Investigating Naloxone’s Efficacy in Reversing Cardiorespiratory Effects of Novel Synthetic Opioids

Introduction: Novel synthetic opioids (NSOs), represent a growing public health concern due to their high potency and association with increasing cases of intoxication and fatal overdose. They include fentanyl analogs, non-fentanyl compounds, and emerging classes such as benzimidazole opioids and nitazenes. Naloxone remains the primary treatment for opioid overdose. However, the efficacy of naloxone can vary depending on the pharmacokinetic and pharmacodynamic profiles of each compound. The aim of this study is to evaluate the role of naloxone pre-treatment in preventing cardio-respiratory impairment induced by a selection of NSOs, ranging from older to newly identified substances. Methods: Male CD-1 mice were used to assess the acute cardiorespiratory effects of various NSOs. The tested compounds included MT-45 (15 mg/kg), fentanyl alone and with xylazine (1 mg/kg + 10 mg/kg), brorphine (15 mg/kg), etonitazene (0.3 mg/kg), and isotonitazene (0.3 mg/kg). To evaluate opioid receptor-mediated effects, naloxone (6 mg/kg, i.p.) was administered as a pre-treatment. Results: All tested NSOs significantly reduced heart rate and respiratory rate in mice. The severity and reversibility of these effects varied across compound classes. Naloxone pre-treatment fully prevented the cardiorespiratory impairments of MT-45 but only partially the effects induced by all other opioids. Notably, nitazenes demonstrated the most potent and resistant profile to naloxone reversal. Conclusions: These results underscore the high toxicity of NSOs, highlighting the need for Naloxone redosing in clinical settings.