 Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect, so reduce the effects of opioid drugs by altering downstream pathways, regardless of MOR activation.Fatal opioid overdose typically occurs due to bradypnea, hypoxemia, and decreased cardiac output (hypotension occurs due to vasodilation, & bradycardia further contributes to decreased cardiac output).A potentiation effect occurs when opioids are combined with ethanol, benzodiazepines, or barbiturates, which results in an increased risk for overdose to occur.