Para‐fluorofentanyl: Coincidence or intentional?

p-Fluorofentanyl (pFF) is a fentanyl analog that differs from fentanyl by the addition of a fluorine group on the aniline ring (see Figure 1). pFF belongs to a class of compounds referred to as illicitly manufactured fentanyls (IMFs) which are ingested unknowingly by consumers, contributing to the increase in opioid overdose deaths around the world [1-3]. In 2022, greater than two-thirds of the 107, 573 drug overdose deaths in the United States were due to synthetic opioids other than methadone, with IMFs being the primary contributor [4]. pFF is rarely found alone and is typically seen in combination with fentanyl. In 2023, the Ohio Bureau of Criminal Investigation (BCI) noted the occurrence of pFF in 1,840 chemistry items submitted to the laboratory, with 99% of those submitted items also containing fentanyl. From September 2020 to October 2022, the state of Michigan reported that the percentage of decedents who tested positive for pFF also tested positive for fentanyl 99% of the time [5]. Additionally, co-involvement of fentanyl with pFF overdose deaths ranged from 100% in September of 2020 to 90.8% in June of 2021, as reported by 42 states and the District of Columbia [6]. Due to a majority of the studies having been conducted in vitro, there are conflicting reports regarding the potency of pFF compared to fentanyl. Ulens et al. [7] found pFF to have a lower EC50 than fentanyl, while Hassanien et al. [8] ascertained pFF to have a greater EC50 than fentanyl in vitro. Interestingly, Hassanien et al. [8] determined pFF and fentanyl to have similar mu opioid receptor binding affinities with Ki values of 4.2 and 1.6 nM, respectively. Additional differences were also noted in animal models. Varshneya et al. [9] showed the antinociception potency ratio of pFF to fentanyl to be 1.30 [9], whereas Higashikawa & Suzuki determined the pFF to fentanyl antinociception potency ratio to be 0.29 [10]. The increasing prevalence (the top five in 2023 as reported by the Ohio BCI and the top 10 in 2023 in the United States, as reported by the National Forensic Laboratory Information System [11]), of pFF combined with differing results of pFF potency studies, brings into question the rationale behind the combination of pFF and fentanyl. One hypothesis is that pFF is a contaminant or byproduct that results from a new synthetic route of fentanyl synthesis involving a fluorinated precursor (F-4-ANPP), and that the inclusion of pFF is purely accidental [12]. Here, we offer a hypothesis that the inclusion of pFF is an intentional addition by clandestine laboratories to potentiate and prolong the effects of fentanyl. The addition of a halogen to fentanyl has the potential to increase the half-life as well as enhance permeation, membrane binding and receptor binding of pFF compared to fentanyl [13-16]. Fentanyl is primarily metabolized by CYP3A4 and pFF is more than likely also metabolized by this same P450 isozyme [17]. Therefore, these two compounds can inhibit the metabolism of one another by competing for the same active site of the enzyme [18]. This competitive inhibition has the potential to lead to a prolongation of the effects of fentanyl and allow the conclusion to be made that the addition of pFF is, in fact, intentional and not accidental. Jeremy R. Canfield: Conceptualization (equal); writing—original draft (equal); writing—review and editing (equal). Kristin V. Canfield: Conceptualization (equal); writing—original draft (equal); writing—review and editing (equal). Jon E. Sprague: Conceptualization (equal); writing—original draft (equal); writing—review and editing (equal). There are no funders to report. None.