Overdose Effects of Medetomidine and Fentanyl in Rats: Reflex, Vital and Analgesic Parameters as Predictive Markers

Objective: To determine the overdose (OD) of medetomidine (MT) in Wistar rats and to evaluate the potentiating effect of fentanyl (FT) when co-administered. The objective was to identify the dose inducing complete abolition of five standard reflexes and significant changes of: heart rate (HR), respiratory rate (RR), tissular oxygen saturation (SpO 2 ), rectal temperature (RT). Methods: Eight groups of Wistar rats (2 males and 2 females each) were used; the group showing the strongest effect was supplemented with 2 additional males and females. In phase one, four groups received intramuscular MT at 0.01, 0.03, 0.05, or 0.1 mg/kg. In phase two, the effective MT dose (0.1 mg/kg) was combined with FT at 0.025, 0.05, 0.075, or 0.1 mg/kg to assess synergistic effects. Reflexes, antinociception (via cold ethanol tail-flick test), and vital signs were recorded at baseline, during OD induction, and up to 60 minutes post-administration. The animals were not euthanised and allowed to recover. Results: The 0.1 mg/kg MT dose produced the shortest time to OD, while for the combination of 0.1 mg/kg MT with 0.1 mg/kg FT, OD time was 48% faster. Fentanyl significantly attenuated the bradycardia induced by MT (p < 0.0001), while RR depression was less pronounced at OD, but became evident at Pt60. The males from MT combined with FT group showed a shorter induction time of OD compared to males from MT alone group. In females, the effect was statistically robust (p = 0.0064), showing a significantly shorter induction time. Conclusion: The MT (0.1 mg/kg) and FT (0.1 mg/kg) combination produced the most consistent and pronounced OD, characterized by rapid reflex loss, marked physiological suppression, and delayed recovery. This interaction carries significant translational relevance for both veterinary anesthesia and human medicine in the context of the opioid crisis. Keywords: opioids, alpha2 adrenergic agonists, antinociception, recreational abuse, overdose risk