The effects of naloxone, diazepam, and quercetin on seizure and sedation in acute on chronic tramadol administration: An experimental study
Abstract Background: Tramadol is a widely used synthetic opioid. Substantial research has previously focused on the neurological effects of this drug, while the efficacy of various treatments to reduce the associated side effects has not been well studied. This study aimed to evaluate the protective effects of naloxone, diazepam, and quercetin on tramadol induced seizure and sedation level in male rats. Methods: The project was performed with 72 male Wistar rats with an average weight of 200-250 g. The rats were randomly assigned to 8 groups. Tramadol was administered intraperitoneally at an initial dose of 25 mg/kg/day. On the 14th day, tramadol was injected at 75 mg/kg, either alone or together with naloxone, diazepam, and quercetin (acute and chronic) in different combinations. The rats were monitored for 6 hours on the last day, and the number, the duration, and the severity of seizures (using the criteria of Racine) were measured at different times. The sedation level was also assessed based on a 4-point criterion, ranging from 0 to 3, at different times after injection. Data were analyzed in SPSS software using Kruskal-Wallis, Chi-square, multivariate regression, and generalized estimating equation (GEE) tests. The significance level was set at P <0.05.Results: The naloxone-diazepam combination reduced the number of seizures, severity, and duration of seizures compared to the tramadol use alone and reduced the number of higher-intensity seizures to a greater extent than other treatments. Naloxone alone reduced the number and duration of seizures, as well as the duration of mild seizures. Diazepam decreased the severity and duration of seizures. However, it increased the number of mild seizures. In comparison with the tramadol alone group, the acute quercetin group had a lower duration of mild and severe seizures, and higher numbers of mild and moderate seizures. Chronic quercetin administration decreased the duration of seizures and significantly increased the number of mild seizures. Naloxone-Quercetin also reduced the duration of mild and severe seizures significantly. In the GEE model, all groups had higher sedation levels than the saline only group (P <0.001). None of the protocols had a significant effect on sedation levels compared to the other groups.Conclusion: The combined administration of naloxone and diazepam in acute on chronic tramadol poisoning can effectively reduce most seizure variables, compared to the tramadol use alone. However, none of the treatments can improve sedation levels.