​In France, buprenorphine is prescribed as an opiate substitution treatment. With more limited effects than other opiates on the respiratory system, it is less likely to cause death by overdose. 

A dangerous combination

However, deaths and episodes of respiratory depression have been reported, particularly when combined with benzodiazepines, another class of psychotropic drugs that do not cause respiratory depression when taken alone. What type of interaction between the two substances leads to this potentiation?

To answer this question, researchers from BioMaps (SHFJ Department) and from the Unit UMR-S 1144 studied in rats the effects of simultaneous administration of buprenorphine and diazepam (a benzodiazepine) on different respiratory parameters (analysis of arterial blood gases, plethysmography^[1], electromyography^[2] of the diaphragm) and on the fixation of buprenorphine in the brain (by PET imaging).

In their study published in the British Journal of Anaesthesia, the researchers first show that simultaneous administration of diazepam and buprenorphine causes early sedation and respiratory depression. They observe in vivo, by PET imaging (with carbon-11 labeled buprenorphine), that benzodiazepines do not cause an increase in the passage of buprenorphine in the brain. Nor are they responsible for a stronger interaction between buprenorphine and its receptor. The observed potentiation is therefore not due to a direct action of diazepam on the behaviour of buprenorphine in the body. 

Several of the respiratory parameters studied are not affected in the same way depending on whether the animal receives an injection of buprenorphine, diazepam or both. For example, buprenorphine injection increases diaphragmatic contraction, indicating the existence of a respiratory compensation mechanism. Conversely, injection of diazepam decreases diaphragmatic contraction. Above all, the injection of both molecules decreases it even more.

The study suggests that the mechanism at the origin of the respiratory depression following the co-administration of benzodiazepine and buprenorphine would result from the combined action of each drug on its target: the respiratory compensation mechanism specific to buprenorphine would be specifically blocked by the benzodiazepines.

Researcher contact at CEA-Joliot :

Nicolas Tournier (nicolas.tournier@cea.fr)