AbstractCombining opioids with benzodiazepines and skeletal muscle relaxants (‘The Holy Trinity’) has been reported to potentiate the ‘high’. Through unique interactions with colocalized μ‐opioid and GABAA receptors, the combined use of these agents induces a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by μ1‐opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAAR to suppress respiration in the medullary respiratory centres. The skeletal muscle relaxant, carisoprodol, appears to bind to a unique binding domain within the GABAAR to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.