**15. Tramadol-related mortalities**

Fatalities have been reported after tramadol overdose or its co-ingestion with other medica‐ tions. In most cases, death occurred after ingestion of high doses within 24 hours post-ingestion with really high blood levels [70]. However, death due to tramadol overdose is rare and consists up to 1% of the hospitalized cases [1,10,44,88]. Blood levels of tramadol have been between 0.03 to 134 mg/L in different fatal cases [26,32,109,110].

The most common mechanisms of death after tramadol overdose are cardio-respiratory depression, resistant shock, asystole, and liver failure [111]. Apnea may increase the risk of tramadol intoxication-related deaths [45]. Fatal toxicity of tramadol has been reported after co-administration of other medications including propranolol, trazodone, ethanol, and especially CNS depressants including benzodiazepines, barbiturates, and serotonergic drugs [88]. M1/M2 (ODT/NDT) metabolite ratio of higher than one in biologic liquids and organs represents more sudden deaths while M1/M2 < 1 shows that death will occur at later stages after the tramadol use [32,112]. In fatal cases of tramadol, femoral blood samples are the best since they have the least redistribution changes after death [113]. Tramadol may remain undetected in muscle samples after death due to its overdose [114].

## **16. Miscellaneous side effects**

Mannocchi and assistants reported a case of death due to tramadol and propofol due to advanced severe dyspnea [115]. A report showed nine deaths due to consumption of krypton (a plant material containing ODT and mitragynine) in whom the concentration of ODT was between 0.4 to 4.3 µg/g [116]. Another study reported death due o tramadol because of respiratory depression accompanying GABA A and GABA B1 alpha1 over-expression in the ambiguus nucleus and medulla oblongata solitary. (Table 3) [117].


**Table 3.** Studies on deaths related to tramadol poisoning
