The recent widespread abuse of high potency synthetic opioids, such as fentanyl, presents a serious threat to individuals affected by substance use disorder. Synthetic opioids generally exhibit prolonged <i>in vivo</i> circulatory half-lives that can outlast the reversal effects of conventional naloxone-based overdose antidotes leading to a life-threatening relapse of opioid toxicity known as renarcotization. In this manuscript, we present our efforts to combat the threat of renarcotization by attempting to extend the half-life of traditional MOR antagonists through the design of novel, fluorinated 4,5-epoxymorphinans possessing increased lipophilicity. Analogues were prepared <i>via</i> a concise synthetic strategy highlighted by decarboxylative Wittig olefination of the C<sub>6</sub> ketone to install a bioisosteric 1,1-difluoromethylene unit. C<sub>6</sub>-difluoromethylenated compounds successfully maintained <i>in vitro</i> potency against an EC<sub>90</sub> challenge of fentanyl and were predicted to have enhanced circulatory half-life compared to the current standard of care, naloxone. Subsequent <i>in vivo</i> studies demonstrated the effective blockade of fentanyl-induced anti-nociception in mice.