**19. Dependency and withdrawal**

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 [22,55].

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 of the patients who recreationally abuse it [128].

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].
