What property of fentanyl primarily contributes to its risk for overdose and death?

Fentanyl's high lipophilicity is a significant factor contributing to its risk for overdose and death. Being highly lipophilic (fat-soluble), fentanyl can rapidly cross cell membranes, including the blood-brain barrier. This property allows it to quickly exert its effects, leading to intense analgesia and sedation.

However, this rapid onset also means that the effects can be unpredictable. When a dose of fentanyl is administered, it can quickly lead to respiratory depression, a critical factor in overdose situations. If the dose is too high or if the drug is used in conjunction with other depressants, it can overwhelm the body's systems, leading to respiratory failure and death.

In contrast, other properties like a short half-life or slow onset of action would typically mitigate the risks associated with medications because they allow for a more controlled and predictable response. Additionally, weak potency would not pose the same level of overdose risk, as it would require higher doses to achieve the desired effect, thus reducing the likelihood of dangerously high levels in the system.