Emesis and Constipation Induced by Methadone and the Active Metabolite of Tramadol (M1) in Animals

Typical prescribed opioids are known to inhibit intestinal transit and induce emesis-like behaviors in animals via distinct mechanisms and varying magnitudes. However, there is limited evidence regarding whether atypical opioids also produce these adverse effects in animals. This study was designed to investigate whether tramadol, its active metabolite O-desmethyltramadol (M1), and methadone cause such side effects and to elucidate their underlying mechanisms. In ferrets, methadone and M1-but not tramadol and oxycodone-elicited adverse effects including emesis and tremor. Notably, the adverse effects associated with high-dose methadone required urgent intervention with naloxone, indicating a more severe toxicity profile. The severity of emesis followed the rank order: M1 > methadone. In contrast to previous findings with morphine, M1-induced retching was significantly inhibited by the selective dopamine D₂ receptor antagonist prochlorperazine, but not by the atypical antipsychotic olanzapine, suggesting a distinct receptor-specific modulation. In mice, both methadone and high-dose M1 significantly suppressed gastrointestinal transit. Notably, suppressed gastrointestinal transit induced by methadone and M1 exhibited different region-specific mechanisms. Taken together with previous findings, the present results suggest that adverse effects caused by atypical opioids and those caused by typical opioids differ both mechanistically and pharmacologically. Recognizing these distinct profiles is essential for evaluating opioid-induced adverse effects and can help refine clinical strategies. Ultimately, these insights may contribute to the development of evidence-based interventions aimed at minimizing opioid-related complications and improving the quality of life for patients receiving opioid-based pain therapies.