Why should benzodiazepines not be combined with opioids?

Combining benzodiazepines with opioids dramatically increases the risk of fatal respiratory depression because both drug classes depress the central nervous system through different mechanisms. Benzodiazepines enhance GABA inhibition while opioids depress the brainstem respiratory center. Together they suppress breathing more than either alone. The FDA issued a black box warning in 2016 requiring labels on both drug classes to warn about this interaction.