Tramadol overdose is responsible for consciousness impairment, self-limiting generalized tonic-clonic seizures and possible induced trauma, agitation, respiratory depression, and serotonin syndrome [13, 33, 34].
The management of tramadol-poisoned patients with naloxone remains controversial. The benzodiazepine/tramadol combination consistently resulted in worsened CNS depression, in both animals and humans making it a risky choice [35, 36]. The current study succeeded in inducing seizures in more than 80% of animals after tramadol intoxication, providing a valid model for studying tramadol intoxication in mice. The seizure severity was rated to 4 and was resolved by diazepam injection.
Previously, [37] used single injection of tramadol (75 mg/kg, i.p.) to SD rats to induce seizures. [38] induced seizures in mice by injecting intravenously delivered tramadol solution that its dose reached the same dose range used in our study. Our findings were consistent with their findings, where tramadol-associated seizures were diminished after diazepam administration. However, CNS depression which is related to the high mortality rate was observed.
The seizure activity of tramadol can be related to opioid receptors’ overactivation. Since opioid delta receptor entails proconvulsant effects, high doses of tramadol can produce seizures by activating this receptor as well [39]. Furthermore, an opioid-dependent GABA inhibitory pathway activation can be linked to tramadol-associated seizures [40]. Seizures associated with tramadol overdose usually do not respond to naloxone but are relieved with benzodiazepines. Naloxone can be used for the treatment of post-seizure complaints [41]. A combination of diazepam/naloxone is reported as an efficient antidote to reverse tramadol-induced CNS toxicity [37].
At the highest dose level tested, CS reduced the plasma tramadol level and seizure score. The current study revealed that CSZn3 was the best remedy for induced seizures and its effect correlated with the decrease in plasma tramadol concentration. On the other hand, CSFe3 did not reduce the seizure score or the plasma tramadol level except at the dose of 160 mg/kg which caused a significant reduction in the plasma tramadol level reflected on the seizure score.
The bioactive material (CSZn3) saved at least 20–30% of animals from mortality encountered after tramadol poisoning and even could have saved 100% of the animals at certain dose levels. Our results showed a dose-dependent amelioration of seizure score reflected on plasma tramadol concentration that was maximal at a dose of 160 mg/kg.
The essential trace element (Zn) was suggested to modulate GABA receptors [42] or induce synaptic membrane depolarization [43], which directed the search for its role in the case of tramadol intoxication.
Previous studies proved a role for Zn ion in opioid receptor mediated physiological actions such as the study of [44] who observed that Zn chelators increased opioid withdrawal manifestations. Moreover, zinc oxide nanoparticles enhanced the analgesic effects produced by tramadol or morphine acute administration providing additional evidence of opioid receptor modulation [45]. Furthermore, Zn acts as a blood brain barrier stabilizer and maintains its integrity in pathological conditions [46]. The role of Zn in tramadol overdose-induced seizures can be crucial; however, it needs further studies. CSZn3 effect declined at the highest dose (320 mg/kg), which may be attributed to the neurotoxic effect of Zn at high doses, where excess Zn acts biophysically on NMDA receptors regulating glutamate release thus promoting excitotoxicity [47]. Besides, excessive extracellular zinc concentrations are responsible for increased oxidative damage [48].
Interestingly, mice were void of mortality after the administration of a dose of 160 mg/kg of either CSZn3 or CS, indicating that the composite related antidote action does not depend solely on the resolution of seizures; it also counteracts tramadol general depressant effects and lowers its circulating level.
Iron micronutrient is critical for neuronal health. Its deficiency was linked to increased seizure susceptibility [49]. Nevertheless, high iron concentration is linked to promoted oxidative damage and induces inflammatory response [49]. Also, iron deposition, as a result of high concentrations, is found in epileptic brain areas [50]. This can explain the current observation of unaffected seizure score of tramadol-intoxicated mice treated with CSFe3 despite the lowered tramadol plasma level.
The calcium silicate nano-biomaterial is a good candidate for drug delivery and increasing the efficacy of loaded drugs for its enhanced chemical and physical characteristics [51]. In addition, it can provide additional value to the desired therapeutic application. This study showed its ability to decrease tramadol plasma concentration though its specific action has not been investigated yet.