**7. CNS manifestations of tramadol toxicity**

to acute, chronic, and acute on chronic overdoses [3]. Most of the patients refer within the first 6 hours postingestion [21,45,49] with a hospitalization period of 15 minutes to 21 days [8,21]. Signs/symptoms of toxicity recover within 24 hours and almost 42% of the patients will need

Tramadol is used as the first-line treatment in musculoskeletal pains [15,54-57] and as an alternative treatment in osteoarthritis (OA) patients in whom NSAIDs are contraindicated or

Tramadol analgesic effects are due to the inhibition of norepinephrine and serotonin reuptake as well as agonism of mu receptors which cause blockage of the pain impulses in the spinal cord [7,56,59]. Direct administration of tramadol on the sciatic nerve can reduce the amplitude and speed of spinal somatosensory evoked potential in the rats emphasizing the analgesic

In tramadol-induced anesthesia, the patient become conscious rapidly, has amnesia during the surgery, and experiences few side effects [61]. Controlled release of tramadol through polyhydroxybutyrate (PHB) microspheres is also available which induces longer anesthesia

According to a study performed on the rats, tramadol reinforces the immune system by increasing phagocytosis. Use of tramadol is therefore favored as an analgesic in immune-

Tramadol is an analgesic with less side effects in comparison with other opioids [64]. It has the least gastrointestinal and renal toxicities [65]. Drug screening for opioids is generally negative

In overdose, lethargy, nausea, tachycardia, agitation, seizure, coma, hypotension, hyperten‐ sion, respiratory depression, dysuria, constipation, dizziness, facial paresthesia, ataxia, headache, edema, movement disorders, perspiration, blurred vision, hallucination, itching, vertigo, palpitation, hypo- and hyper-reflexia, diplopia, multi-organ failure, acute liver failure due to fulminant liver necrosis, renal failure, and urine retention have been reported [8,17,23, 48-51,64,67,68]. Dizziness, nausea, constipation, vertigo, and headache are the most common symptoms [57,69,70]. Miosis is not as common as that in toxicities with other opioids and is detected in up to one-thirds of the patients probably due to serotonin and norepinephrine

ICU admission [49,50,53].

**5. Biologic characteristics**

104 Toxicology Studies - Cells, Drugs and Environment

compromised patients [63].

reuptake inhibition [71].

those with resistant pain to oral analgesics [58].

effects of tramadol on the peripheral nerves [60].

after epidural use in comparison with tramadol alone [62].

**6. Side effects and clinical/paraclinical findings**

in the patients with tramadol overdose [66].

The CNS manifestations are of the most common signs/symptoms of tramadol overdose ranging from CNS depression to lethargy and deep coma [6]. O-desmethyltramadol impairs consciousness and causes electrocardiographic (ECG) changes and seizure [44]. n a study by Spiller et al, significant neurologic toxicity was seen in tramadol overdose [49] which was mainly due to the monoamines reuptake inhibition [3,72].

In sub-acute and chronic toxicities, clinical manifestations are mostly behavioral disorders and seizure and may occur with doses of 25mg/kg or higher [17]. Seizure is an important problem in tramadol toxicity with its frequency being reported between 8% and 14% in different social studies and 15% to 55.3% in hospital studies. Most of the patients experience only one episode of seizure [44,47, 49,50]. Seizure is more common in young males (mean age of 22 – 39.5 y) [8,23,43,44,52]; however, some studies reported no significant difference in the frequency of seizure between different genders [3,47,72,73].

Seizure happens in less than 1% of the patients with therapeutic levels [23,74]. It seems that tramadol causes seizure in a dose-dependent manner [3,21,23] while some other studies have not confirmed this [43,44,75]. The least tramadol amount that has resulted in seizure is 100 mg. Tramadol neurotoxicity generally occurs within the first 24 hours postingestion (mainly in the first 6 hours) and seizures are usually tonic-clinic [3,6-8,11,21,23,50,75-78]. Status epilepticus has also been reported [6,11,59,76]. This shows that tramadol can cause seizure at both therapeutic and toxic levels [43,52,77,79].

Brain computed tomography (CT) of the tramadol-intoxicated patients has often been reported to be normal [43,77]. Künig and assistants reported two cases of fluctuating dizziness and cognitive problems due to long-term treatment with tramadol who recovered with cessation of the drug [80]. In a study performed to evaluate the risk of idiopathic seizure in tramadol users, only 17 cases of idiopathic seizure were found among 10917 patients, all of whom, used tramadol in combination with some other medication; it, therefore, is difficult to relate their seizure to tramadol use [71]. Seizure is less frequent in the patients who use tramadol with benzodiazepines. Psychological and somatic complications (hepatitis C and liver injury) were detected in those who had seized. Ethanol can reduce the seizure threshold in tramadol use. Seizure is also more common in younger patients who have abused tramadol for a long period of time [23].

Background seizing disorders, medications causing seizure, ethanol withdrawal, CNS depressants, or head injury can affect seizure occurrence in tramadol overdose, as well [45]. Mydriasis and tachycardia can accompany with a higher risk of seizure [44].

In a cohort study comparing 9218 tramadol users and 37232 non-users, less than 1% of the users experienced seizure after the first use. Risk of seizure was 2-to 6-fold in the patients who had background diseases or consumed other medications. The risk was also higher in those between 25 and 54 years of age, those who use tramadol for more than 4 times, or those with the history of alcohol abuse, infarction, or head injury [74].

In another study on 97 patients with seizure, electroencephalographic (EEG) evaluations were normal in seven and isolated sharp slow-wave feature of EEG was seen in one patients. Brain CT was normal in all and magnetic resonance imaging (MRI) was normal in five patients [77]. Tramadol-induced seizure can cause trauma, intra-articular dislocation, and tongue laceration [67,81,82].

In a study on 70 rats, it was revealed that tramadol could inhibit electron transfer cycle (ETC), cause ATP depletion, and disrupt the mitochondrial integrity. Apoptosis may also happen due to tramadol use [83]. In the neonates, tramadol can trigger pentylenetetrazole-induced seizure in an age-dependant manner causing fewer seizures in the neonatal period and more seizures after the lactating period [84].

Administration of tramadol hydrochloride to a zebrafish caused abnormal behaviors, reduced activity, and reduced brain and body weight. In the zebrafish brain, functional cytoskeletal proteins engaged in the energy metabolism had changed due to tramadol. Lower levels of ATP synthetase, creatine kinase, pyruvate dehydrogenase, kinase, and aldolase C could be due to the impaired production of energy because of tramadol. Weak regulation of the proteins engaged in the oxidative stress, mitochondrial functional abnormalities, and impaired production and destruction of the proteins represented the neurotoxicity of tramadol (Table 1) [85].


**Table 1.** Studies on tramadol-induced seizures
