The abuse-related effects of illicitly manufactured fentanyls (IMFs): A mini review

Illicitly manufactured fentanyls (IMFs) continue to drive opioid morbidity and mortality, yet their abuse-related effects vary widely across analogs. Here, we review preclinical evidence from drug discrimination, conditioned place preference, and self-administration studies to relate structural modifications of the fentanyl scaffold to abuse liability. Across amide-modified IMFs, lengthening or bulkier side chains generally reduce μ-opioid receptor (MOR)-mediated potency and reinforcing efficacy, with only acrylfentanyl and 2-furanylfentanyl approaching that of fentanyl. Compounds bearing concurrent amide and aniline substitutions are typically less potent, except ocfentanil, in which an ortho-fluoro aniline group appears to overcome amide-related steric hindrance and yields greater potency than fentanyl. Introduction of a 4-piperidine ester, as in carfentanil and isobutyrylcarfentanil, produces some of the most potent IMFs reviewed, consistent with enhanced hydrogen bonding and stabilization of the ionic piperidine-aspartate interaction at the MOR. Non-amide modifications further demonstrate that halogenation of the aniline ring (o-fluorofentanyl, p-fluorofentanyl, 2'-fluoro ortho-fluorofentanyl) reliably increases potency, whereas fluorination of the piperidine ring (NFEPP) markedly attenuates potency. Fluorination on the N-alkyl chain (FF3) and β-hydroxy/thiophene substitutions (β-hydroxythiofentanyl) produce minimal to modest changes in potency, while the stereochemistry of ohmefentanyl dramatically shapes potency strength across isomers. Collectively, these findings highlight structural motifs that either amplify or blunt IMF abuse-related effects and support a predictive structure-activity relationship for newly emerging analogs. Such mechanistic insight may aid forensic interpretation, regulatory prioritization, and anticipation of clinical risk associated with future IMF exposures. We also identify gaps, including limited sex-specific analyses and antagonist sensitivity, that warrant targeted studies.