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Opioid overdose is predominantly linked to poly-drug use. When individuals consume opioids in combination with other substances, particularly central nervous system (CNS) depressants such as benzodiazepines or alcohol, the risk of respiratory depression and overdose significantly increases. This combination can amplify the sedative effects, leading to a higher likelihood of fatal outcomes.

While under-prescribing of opioids might limit the availability for some patients, it does not directly contribute to overdose cases. Increased illicit drug use, while a concerning trend, does not encapsulate the main risk profiles observed during overdose incidents compared to the dangers of mixing drugs. Improper patient education is important as well, as it can lead to misuse; however, it is the poly-drug use that most directly enhances the risk of overdose through compounded effects on the body's systems. Understanding the interplay between opioids and other substances is crucial in addressing the overdose crisis effectively.