**20. Conclusion**

decreased level of consciousness in tramadol toxicity unless respiratory depression has developed [21,45]. Seizures due to tramadol do not respond to naloxone but improve with administration of benzodiazepines. Naloxone can be considered for treatment of post-seizure

Shadnia et al suggested that because of the low risk of multiple seizures in tramadol toxicity, anticonvulsant treatment should not be routinely given even in those with initial seizures [52]. Stoops et al evaluated naltrexone and showed that it could reverse the opioid-induced effects such as miosis; but, increased the serotonergic and adrenergic effects such as mydriasis [56]. Intravenous lipid emulsion (ILE) can reduce mortality due to acute toxicity of tramadol in rabbits, but increasing the ILE dose may cause reverse effects. In a study on 30 rabbis, ILE reduced tramadol-induced tachycardia when administered within 30 minutes of poisoning and showed positive effects on normalizing mean arterial pressure and diastolic blood pressure but it did not have major effect on systolic blood pressure. Intralipid also prevented tramadol-related seizures in low doses and reduced the frequency of increased CPK with

Although tramadol has less side effects, addicting capacity, and respiratory depression power in comparison with other opioids, many cases of dependency, abuse, intentional overdose, or poisoning have been reported following its use [20,27,48,56,70,113,125,126]. Tramadol with‐ drawal lasts longer compared with other opioids [111]. Where ultrarapid metabolizers are high in number, people are expected to have a higher risk of dependency to tramadol [127].

Tramadol is as potent as heroin to cause euphoria [2,55,112]. Withdrawal occurs after rapid abrupt discontinuation of tramadol with clinical manifestations including abdominal cramps, anxiety, skeletal pain, depression, diarrhea, goose flesh, insomnia, lacrimation, nausea, restlessness, rhinorrhea, and sweating. The manifestations may sometimes be atypical and include hallucination, paranoia, panic attack, confusion, and atypical sensational experiences such as paresthesia, itching, tingling, delusion, depersonalization, derealization, and tinnitus

Tramadol dependency happens faster in those who abuse it with other analgesics or ethanol [55]. Clinical therapeutic doses of tramadol may affect psychomotor and physiologic capacities

Tramadol abuse in pregnancy may cause preterm labor and withdrawal manifestations in the newborn baby depending on the age of pregnancy, time elapsed since the beginning of tramadol use, dose of tramadol, CYP450 D2 polymorphism, development of the liver conju‐ gation, and renal function of both mother and baby. Attempts have been performed to treat this syndrome in neonates using clonidine alone or in combination with the thin opioid tinctures, chloral hydrate, benzodiazepines, and methadone [55]. In a study on patients with chronic non-cancer pain, it was shown that the frequency of abuse and dependency on

tramadol and NSAIDs were the same and significantly less than hydrocodone [129].

complaints [123].

114 Toxicology Studies - Cells, Drugs and Environment

higher doses [124].

[22,55].

**19. Dependency and withdrawal**

of the patients who recreationally abuse it [128].

Weak opioids such as tramadol can be used in the treatment of reumatologic pains after development of complications following use of NSAIDs or if they are unable to alleviate the patients' pain [130]. It is less dangerous to the organs in comparison with selective and nonselective NSAIDs and very powerful in the treatment of chronic pains [131]. Tramadol can also be used in moderate to severe toothaches alone or in combination with acetaminophen or codeine [132,133]. In opioid-addicted patients, tramadol can be used for the treatment of withdrawal pain [68]. Tramadol in combination with paracetamol has a fair efficacy, immunity, and acceptance rate by the patients without development of dependency syndrome [131,134,135].

Complications can be decreased by adding tramadol to the controlled medications [136]. Monitoring of the liver function especially when the maximum daily doses are given is mandatory. Also, because of drug-drug interactions and differences in the individual metab‐ olism and the chance of dependency, tramadol administration should be controlled by the treating physician. If the patient is an opioid-addict, tramadol should not be administered unless absolutely indicated [137,138].
