Background/Objectives: The recreational use of fentanyl (FT) combined with xylazine (XZ), known as “tranq-dope,” poses a growing public health threat due to its high toxicity and mortality. This study evaluated the effectiveness of naloxone (NX), its lipophilic prodrug NX90, and their combinations with the mixed κ-agonist/µ-antagonist nalbuphine (NB) in reversing overdose and restoring respiratory function in a rat model. Methods: Male and female Wistar rats received intramuscular FT (0.104 mg/kg) + XZ (1 mg/kg) to induce overdose, followed by intranasal administration of NX, NX90, or combinations with NB. Physiological parameters, reflex recovery, time to overdose, and reversal outcomes were assessed during individualized clinical monitoring. Results: At the low FT dose (0.052 mg/kg), adding XZ (1 mg/kg) shortened time to overdose by ~2600 s compared with FT alone, whereas onset times were similar at medium and high FT doses. In the dose-finding cohort, FT + XZ co-administration was associated with a higher respiratory rate than FT alone at the highest fentanyl dose tested, an exploratory finding warranting confirmation in larger studies. Most interventions did not significantly shorten time to reversal; however, NX + NB (females) and NX90 + NB (both sexes) showed shorter reversal times than NX alone. However, respiratory rate at reversal was significantly improved with NX + NB, ½NX90 + NB and NX90 + NB (90 ± 6, 86 ± 5 and 92 ± 5 breaths/min) compared with naloxone alone (80 ± 6 breaths/min). Interventions containing nalbuphine (κ-agonist/µ-antagonist) yielded higher RR and HR at reversal than NX alone, consistent with an interpretive framework in which κ–µ opioid balance may influence observed physiological recovery patterns. Conclusions: Comparable or improved reversal outcomes could be achieved using half-doses of NX or NX90 with NB—potentially reducing the total dose of naloxone and mitigating the risk of precipitated withdrawal in individuals with opioid use disorder.

Background/Objectives: The drug development response to the unique pharmacology of fentanyl, which drives the current opioid epidemic, has primarily focused on increasing naloxone doses and employing longer-acting antidotes. While having lower withdrawal liability, the commonly perceived disadvantage of naloxone is its reduced effectiveness against re-narcotization or “fentanyl rebound,” due to a significant mismatch between its half-life (t_1/2) and that of fentanyl. Methods: We conducted a pharmacokinetic profile (PK) crossover study in fentanyl-sedated dogs to assess naloxone (NX) and its lipophilic prodrug (NX90) with regard to fentanyl PK and re-narcotization risk. Results: Our findings showed that naloxone redistributed fentanyl into the plasma, with correlating (R² = 0.9121) fentanyl and naloxone plasma levels when seven plasma samples per dog for each treatment (including placebo) were analyzed. This redistribution led to reductions in fentanyl’s volume of distribution at steady state (V_ss: 11.8 ± 1.7, 8.4 ± 2.4, and 8.7 ± 2.6 L/kg), mean residence time (MRT: 19.9 ± 1.8, 18.6 ± 7.2, and 16.2 ± 8.8 min), and half-life (t_1/2: 14.3 ± 1.9, 13.0 ± 4.9, and 11.2 ± 6.1 min) after the administration of a placebo, NX, and NX90, respectively. Additionally, we observed that the delay in the transient re-sedation (re-narcotization) of the dogs correlated (R² = 0.794) with naloxone’s exposure (AUC_inf). These data suggest that (i) the displacement of fentanyl into a metabolically active compartment and (ii) the delay in re-narcotization risk are both independent of naloxone’s half-life and are likely to be more effectively achieved with higher doses of naloxone. Conclusions: Combined with the lower risk of precipitating protracted withdrawal, these findings support the clinical use of higher-dose naloxone over longer-acting antidotes for reversing fentanyl-related overdoses.

The recreational use of fentanyl (FT) combined with xylazine (XZ), known as “tranq-dope,” poses a growing public health threat due to its high toxicity and mortality. This study evaluated the effectiveness of naloxone (NX), its lipophilic prodrug NX90, and their combinations with the κ-agonist/µ-antagonist nalbuphine (NB) in reversing overdose and restoring respiratory function in a rat model. At the low FT dose (0.052 mg/kg), adding XZ (1 mg/kg) shortened time to overdose by ~2,600 seconds compared with FT alone, whereas onset times were similar at medium and high FT doses. Respiratory rate at overdose was also higher with XZ, showing a 2.2-fold increase at high FT doses. Most interventions did not significantly shorten time to reversal. Only NX+NB in females and NX90+NB in both sexes reduced reversal time compared with NX alone. However, respiratory rate at reversal was significantly improved with NX+NB, ½NX90+NB, and NX90+NB (90–92 breaths/min) compared with naloxone alone (80 ± 6 breaths/min). Interventions containing nalbuphine (κagonist/µantagonist) yielded higher RR and HR at reversal than NX alone, suggesting a contribution of κagonism to physiological recovery. In this FT+XZ dose range, coadministration of xylazine (1 mg/kg) was associated with higher respiratory rates at the time of overdose onset across ascending fentanyl doses, blunting the dosedependent RR decline observed with fentanyl alone at that specific endpoint. Comparable or improved reversal outcomes could be achieved using half-doses of NX or NX90 with NB—potentially reducing total dose of naloxone and mitigating the risk of precipitated withdrawal in individuals with opioid use disorder.