The potent affinity of (+)-desmetramadol for the human MOR and the clinical properties of tramadol prompted us to hypothesize that G protein-biased MOR agonism by desmetramadol might account for the apparent discrepant potent MOR binding by desmetramadol and the empirical sparing of lethal respiratory depression in tramadol overdose. This evidence concerns the gene OPRM1 and respiratory depression.