwithgreat interest thecase reportof fatalpoisoningsdue to snorting buprenorphine (BUP) combined with alcohol consumption by Ferrant et al. [1]. As explained by the authors, snorting of crushed BUP tablets is common in drug addicts under maintenance treatment and may result in fatal poisonings. We recently reported thirty-nine acute poisonings with typical life-threatening opioid syndrome attributed to BUP after the exclusion of any other associated opioid [2]. Among these cases, three (8%) were related to BUP intake by exclusive nasal inhalation. A psychotropic drug coingestionwas assessed in thirty-seven of these cases (95%),mainly a benzodiazepine or ethanol. Despite reported ‘‘ceiling effects’’ for BUP, mental status as well as respiratory depression were not significantly different in these BUP-overdosed patients in comparison to those overdosed with heroin or methadone. Nasal route reduces the first liver bypass, thus increasing BUP bioavailability and diminishing the production of norbuprenorphine (N-BUP), its main N-desalkylated metabolite. Based on rat data, we clearly assessed that BUP up to 80% of its lethal dose-50% is devoid of any deleterious respiratory effect on arterial blood gases and plethysmography parameters [3], while N-BUP administration results in a sustained and profound respiratory depression [4]. In rats, we showed that BUP protects as well as reverses NBUP-related toxic respiratory effects, which mechanism should play a role in vivo to explain BUP-associated limited respiratory effects [4]. Thus, althoughwe acknowledge that extrapolation from data collected in rats to humans present some limitations, we may hypothesize that increasing BUP availability by decreasing its liver metabolism should be rather protective against respiratory toxicity. Thus, we do not believe that snorting-related alterations in BUP pharmacokinetics in comparison to its sublingual administration may explain any increased toxicity in drug addicts. Consistently, as reported by the authors [1], blood BUP concentrations were foundwithin the therapeutic range. Interestingly, in the two patients with measured N-BUP concentrations, free as well as total N-BUP-to-BUP concentration ratios in blood were within the same range determined in thirty-nine other reported BUPattributed fatalities (0.45 [0.08–2.00], median [10–90% percentiles]) [4]. These values were also included within the range allowing protective effects of BUP against N-BUP-induced respiratory depression that we assessed in our rat model [4], thus calling into question the exact role of N-BUP alone in the mechanism of BUP-associated deaths in humans. Interestingly, wewere unable to demonstrate any enhanced BUP-related respiratory toxicity in rats by increasing N-BUP-to-BUP ratio following cytochrome P450 3A induction of BUP metabolism into N-BUP [5]. Therefore, we believe that BUP-related toxicity whatever its route of administration is, should mainly result from its