The results of this study showed that tramadol overdose does not affect blood glucose levels, although its changes are aimed at lowering blood glucose. Conflicting results have been reported in several studies. Some studies have reported hypoglycemia in tramadol poisoning [5, 6, 23–32], and others have reported elevated blood glucose levels in these individuals [6, 24, 33, 34]. Consistent with our results, several studies have shown normal blood glucose levels in people with tramadol poisoning [4, 6, 23–25, 35, 36].
The different results in different studies can be attributed to differences in the samples studied, different doses of tramadol, different measurement times of BGL, and various forms of administration. The proposed mechanism for tramadol's hypoglycemic effects is the activation of opioid receptors by tramadol, resulting in glucose utilization in peripheral tissues .
Previous reports indicate that the opioid receptor is the main target involved in the hypoglycemic mechanism..
Some studies also showed that serotonin could increase insulin levels, release beta-endorphins, and ultimately stimulate muscle glucose utilization [39, 40].
Catecholamines have been shown to directly suppress insulin secretion from the pancreas, causing glycogenolysis in the liver by stimulating the α-adrenergic receptor and ultimately causing hyperglycemia [41, 42].. Some studies showed a hyperglycemic effect of tramadol. For example, Kara et al. (2013) attributed the induction of tramadol-induced hyperglycemia to α2 adrenergic receptors' activity, suggesting that monoamine pathways effectively affect the analgesic effects of tramadol and may be involved in the development of drug-induced hyperglycemia . Another result of this study was the increasing effect of diazepam alone and in combination with naloxone on BGL. Diazepam is widely used as a sedative and an anticonvulsant. The benzodiazepine receptor mediates its action by increasing synaptic GABA inhibition and, according to some reports, prevents various stress-induced changes, such as activation of the HPA axis . Dexit et al. prescribed diazepam (0.6 mg/kg/day) to rabbits for one month and reported no effect on blood glucose .
In contrast, some studies have reported that diazepam increases blood glucose in humans and animals. For example, the results of a study in mice showed that administration of diazepam (13.3 mg/kg) resulted in an increase in blood glucose at different times after injection . Another study in rabbits showed that diazepam (2 mg/kg/iv) could increase blood glucose levels .
Furthermore, another study in rats showed that diazepam could increase blood glucose levels in a dose-dependent manner . Their research suggested that diazepam effects on peripheral glucose were the possible cause of benzodiazepine-related hyperglycemia . In an experimental model, the 2α-adrenergic receptor antagonist was able to prevent diazepam-induced hyperglycemia. The results of this study suggested that diazepam-induced hyperglycemia may be associated with adrenaline release from the adrenal gland .
The GABA-A receptor subunit expression has also been reported in the pancreas  and chromaffin cells of the adrenal medulla . GABA can regulate the endocrine function of β cells through direct or indirect activation .
It is hard to explain the glycemic changes of diazepam at an animal stage of examination, and the results should be interpreted with caution at the animal stage.
The effects of diazepam also need to be interpreted in the context of tramadol poisoning due to drug interactions. The racial and dose-dependent characteristics of glucose homeostasis must be considered when interpreting the results of various studies. And we propose to investigate these treatments in several doses. Different single-dose therapies were used in tramadol overdose in this study.
Additionally, future studies may consider providing a dose-response curve and other factors related to blood glucose homeostasis.
The generalization of animals' findings to humans should be made with caution due to this study's empirical nature. Assume that these treatments' effects on blood glucose and glucose homeostasis in human tramadol overdose, the hyperglycemic effects of diazepam, and the hypoglycemic effects of naloxone in the early hours must be considered especially for people with diabetes.