People who use tramadol recreationally may chew, crush, snort, or inject the pill for a stronger effect. Others may mix tramadol with another drug, such as alcohol or benzodiazepines. Some people who take opioids keep naloxone name brand Narcan on hand. Naloxone is a drug that reverses the effects of opioids on the central nervous system. In the event of a tramadol overdose, the person suffering will not likely be able to give themselves naloxone. It is often up to another person present to administer the medication.
Every day in the U. Anyone who takes tramadol is at risk for potential dependence, addiction, and overdose. However, those who abuse this narcotic medication will be at an increased risk. Tramadol is often prescribed due to its dual benefits of being able to treat pain while being less addictive.
However, tramadol can still be habit-forming. People who take this drug over long periods can become physically dependent on the drug, which could cause a person to take large or frequent doses. Over time, the body becomes accustomed to having high amounts of the drug in order to function normally. If a person suddenly stops or decreases their use, the body may display symptoms of opioid withdrawal. These symptoms can be extremely uncomfortable, including nausea, sweating, and muscle cramps.
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. 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 ].
Acute pulmonary hypertension and right heart failure are the uncommon presentations reported in a young tramadol-overdosed patient [ 86 ]. Cardiopulmonary arrest was reported in some cases that had ingested more than 5 g of tramadol [ 8 ].
Higher doses of tramadol can block sodium channels and cause Brugada pattern in the ECG [ 11 , 47 ] which can be accompanied by ventricular dysrhythmias including ventricular fibrillation [ 11 ].
Almost one-thirds of the patients had terminal 40 msec frontal plane axis deviation and one-fourth had QT prolongation more than 0. Some cases of right heart failure, resistant shock, asystole, hypotension especially systolic , and sinus tachycardia have also been recorded [ 6 , 35 , 44 , 49 ].
Hypertension has also been reported. The least tramadol dose that has resulted in hypertension and agitation is mg [ 49 ]. Eleven suspected cases of tramadol-related angioedema have been reported from Sweden. Tramadol causes respiratory depression with less frequency in comparison with other opioids [ 28 , 57 , 88 ].
Renal failure is a probable risk factor for respiratory depression [ 28 , 89 ]. Tramadol overdose can cause respiratory depression; but in therapeutic oral doses, it does not cause respiratory complications. In a study on IV administration of 50 to 75 mg of tramadol, no significant changes were detected in the respiratory rate, respiratory volume per minute, and arterial PaO2 [ 90 ]. Sixteen cases of non-fatal hepatobiliary dysfunction due to tramadol ingestion have been reported [ 74 ].
Tramadol has caused centrilobular congestion and focal necrosis of the liver cells and minimal vacuolization in the kidney tubular cells of the rats. No changes were detected in the lactate dehydrogenase, blood urea nitrogen BUN , aspartate aminotransferase AST , and malondialdehyde MDA ; however, alanine aminotransferase ALT increased significantly showing the possible hepatotoxicity of tramadol [ 91 ].
It was shown that acute or chronic toxicity did not affect liver weight or cause histopathological changes in its tissue [ 17 , 92 ]. In the rats, mu receptor activation increases glucose use or decreases the liver gluconeogenesis which results in the low levels of plasma glucose in diabetic rats [ 88 , 93 ].
It has been shown that tramadol improves the peripheral metabolism of glucose by central activation of the mu receptors. Therefore, central and peripheral metabolisms of glucose unite and cause hypoglycemia.
It has also been suggested that tramadol changes the liver glucose output regulated by other organs likely CNS [ 93 ]. Some patients discontinue tramadol consumption because of nausea and vomiting.
It has been shown that slow titration decreases the frequency of tramadol discontinuation due to these complications [ 94 ]. In long-term studies on rats and mice, no tramadol-attributed carcinogenic changes were detected. Histopathologic evaluations showed increased risk of hepatic adenoma in the males and non dose-related pulmonary adenoma in females. No specific mutations or chromosomal impairments were detected in rats, mice, or hamsters due to tramadol use.
Oral administration of tramadol was reported to have no carcinogenic effects on the mice and rats. No mutations or increased risk of gene toxicity were detected in human-beings, either [ 17 ].
Tramadol can cause urinary retention because of opioid agonistic effects that can increase the tonicity of the bladder sphincter [ 68 ]. Also, it was shown to have hazardous effects on the growth, survival, and reproduction system of Daphnia Magna with the most effects on the latter. Long-term exposures decreased expression of the vtg gene which is an important biomarker in the reproduction of the oviparous animals [ 64 , 95 ].
In a study by Matthiesen et al, low dose of tramadol had no effect on the fertility, giving birth, and lactation of the rats and had no teratogenic effects on the fetus [ 17 ]. These results are however in contrast to the results withdrawn by Bornas who mentioned that laboratory studies had confirmed the teratogenic effects of tramadol on the animals.
Tramadol and M1 metabolite can cross the placenta easily because of their low molecular weights [ 55 ]. Bleeding time BT , clotting time CT , prothrombin time, partial thromboplastin time, and body temperature were not affected by tramadol [ 17 ]. But, leukocytosis has been reported [ 44 ].
Tramadol overdose may result in increased creatine phosphokinase CPK which may be seen with or without seizure and can be accompanied by acute renal failure Table 2 [ 13 ].
Serotonin syndrome SS is a potentially fatal syndrome due to increased synthesis, decreased metabolism, increased release, and reuptake inhibition of serotonin or direct agonism at the serotonin receptors [ 5 , 53 ]. This syndrome is often due to complex interactions between the consumed medications. Three key clinical features of this syndrome include:. Neuromuscular hyperactivity tremor, clonus, myoclonus, hyper-reflexia, stiffness, impaired coordination.
Autonomic hyperactivity profuse sweating, fever, tachycardia, tachypnea, chills, nausea, diarrhea, vomiting. Usually, SS happens after tramadol overdose or its concurrent use with other medications especially antidepressants; however, it may happen even after a single therapeutic dose of tramadol [ 5 , 98 , ].
Patients who consume mono amine oxidase MAO inhibitors are at the risk of development of SS [ 66 , ]. SS has been reported after concurrent use of tramadol with serotonin reuptake inhibitors SSRIs , venlafaxine, atypical antipsychotics, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, moclobemide, clomipramine, mirtazapine, and tricyclic antidepressants [ 5 , 7 , 53 , 97 , ].
In patients who develop lethargy, hypotension, hypoxia, agitation, tachycardia, hypertension, confusion, hyperthermia, or hyper-reflexia, diagnosis of SS should be borne in mind [ 7 , , ]. Treatment is conservative and includes cessation of the culpable medication as well as administration of the antiserotonergics ciproheptadine, metisergide, propranolol, and chlorpromazine. Clinical manifestations recover within 24 hours except in those who have consumed medications with longer half-lives [ 5 , 53 , 97 ].
Pretreatment with chlordiazepoxide may prevent tramadol-induced SS [ 48 ]. Opioids metabolized by CYP including tramadol may induce many drug-drug interactions [ ]. In an Australian study, unwanted drug interactions were evaluated in patients who consumed antidepressants. As previously clarified, tramadol is similar to venlafaxine in structure and is believed to have antidepressant effects. Venlafaxine can even cause false positive results for tramadol in urine tests [ 5 ].
Co-administration of tramadol and antidepressants especially TCAs, SSRIs, venlafaxine, bupropion, and phenothiazines should be performed cautiously because of the increased risk of seizure [ 6 , 25 , 72 ].
Concurrent administration of tramadol and NSAIDs can result in gastrointestinal hemorrhages due to severe platelet inhibition [ ]. Fatal toxicities have been reported after tramadol-TCA overdoses [ ].
It has been shown that tramadol-related mortality is more common after co-ingestion of benzodiazepines [ 8 , 26 ]. Tramadol can also interact with antitumor medications. For instance, tramadol decreases the efficacy of cisplatin by affecting gap junctions [ ]. In a case report, combination of paroxetine, dosulepin, and tramadol caused hallucination which improved after cessation of the medications [ ]. Fatalities have been reported after tramadol overdose or its co-ingestion with other medications.
In most cases, death occurred after ingestion of high doses within 24 hours post-ingestion with really high blood levels [ 70 ]. Blood levels of tramadol have been between 0. The most common mechanisms of death after tramadol overdose are cardio-respiratory depression, resistant shock, asystole, and liver failure [ ]. Apnea may increase the risk of tramadol intoxication-related deaths [ 45 ]. Typically, the maximum recommended dosage is mg per day.
Most people are not even prescribed this much; they are usually prescribed mg per day or less. Often, an overdose occurs when tramadol is mixed with a different kind of drug or alcohol.
Anything taken in conjunction with Tramadol that can depress the nervous system even more can lead to overdose or death. In overdose, Tramadol induces significant neurological toxicity seizures, coma, respiratory depression , but cardiovascular toxicity is mild.
Anyone in close proximity to someone taking it or as the patient prescribed this particular drug should know the signs of an overdose. Medical attention should be sought immediately if any of the signs of an overdose begin to appear.
The earlier you seek help, the better the outcome may be. Although respiratory depression and constipation are less common with Tramadol, even amongst other opioids, it can occur, in particular, after overdose and with impaired renal function.
Unlike other opioids, Tramadol abuse is not usually associated with the development of tolerance, physical dependence or psychological addiction.
There is an increase in the risk of seizures where epilepsy is prevalent. Based on the severity of the overdose, a user can be at risk of long-term organ damage. To diagnose a possible overdose, look for these signs:. Death does have the chance of occurring in the first hour of overdose so proper procedures must be followed.
Simply not exceeding the dosage recommended by the physician puts a patient at a lower risk for overdose. Conclusion: Tramadol overdose is associated with seizures and respiratory depression, but is unlikely to cause serotonin toxicity.
Abstract Context: Tramadol is a commonly used centrally acting analgesic associated with seizures and suspected to cause serotonin toxicity in overdose.
Substances Analgesics, Opioid Tramadol.
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