Enhanced pharmacokinetic and pharmacodynamic effects of combining p-fluorofentanyl and fentanyl

In 2023, the Ohio Bureau of Criminal Investigation reported para-fluorofentanyl (pFF) co-occurring with fentanyl 99 % of the time. Similarly, the state of Michigan also reported 99 % of decedents testing positive for pFF also tested positive for fentanyl. The rationale behind this co-occurrence has not been elucidated. One theory postulates pFF to be a coincidental inclusion while other evidence suggests pFF is an intentional addition. In the present study, the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the co-administration of pFF and fentanyl were examined in male Sprague-Dawley rats. Fentanyl and pFF (50, 100 and 200 μg/kg, sc.) resulted in dose-dependent effects on antinociception as measured by tail flick latency and hypothermia. The co-administration of fentanyl (100 μg/kg) and pFF (100 μg/kg) was found to have enhanced antinociceptive potency compared to equivalent doses (200 μg/kg) of either compound administered singularly, and an enhanced hypothermic response compared to an equivalent individual dose of fentanyl. Fentanyl co-administered with pFF resulted in fentanyl having a significantly greater AUC_0-∞and C_max and significantly lower Cl_p/F and V_D/F than pFF. No significant differences were seen in the PK parameters between fentanyl and pFF when administered singularly. The brain to plasma ratio of pFF was significantly lower in the hippocampus and striatum when co-administered with fentanyl compared to singular administration of pFF. The potentiation of the hypothermic response and increase in AUC_0-∞ and C_max of fentanyl (suggesting prolonged exposure) when these drugs are co-administered over given individually suggest they are combined to enhance toxicity.