Dynamic mechanistic dominance in fentanyl and polysubstance overdose: Implications for next-generation reversal.

High-potency synthetic opioids, such as fentanyl, now dominate the opioid crisis and are often mixed with other active substances. Naloxone, while essential, increasingly produces incomplete or transient reversal-not because the antagonist "fails," but because respiratory depression reflects shifting mechanistic dominance rather than a single μ-opioid receptor pathway. The mechanism currently limiting ventilation-whether μ-opioid receptor, α2-adrenergic, or other central nervous system depressant-determines both clinical trajectory and reversibility of the overdose. Preclinical, clinical, and forensic data indicate that polysubstance exposures can alter this dominant mechanism over time, creating pharmacokinetic-pharmacodynamic mismatches in which μ-antagonism alone may be insufficient. Viewing overdose as a sequence of pharmacokinetic-pharmacodynamic-driven state transitions provides a translational framework for intervention. We highlight pharmacologically grounded strategies to sustain ventilatory control, including optimized μ-antagonist dosing, ligand sequestration, α2-directed adjuncts, and receptor-independent respiratory network modulation, and propose a dominance-centered framework for developing and prioritizing next-generation reversal approaches in mechanistically complex polysubstance overdoses. SIGNIFICANCE STATEMENT: Contemporary fentanyl and polysubstance overdoses often show incomplete or transient naloxone responses better explained by shifting mechanistic dominance and loss of compensatory reserve than by inadequate μ-opioid receptor blockade. This review organizes overdose into a few pharmacokinetic-pharmacodynamic-driven mechanistic states and asks which pathway actually limits ventilation. By mapping μ-antagonists, ligand sequestrants, α2-directed adjuncts, and respiratory stimulants onto these states, it offers a mechanistically grounded way to prioritize next-generation reversal strategies.