Buprenorphine Alters Desmethylflunitrazepam Disposition and Flunitrazepam Toxicity in Rats

Abstract

High-dosage buprenorphine (BUP) consumed concomitantly with benzodiazepines (BZDs) including flunitrazepam (FZ) may cause life-threatening respiratory depression despite a BUP ceiling effect and BZDs' limited effects on ventilation. However, the mechanism of BUP/FZ interaction remains unknown. We hypothesized that BUP may alter the disposition of FZ active metabolites in vivo, contributing to respiratory toxicity. Plasma FZ, desmethylflunitrazepam (DMFZ), and 7-aminoflunitrazepam (7-AFZ) concentrations were measured using gas chromatography-mass spectrometry. Intravenous BUP 30 mg/kg pretreatment did not alter plasma FZ and 7-AFZ kinetics in Sprague-Dawley rats infused with 40 mg/kg FZ over 30 min, whereas resulting in a three-fold increase in the area under the curve (AUC) of DMFZ concentrations compared with control (p < 0.01). In contrast, BUP did not significantly modify plasma DMFZ concentrations after intravenous infusion of 7 mg/kg DMFZ, whereas resulting in a similar peak concentration to that generated from 40 mg/kg FZ administration. Regarding the effects on ventilation, BUP (30 mg/kg) as well as its combination with FZ (0.3 mg/kg) significantly increased PaCO(2), whereas only BUP/FZ combination decreased PaO(2) (p < 0.001). Interestingly, FZ (40 mg/kg) but not DMFZ (40 mg/kg) significantly increased PaCO(2) (p < 0.05), whereas DMFZ but not FZ decreased PaO(2) (p < 0.05). Thus, decrease in PaO(2) appears related to BUP-mediated effects on DMFZ disposition, although increases in PaCO(2) relate to direct BUP/FZ additive or synergistic dynamic interactions. We conclude that combined high-dosage BUP and FZ is responsible for increased respiratory toxicity in which BUP-mediated alteration in DMFZ disposition may play a significant role.

Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome

“…These observations point towards a combined effect of buprenrophine and bensodiazepines. Bensodiazepines though, cannot be treated as a group because their interactions with buprenorphine vary as shown in several animal studies [13][14][15]. Among the evaluated substances flunitrazepam and midazolam were more likely to enhance the respiratory depressant effects.…”

An Unusual Case of Death Probably Triggered by the Association of Buprenorphine at Therapeutic Dose with Ethanol and Benzodiazepines and with Very Low Norbuprenorphine Level

“…The association of these deleterious effects translates into blood gas perturbations. Indeed, comparison of the effects of flunitrazepam and BUP alone or in combination shows that, on their own, these drugs have no or few effects on PaO 2 , whereas their association leads to an important PaO 2 reduction , suggesting that BUP and benzodiazepines have a synergistic effect on ventilation.…”

Prospective comparative assessment of buprenorphine overdose with heroin and methadone: Clinical characteristics and response to antidotal treatment

“…In buprenorphine overdoses, no response to 0.4-0.8 mg naloxone was observed, whereas flumazenil improved mental status if benzodiazepines were coingested, suggesting a pharmacodynamic interaction between buprenorphine and benzodiazepines. Although previous studies have demonstrated synergies between benzodiazepine and opiate/opioid drug families in their effects on pain, anxiety, sedation, and respiration, the exact mechanism of these interactions in overdoses is still unclear (Mégarbane et al, 2005;Mégarbane, Hreiche, Pirnay, Marie, & Baud, 2006;Pirnay et al, 2008).…”