Buprenorphine and Midazolam Act in Combination to Depress Respiration in Rats

Abstract

High dose buprenorphine is used as substitution treatment in human heroin addiction. Deaths have been reported in addicts using buprenorphine, frequently in association with benzodiazepines. In the current study, we observed the effects of buprenorphine and midazolam alone and in combination on arterial blood gases. Four groups of 10 male Sprague-Dawley rats received a parenteral injection of aqueous solvent, buprenorphine (30 mg/kg, iv), midazolam (160 mg/kg, ip), or buprenorphine (30 mg/kg, iv) plus midazolam (160 mg/kg, ip). Serial blood gases were obtained over 3 hours. There was a mild but significant effect of buprenorphine alone in comparison with the aqueous solvent on PaCO2 at 60 min (6.24 vs. 5.65 kPa, p< 0.01). There was also a mild but significant effect of midazolam alone in comparison with aqueous solvent on arterial pH at 90 min (7.33 vs. 7.41,p< 0.001) and PaCO2 at 60 min (6.52 vs. 5.65 kPa,p< 0.01). The combination of midazolam and buprenorphine produces a rapid, profound, and prolonged respiratory depression, as demonstrated by an increase in PaCO2 at 7.65 +/- 0.12 kPa at 20 min and a decrease in arterial pH at 7.25 +/- 0.02 at 20 min, with appearance of delayed hypoxia with a decrease in PaO2 at 8.74 +/- 0.20 kPa at 120 min. These data show that high doses of midazolam and buprenorphine alone have limited effects on arterial blood gases in rats while midazolam and buprenorphine appear to act in an additive or synergistic fashion to depress ventilation in rats.

A survey of buprenorphine related deaths in Singapore

“…Animal studies confirmed the potential dangers of the concurrent administration of buprenorphine and benzodiazepines [9,10].…”

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

“…The co-ingestion of other drugs in combination with buprenorphine has been postulated as a risk factor by several groups [4][5][6][7][8][9]11,13,45].…”

“…As an example, midazolam alone have been shown to express moderate effects on respiration similarly to buprenorphine. However, combined they produced a profound respiratory depression [13]. Thus, one must be cautious to extrapolate findings from one combination to a whole group of drugs even though they are pharmacologically similar.…”

“…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.…”

Development and validation of a gas chromatography‐mass spectrometry method for the determination of phenazopyridine in rat plasma: application to the pharmacokinetic study

“…The catheters were then tunneled subcutaneously and fixed at the back of the neck [20]. The rats were given at least a 24 h recovery period to allow for washout of anesthesia.…”